Current controversies in breast cancer management

Current Problems in

S u r Volume 36 Number 3

ry ° March 1999

Current Controversies in Breast Cancer Management

Monica Morrow, MD Professor of Surgery

Director, Lynn Sage Comprehensive Breast Program Northwestern University Medical School

Chicago, Illinois

V. Craig Jordan, PhD, DSc Professor of Cancer Pharmacology

Director, Breast Cancer Research Program Robert H. Lurie Comprehensive Cancer Center

Northwestern University Medical School Chicago, Illinois

Hiroyuki Takei, MD Assistant Professor

Second Department of Surgery Gunma University School of Medicine

Gunma, Japan

William J. Gradishar, MD Associate Professor of Medicine

Director, Breast Medical Oncology Northwestern University Medical School

Chicago, Illinois

Lori J. Pierce, MD Associate Professor of Radiation Oncology

University of Michigan Health System Ann Arbor, Michigan

~v~ Mosby

Current Problems in

Sur ry Volume 36 Number 3 March 1999


Foreword

In Brief

Biographical Information

II.

The Role of Prophylactic Mastectomy in the Management of the Woman at Increased Risk for Breast Cancer

Efficacy of Prophylactic Mastectomy Surgical Technique Psychologic Response to Prophylactic Mastectomy Indications for Prophylactic Mastectomy Approach to the Woman at Risk

Selective Estrogen Receptor Modulation and the Prevention of Breast Cancer

Tamoxifen: The First SERM Raloxifene to Prevent Osteoporosis The Prevention of Breast Cancer With SERMs Conclusion and Prospects for the Future

Controversies Related to the Use of Primary Chemotherapy Evolution of Multimodality Therapy Theoretic Advantages and Disadvantages Associated With Primary

Chemotherapy Clinical Trial Results Future Directions

Postmastectomy Radiotherapy Revisited: Implications for Improved Breast Cancer Survival

Historical Perspective of Postmastectomy Radiotherapy

157

158

161

163

163 167 170 171 173

174

175 178 179 180

181 183 186

189 192

193

194

Curr Probl Surg, March 1999 155

Reanalysis of the Postmastectomy Randomized Trials Postmastectomy Trials With Adjuvant Chemotherapy With

or Without Radiotherapy Critiques of the British Columbian and Danish Breast

Cancer 82b Trials Further Support of the Importance of Locoregional

Control on Survival Current Recommendations for Treatment Radiotherapy Considerations Future Directions

References

195 197

201

202

203 203 206

206

156 Curr Probl Surg, March 1999

.11

Foreword

Over the last 3 decades there has been substantial progress in the management of patients with carcinoma of the breast, yet there are still areas of controversy, some of which are addressed in this issue of Current Problems in Surgery. The collective wisdom expressed by the authors, all experts in their respective field of specialization, is clearly evident throughout the monograph. The 4 topics addressed are the role of prophylactic mastectomy in the management of women at increased risk for breast cancer, selective estrogen receptor modulation and the prevention of breast cancer, controversies related to the use of primary chemotherapy, and postmastectomy radiotherapy revisited, an implication for improved breast cancer survival. This is an excellent contribution and should be required reading for all clinicians who care for patients with this most common and dreaded disease. Dr Morrow is to be commended for assembling such an outstanding group of collaborators and for writing such an excellent monograph.

Samuel A. Wells, Jr, MD Editor-in-Chief

Curr Probl Surg, March 1999 15"7

In Brief

For most of the past century, the radical mastectomy was the mainstay of breast cancer therapy. Over the past 25 years, changes in our understanding of the biologic features of breast cancer, the increasingly frequent detection of small breast cancers with screening mammography, and the greater participation of patients who have breast cancer in the therapeutic decision-making progress have dramatically changed our approach to the management of patients with breast cancer. In addition, breast cancer therapy has gone from being the sole domain of the surgeon to a multidisciplinary collaboration involving a variety of disciplines including radiology, surgery, radiation oncology, and medical oncology. Rapid changes in clinical management, coupled with the need to assimi- late large amounts of data in areas not traditionally considered "surgical," have resulted in confusion about the appropriate care for many patients.

Awareness of breast cancer risk by women and their physicians is proba- bly at an all-time high. Until very recently, the only method for breast cancer prevention that was clinically available was prophylactic mastectomy. Although this procedure has been used for decades, little scientifically valid information is available regarding its effectiveness in women who are at high risk for the development of breast cancer. Both subcutaneous and simple mastectomy have been proposed for prophylaxis. Subcutaneous mastectomy leaves behind 5% to 10% of the breast tissue. Although the risk of breast cancer after this procedure is reported to be less than 1% in 1 large series, most women in the study did not have major breast cancer risk factors. Simple mastectomy results in more complete removal of the breast tissue and provides 97% to 99% protection against breast cancer development in women at risk on the basis of lobular carcinoma in situ or ductal carcinoma in situ. Data are not available about the efficacy of prophylactic mastectomy in women who have BRCA-1 and BRCA-2 mutations. However, assuming that the procedure reduces the breast cancer risk by 85%, a 30- year-old woman with a 40% risk of breast cancer development would gain 2.9 years of life from prophylactic mastectomy. The benefit increases to 5.3 years for women with an 85% risk of cancer development.

Breast reconstruction is an important adjunct to prophylactic mastectomy. Although the immediate morbidity of implant reconstruction is lower than that encountered with flap reconstruction, approximately 20% to 30% of patients with implant reconstruction require reoperation for complications, most commonly capsular contracture.


Suggested indications for prophylactic mastectomy vary with physicians' attitudes toward this procedure. One study indicates that plastic surgeons are more likely to recommend prophylactic mastectomy than general surgeons or gynecologists and to recommend it for women at a lower level of risk.

An alternative approach to breast cancer prevention is the use of selective estrogen receptor modulators (SERMs). Tamoxifen, the first SERM, is widely used as an adjuvant therapy. The observation that tamoxifen reduced the risk of contralateral breast cancer by approximately 40% led to great interest in the use of the drug for prevention. However, because tamoxifen is an antiestrogen, there was concern that its use would increase the incidence of coronary heart disease and osteoporosis. Clinical studies have now demonstrated that tamoxifen is estrogenic for bone and lipids and acts to lower circulating cholesterol levels and maintain bone density. A major concern about the widespread use of tamoxifen in healthy women is the increased incidence of endometrial cancer, which is due to the drug's estrogenic effect on the uterus. Several large prevention trials that help define the risk-benefit ratio for tamoxifen prevention in women at increased risk have been reported. A major problem with confining prevention to women at high risk is that most breast cancers occur in women with no, or only minor, identifiable risk factors. Raloxifene is another SERM that was developed to prevent osteoporosis. Initial studies in 12,000 women have demonstrated that raloxifene maintains bone density and low- ers the low-density lipoprotein cholesterol level. In addition, raloxifene does not appear to have any stimulatory effects on the uterus. In animals, raloxifene prevents rat mammary carcinogenesis, and the early data in women suggest that this effect is replicated in women after menopause. On the basis of these findings, SERMs offer the potential to reduce the incidence of 3 major health problems in women after menopause: osteoporosis, coronary heart disease, and carcinoma of the breast.

Another change in the approach to the patient with early-stage breast cancer is the use of primary or neoadjuvant chemotherapy. Chemotherapy before local treatment is the standard practice for patients with locally advanced breast cancer, with responses observed in 50% to 95% of cases and clinical complete responses in approximately 20% of cases. The rationale for the use of primary chemotherapy in patients with operable breast cancer includes the ability to observe directly the sensitivity of the primary tumor to the chemotherapy agents being used, the potential to increase the number of patients eligible for breast-conserving therapy, and the hope that initiating chemotherapy at the earliest time possible will be associated with a decreased risk of the development of drug resistance as the result of


a small tumor burden. Randomized trials that compare primary chemotherapy to postoperative adjuvant therapy have failed to demonstrate a survival advantage for the primary treatment, however. Objective response rates are similar to those for patients with locally advanced breast cancer. An increase in the number of patients able to undergo breast conservation has been observed, but this increase has been relatively modest. The disadvantages of primary chemotherapy include overtreatment of some patients because of the lack of complete information on tumor size, nodal status, and receptor status and the loss of the prognostic information provided by the axillary lymph node status.

The final controversy addressed in this monograph is the use of postmastectomy radiotherapy. Postmastectomy radiotherapy had largely fall- en out of favor because of the absence of a survival benefit in older studies comparing mastectomy alone to mastectomy and radiotherapy and because of the observation that the risk of cardiac death was increased in patients who had undergone radiotherapy. However, reanalyses of these trials with further follow-up demonstrated a striking reduction in the risk of locoregional relapse compared with operation alone (67% reduction in risk in the overview analysis) and a 6% reduction in the breast cancer mortality rate. Most of these studies were performed in the prechemother- apy era. Newer trials that examine the role of radiotherapy in patients receiving chemotherapy demonstrate that the combination of chemotherapy and radiotherapy is superior to either modality alone at reducing the risk of locoregional recurrence. In 1997, 2 large studies in women who were at high risk due to positive lymph nodes and were premenopausal demonstrated that the use of chest wall and nodal radiotherapy, in addition to chemotherapy, resulted in a significant survival improvement. This has led to the recommendation that postmastectomy radiotherapy be administered routinely to patients who are premenopausal and lymph node positive. The need to irradiate a separate axillary and internal mammary lymph node field is controversial, and additional data from randomized trials will help to clarify these issues.


-••,•,•.••• Monica Morrow, MD, is Professor of Surgery and Director of the Lynn Sage Comprehensive Breast

Program at Northwestern University Medical School. She served her surgical residency at the University of Vermont and then completed a 2-year surgical oncology fellowship at Memorial Sloan-Kettering Cancer Center. Before join- ing the faculty at Northwestern in 1993, she held faculty appointments at the SUNY Health Science Center at Brooklyn and the University of Chicago. Her current interests include the application of decision analysis theory to treatment selection in ductal carcinoma in situ and methods to increase patient access to modern multidisciplinary breast cancer care.

~ ~ V. Craig Jordan, PhD, DSc, is ~ r , Professor of Cancer Pharmacology

and Director of the Breast Cancer Research Program at the Robert H. Lurie Comprehensive Cancer

Center at Northwestern University Medical School. He received his doctorate degrees in the pharmacology of antiestrogen action from the Department of Pharmacology, University of Leeds, England. He is recognized for the development of tamoxifen and for establishing the principles that are being applied for the prevention of breast cancer with raloxifene.

~ ~ ~ ~ Hiroyuki Takei, MD, is Assistant Professor in the 2nd Department of Surgery, Gunma University School of Medicine, Gunma, Japan. He received

his medical degree in 1986 from Jichi Medical School, Jichi, Japan. From 1997 to 1998, he was Visiting Assistant Professor at Northwestern University Medical School. His research interests are tamoxifen-stimulated tumor growth and angiogenesis.

~ . / 2 t / / S ~ " ' ~ William J. Gradishar, MD, is Associate Professor of Medicine and Director of Breast

Medical Oncology at Northwestern University Medical School. He completed his internal medicine residency at the Michael Reese

Hospital and served a fellowship in hematology-oncology at the University of Chicago. His current interests include the use of antiangiogenic agents, novel endocrine therapies, and the taxames in breast cancer management.


~ f J _ _ . A . . ( ~ Lori J. Pierce, MD, is Associate IL,~_" Professor in the Department of

Radiation Oncology at the University of Michigan Medical Center. Dr Pierce received her undergraduate degree in biomedical engineering at the University of Pennsylvania and completed medical school at Duke University. She completed her residency training and chief residency in the Department of Radiation Oncology at the University of Pennsylvania. Dr Pierce's scientific interests include the use of radiation therapy as adjuvant treatment in breast cancer, the identification of factors that predict the successful use of breast conservation in locally advanced breast cancer, and the role of BRCA-1 and BRCA-2 posi- tivity in patients treated with radiotherapy to the breast.



I lthough advances in the diagnosis and treatment of breast cancer reduced the mortality rate by 6.8% between 1989 and 1993,1 it is estimated that 43,500 women died of this disease in 1998. 2 As a

result, the chemoprevention of breast cancer is the subject of intense interest. Until recently, however, the only clinically available method of breast cancer prevention was prophylactic mastectomy.

The Role of Prophylactic Mastectomy in the Management of the Woman at Increased Risk for Breast Cancer

The topic of prophylactic mastectomy has long been a source of controversy. Evaluation of the efficacy of the procedure is complicated by wide variations in the indications for its use, the removal of different amounts of breast tissue, and the lack of systematic follow-up for most women undergoing prophylactic mastectomy. Scientific study is onty now being applied to prophylactic mastectomy. However, in spite of the inadequacies of the available data, surgeons are regularly called on to make decisions about the appropriateness of this procedure for individual patients. The identification of mutations in breast cancer predisposition genes and the high level of risk associated with these mutations has once again made prophylactic mastectomy a subject of intense interest.

Efficacy of Prophylactic Mastectomy Both subcutaneous and total (simple) mastectomy have been advocated for prophylaxis. In a subcutaneous mastectomy, the breast parenchyma is removed through an incision in the inframammary crease, preserving the nipple-areolar complex. Breast tissue must be left behind to prevent devascularization of these structures (Fig 1). In addition, access to all of the breast tissue may be difficult with a submammary incision, particularly in large-breasted women. In 1 study of 12 subcutaneous mastectomies performed on 6 cadavers, residual breast tissue was present in the subareolar tissue in all cases, and there was evidence of retained breast tissue elsewhere in 83% of cases. 3 The most common sites of retained breast tissue were the infraclavicular area, the axillary tail (of Spence), and the inferior skin flap. It is estimated that a carefully performed subcutaneous


FIG 1. A photograph of a patient after bilateral subcutaneous mastectomy. The residual tissue in the subareolar region is readily apparent. Microscopic infiltrating Iobular carcinoma was found when the mastectomies were completed.

mastectomy will remove between 90% and 95% of the breast tissue. However, attempts to improve the cosmetic results of breast reconstruction through the construction of thick skin flaps may leave behind much larger amounts of breast tissue (Fig 2). Advocates of subcutaneous mastectomy readily agree that the procedure does not completely remove all of the breast tissue 4-6 but contend that the removal of most of the breast tissue results in a proportional reduction in the risk of breast carcinoma. 6 Proof of this theory is difficult to find.

Several animal studies have examined ~ the effect of the incomplete removal of breast tissue on the incidence of mammary carcinoma. Jackson and colleagues 7 reported that, in Sprague-Dawley rats that received the carcinogen 7,12-dimethylbenzanthracene, the removal of 50% or 75% of the mammary tissue did not result in a reduction in the number of mammary tumors. Using the same model, Wong and colleagues 8 also failed to show a relationship between the amount of mammary tissue removed and the occurrence of mammary carcinoma. Nelson and colleagues 9 performed a similar study in C3H mice, a strain with a high rate of spontaneous mammary tumor formation. Again, no difference in the incidence of breast tumors was observed between mice undergoing removal of 50% or 100%


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FIG 2. A, An MLO projection of a mammogram from a patient who underwent a prophylactic mastectomy with implant reconstruction. Residual breast tissue is clearly visible. B, A pushback view of the same patient that shows large amounts of residual breast tissue. ¢, Completion mastectomy specimen demonstrates the implant and residual breast tissue.


of the mammary tissue, although the rate of tumor formation in these groups was somewhat lower than in sham-operated controls (89% for control vs 57% for partial and 48% for total removal).

The clinical data on subcutaneous mastectomy are difficult to evaluate because of the lack of information about risk status in the patients undergoing mastectomy and the young age of many of these women. Pennisi and Capozzi I° reported a series of 1500 patients who underwent subcutaneous mastectomy. The data were collected by written report from 165 plastic surgeons, and the average follow-up period was 9 years. Thirty percent of the patients were lost to fonow-up. The cancer incidence was reported as 0.4%, despite the large number of women lost to follow-up. If the incidence is calcuIated only for the 1007 patients for whom follow-up is available, it is 0.6%. Notably, only 20% of the patients in this study had a family history of a first-degree relative with breast cancer, and 45% were less than 40 years old at the time of operation, suggesting that a substantial number were at minimal risk for the development of breast cancer. Woods and Meland n have reported 5 cancers occurring after subcutaneous mastectomy in over 1500 patients who were treated over a 22-year period, but further clinical details were not reported. The literature contains many reports of breast cancer occurring in women after subcutaneous mastectomy, 5,~2,13 and many of these cancers are advanced because of a false sense of security that the woman was no longer at risk for breast cancer after the procedure. 12,13 It is noteworthy that, in 1 of these reports, cancer was identified 42 years after subcutaneous mastectomies were performed) 3 These findings emphasize the need for prolonged follow-up after the procedure before drawing conclusions about its protective effects, particularly when it is performed in young women with few actual breast cancer risk factors who will not experience most of their breast cancer risk until after age 65 years.

The alternative to subcutaneous mastectomy is total or simple mastectomy, in which the nipple-areolar complex is removed. Traditionally, an ellipse of breast skin was also removed to allow exposure of the underlying breast tissue. Today, a skin-sparing approach with removal of only the nipple-areolar complex is often used. It is clear that even total mastectomy does not remove all of the underlying breast tissue. Holleb and colleagues TM have reported 2 cases of breast cancer occurring 10 to 15 years after prophylactic total mastectomy. Data regarding the efficacy of total mastectomy as a prophylactic procedure can be obtained from the experience with the operation in women with lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS). Although mastectomy was initially regarded as therapeutic in these cases, LCIS is now widely considered to


TABLE 1. Recurrence rates after mastectomy for in situ carcinoma

Authors Hlstologlc finding No. of patients Recurrence (%) Follow-up

Walt eL a115 LCIS 162 0 93.1 Mo (mean) Bradley et a116 LCIS 371 2.7 10.2 Yr Kinne et a117 DCIS 82 1.2 11.5 Yr Silverstein et al ~ DCIS 97 1.0 45 Mo Cataliotti et a119 DCIS 129 1.6 10.4 Yr

be a risk factor for cancer development rather than an early form of cancer. More controversy surrounds the natural history of DCIS, but mastectomy for this condition can be regarded as prophylactic because micrometastases, by definition, are not present at the time of a diagnosis of DCIS. Studies of simple mastectomy for the treatment of in situ carcinoma demonstrate recurrence rates of 1% to 3% 15-19 (Table 1), even when the patients being studied are those with gross or palpable DCIS, for whom there is a significant potential for unrecognized microinvasion. In contrast with the patients in the subcutaneous mastectomy studies, these patients have a quantifiable invasive breast cancer risk of at least 1% per year if left untreated. 2° The results of these studies suggest that total mastectomy provides a high level of risk reduction in high-risk women, but the potential for breast cancer development still remains.

Surgical Technique Although clinical data are limited, it is apparent that neither subcutaneous nor simple mastectomy provides complete protection against breast cancer development. We believe that the attempted removal of all breast tissue, as in a mastectomy performed for the treatment of breast cancer, is the key consideration in prophylactic mastectomy. The boundaries of the dissection should be defined carefully to ensure that the removal of breast tissue is maximized. The dissection should extend superiorly to the level of the clavicle, medially to the sternal border, inferiorly to the superior border of the rectus abdominis, and laterally to the latissimus dorsi. Particular care must be taken to remove the entire axillary tail of the breast. There is no indication for axillary dissection in prophylactic mastectomy, and dissection of the tail of the breast should not extend to the point where the upper intercostobrachial nerves are sacrificed. Posteriorly, excision of the fascia of the pectoralis major aids in breast removal, but this fascia can be preserved when implant or expander reconstructions are undertaken, provided that meticulous attention is paid to the removal of all of the breast tissue.

Thin skin flaps similar to those used for a therapeutic mastectomy


FIG 3. A, Cosmetic outcome after bilateral skin-sparing mastectomies and TRAM flap reconstruction. Visible scarring on the breast is minimized. B, The specimen after skin-sparing mastectomy demonstrates removal of only the nipple-areolar complex.


should be used. The creation of thick flaps to improve cosmesis increases the risk that breast tissue will be left behind. Temple and colleagues 21 performed random frozen-section sampling of margins in 5 patients undergoing prophylactic mastectomy and found that the lower flap and the tail of the breast often harbored residual breast tissue. The actual thickness of the flaps will vary with the amount of subcutaneous fat present, and if there is uncertainty regarding the adequacy of the removal of all of the breast tissue, frozen sections of the areas in question may be used.

Many women choose to undergo immediate breast reconstruction at the time of prophylactic mastectomy. Women undergoing prophylactic mastectomy are excellent candidates for immediate reconstruction because the skin of the breast can be preserved, and postoperative chemotherapy and radiotherapy are only considered if occult invasive carcinoma is identified. A skin-sparing approach to prophylactic mastectomy includes removal of only the nipple-areolar complex. If adequate exposure at the periphery of the breast cannot be obtained with this approach, incision rather than excision of the lateral breast skin is undertaken. The use of a skin-sparing approach provides a larger skin envelope if implants or expanders are to be placed and minimizes scarfing on the breast when autogenous tissue is used (Fig 3).

Breast reconstruction can be accomplished With implants or tissue expanders or with autogenous tissue. The advantages of implant/expander reconstructions are a shorter operative time, a more rapid recovery, and lower cost. However, a substantial incidence of long-term sequelae is reported after this type of reconstruction. The Plastic Surgery Educational Foundation 22 reported the results of an 11-center retrospective study of 504 patients with 995 saline breast implants who were followed up for a mean period of 6 years. Most of the implants were placed for augmenta- tion. A total of 20.6% of the patients required reoperation for open cap- sulotomy or replacement of a deflated implant. Patients who had implant reconstruction after prophylactic mastectomy were noted to be significantly less satisfied with the procedure (P = .005) than those who had implants placed for other reasons. Gabriel and colleagues 23 have reported similar results in a group of 749 women who received breast implants at the Mayo Clinic and were followed up a mean period of 7.8 years. Two hundred eight women (27.8%) underwent 450 additional implant-related procedures. In 20.2% of cases the secondary procedures were planned, and the remainder were performed for complications. Capsular contracture was the most frequent complication, followed by implant rupture. The rate of complications in women having prophylactic mastectomy was 17.3% at 1 year and 30.4% at 5 years, compared with 6.5% at 1 year and


12% at 5 years for women with cosmetic implants (P < .001). Slade 24 has reported a 26% rate of complications in patients who had implant reconstructions after subcutaneous mastectomy. Thus some of the immediate advantages of implant reconstruction may be nullified by the development of complications requiring operation in a substantial minority of patients. In a review of 216 patients undergoing immediate breast reconstruction after mastectomy for carcinoma, Ebedein and colleagues 25 reported partial flap loss in 7% of 124 patients having flap reconstructions, and 9% of the flap group required secondary operative procedures. In this study, patients who had flap reconstruction ranked their overall satisfaction with the procedure significantly more favorably than patients who underwent implant or expander reconstruction.

Psychologic Response to Prophylactic Mastectomy Just as the efficacy of prophylactic mastectomy in preventing breast carcinoma has not been well documented, neither have the psychologic consequences of the procedure. Meyer and Ringberg 26 reported on 25 patients who had bilateral subcutaneous mastectomy and underwent psychiatric evaluation before the operation and at 8 weeks and 1 year after the operation (mean patient age, 47 years). At 8 weeks, 19 patients were satisfied with the operation, and at 1 year this figure decreased to 17 patients. Approximately 50% of the patients reported postoperative mood impair- ment and increased anxiety or tension, and one quarter of the patients desired psychiatric care, although none had actually made an appointment with a psychiatrist. Stefanek and colleagues 27 studied the attitudes of a group of women at increased risk for breast cancer development on the basis of their family history. Fourteen women had undergone bilateral prophylactic mastectomy; 92 women had been interested in the procedure but opted not to have it performed, and 58 women were not interested in a prophylactic operation. The women who opted for the operation reported more breast cancer worry and were satisfied with their decision to undergo the operation. Biggs and colleagues 28 surveyed 370 women who had undergone bilateral prophylactic mastectomy at a median period of 14.6 years before the survey. Regrets about the procedure were expressed by 5% of the respondents. Patients who did not receive preoperative psychologic counseling, those without a family history of breast cancer, and patients older than 40 years at the time of the operation had more regrets than their counterparts, although these differences did not reach statistical significance. Physician initiation of a discussion about prophylactic mastectomy was associated with a significantly higher incidence of regret than when the discussion was patient initiated.


TABLE 2. Society of Surgical Oncology position on indications for prophylactic mastectomy

Women with unilateral breast cancer Diffuse microcalcifications Lobular carcinoma in sRu Large breast difficult to evaluate clinically and mammegraphically History of Iobular carcinoma in situ followed by unilateral breast carcinoma Risk factors such as atypical hyperplasia, family history in a first-degree relative, or less

than age 40 years at diagnosis Women with no previous history of breast carcinoma

Atypical hyperplasia Family history of breast cancer in a premenopausel first-degree relative that is bilateral Dense, nodular breasts in association with atypical hyperplasia and/or a family history of

premenopausal bilateral breast cancer in a first-degree relative

Indications for Prophylactic Mastectomy The suggested indications for prophylactic mastectomy have varied, and physician specialty and experience with breast cancer risk assessment may impact the use of prophylactic operations. For example, Pennisi and Capozzi ~° include bilateral breast nodules, "significant macrocyst disease," hyperplasia without atypia, papillomatosis, a mammogram with severe "dysplasia," great concern by the patient and her doctor about nodular breasts, and multiple biopsies as indications for bilateral subcutaneous mastectomies. Unfortunately, none of these conditions are associated with a significant increase in the risk of breast cancer development. The authors' confusion about breast cancer risk is reflected in their statement ". . .when a family history of breast cancer was present along with proliferative disease and atypia, the risk to the patient was 11 times, or 100%. "9'10 In fact, the 15-year risk of breast cancer development when these 2 factors are present is 20%, as noted in the study of Dupont and Page, 29 which was used as the reference for this statement. In an attempt to define some parameters for appropriate patient selection, the Society of Surgical Oncology developed a position statement on individuals for whom prophylactic mastectomy might be considered 3° (Table 2). Separate indications were developed for women who had already been treated for unilateral breast carcinoma and for those women without a preexisting diagnosis of cancer. All of the indications mentioned in the statement are well documented to increase the breast cancer risk or are clinical conditions known to make the evaluation of the breasts more difficult. However, the cancer risk associated with these conditions varies widely, and other important variables are not considered.

The Society's position on contralateral prophylactic mastectomy after a unilateral diagnosis of carcinoma ignores the critical issue of the risk of


TABLE 3. Attitudes toward prophylactic mastectomy

General surgeons*(%)

Plastic Gynecologists~ surgeonst(%) (%) P value

Agree prophylactic maatectomy 47 84.6 38.3 .0001 has a role in high-risk management

Ever recommended prophylactic 38.8 81.1 17.7 .001 mastectomy

Level of risk at which would recommend 51.1 41.2 54.1 .008 prophylactic mastectomy (mean)

"n = 219. tn = 53. ~'n -- 440.

death from the initial carcinoma. The risk of a new primary carcinoma is approximately 1% per year. For women with axillary lymph node metastases, the risk of death from the original breast cancer almost always exceeds this risk, and this is also true for women with larger, high-grade lymph node-negative malignancies. Under these circumstances, prophylactic mastectomy does not reduce the risk of breast cancer death and is best avoided in most patients. The risk of cancer development after a diagnosis of LCIS has been reviewed and is approximately 1% per year} ° It is not clear that, once a unilateral carcinoma develops, the same level of risk persists in the opposite breast even if LCIS is present in that breast.

In women with no previous history of breast carcinoma, the level of risk is the major factor in determining the appropriateness of prophylactic operation because competing causes of death are usually of less concern. A diagnosis of atypical hyperplasia carries with it a 4- to 5-fold increase in the breast cancer risk. 29 For a woman at age 35 years, this translates to a risk of only 10% to 12.5% for the 20 years after the diagnosis. In our opinion, this level of risk is not sufficient to justify prophylactic mastectomy in most women. The level of risk associated with a family history of breast cancer varies considerably; depending on whether a mutation in a breast cancer predisposition gene is present. In the woman with a mutation of BRCA-1 or BRCA-2, the lifetime breast cancer risk is estimated to range from 50% to 85%. 31'32 This high level of risk makes prophylactic operation a serious consideration for these women. There is particular concern about the level of protection afforded by prophylactic mastectomy in women with genetic mutations. At this time, no clinical data that address this question are available. Schrag and colleagues 33 used decision analysis methods to estimate the effect of prophylactic mastectomy on life expectancy among women with mutations of BRCA-1 and BRCA-2. In their model, prophylactic mastectomy was assumed to reduce the risk of breast cancer development by 85%. The model also assumes that high-

172 Curt Probl Surg, March 1999

risk women will undergo regular breast cancer screening and that 80% of the breast cancers that occur will be lymph node negative. Using these assumptions, a 30-year-old woman with a 40% risk of breast cancer development gains 2.9 years of life by prophylactic mastectomies. If the lifetime risk of breast cancer is 85%, 5.3 years of life are gained with the operation. These gains in life expectancy reflect the benefits that will accrue to a cohort of women at the risk levels described, rather than to any specific individual. Finally, when considering such a radical preventive operation, it is important to remember that approximately 80% of women with invasive breast carcinoma are eligible for treatment with breast- preserving operation, 34 making prevention more radical than the treatment of the established disease.

In an attempt to analyze factors influencing a surgeon's approach to prophylactic mastectomy, Houn and colleagues 35 surveyed 803 surgeons in the state of Maryland. The respondents included 219 general surgeons, 53 plastic surgeons, and 440 gynecologists. Significant differences in attitudes toward prophylactic mastectomy were noted according to the respondent's specialty (Table 3). Plastic surgeons were more likely to believe that prophylactic mastectomy had a role in the management of the high-risk woman and recommended prophylactic mastectomy at a significantly lower level of risk than general surgeons or gynecologists. Male surgeons were also significantly more likely than female surgeons to recommend the procedure for a lower level of risk. Gynecologists recommended subcutaneous mastectomy in 63.4% of cases, compared with 40.5% for plastic surgeons and 28.2% for general surgeons (P = .0001).

Approach to the Woman at Risk It is apparent from the foregoing information that there is much uncertainty surrounding prophylactic mastectomy. In the woman referred for evaluation, we begin with an attempt to quantify the level of risk. This includes genetic counseling for those women with a family history of breast cancer and consideration of genetic testing. For women at risk on the basis of benign breast disease, a review of the biopsy specimen by an experienced breast pathologist is critically important. For many women, the reassur- ance that if cancer occurs it is likely to be detected at an early stage is very important in the decision-making process. It is also important to emphasize that the risk figures cited are for the risk of breast cancer occurring, not breast cancer death. Women are informed specifically that even the most meticulous prophylactic mastectomy does not afford 100% protection against breast cancer development. The availability of breast-preserving therapy for the treatment of most breast cancers is discussed. Patients are


informed of the availability of tamoxifen for chemoprevention and the ongoing STAR prevention trial (discussed below). Psychologic consultation is used liberally, both for patients at low risk for breast cancer development who are cancerphobic and for those patients at increased risk. Consultation with a reconstructive surgeon provides detailed information about reconstructive options and their potential risks and benefits. There are no absolute indications for prophylactic mastectomy. Each woman must determine whether her level of risk is personally acceptable. Prophylactic operation is never an emergency. It should not be undertaken because of misinformation about risk status or anxiety over the death of a relative or friend. Risk assessment has not traditionally been a part of surgical training, but for surgeons who undertake prophylactic mastectomy, knowledge in this area is essential.

Selective Estrogen Receptor Modulation and the Prevention of Breast Cancer

In 1936 Lacassagne 36 suggested that breast cancer could be prevented by reducing the access of estrogen to the breast. However, at that time, the only approach to achieve the required result was to perform an oophorectomy. Today we know from epidemiologic studies that, indeed, an oophorectomy will reduce the risk of breast cancer, 37 but this approach is too radical to be useful as a public health measure. The discovery of the estrogen receptor 38 and the knowledge that breast cancer growth can be controlled by specific antiestrogenic drugs 39 has provided the opportunity to treat and prevent breast cancer with targeted therapies. Tamoxifen is used for the treatment of all stages of breast cancer and provides a significant survival advantage for patients who are lymph node positive or lymph node negative. 4° The extensive use of tamoxifen has led to the evaluation of the drug as a preventive for breast cancer in women who are at high risk for breast cancer development. However, the success of tamoxifen and the discovery of a novel selective estrogen receptor modulation (SERM) has focused intense interest in developing new agents. The discovery of the target site-specific effects of antiestrogens a decade ago 41,42 resulted in a paradigm shift in the prospects for the prevention of breast Cancer. Tamoxifen and raloxifene (Fig 4) maintain bone density in laboratory rats 41'43 but inhibit mammary tumorigenesis. 44 Why not develop a drug to prevent osteoporosis but, at the same time, prevent breast cancer as a beneficial side effect? 41,45 This goal has become a reality 46 with the clinical availability of raloxifene as a medicine to prevent osteoporosis in women after menopause. 47


Tamoxifen Breast Cancer Therapy

and Prevention

HO ~ OH Raloxifene

Prevention of Osteoporosis

FIG 4. Structures of the therapeutic agents tamoxifen and raloxifene.

Tamaxifen: The First SERM Tamoxifen is classified as an antiestrogen in laboratory animals; this property encouraged its testing as a therapy for advanced breast cancer in women after menopause. However, the finding that there was a low- reported incidence of side effects resulted in the evaluationof tamoxifen as an adjuvant therapy.

The clinical community initially used tamoxifen for about a yea r 48,49

because the drug is active in advanced disease, on average, for only about 1 year. There was also a concern about premature drug resistance. However, based on numerous clinical studies, 5°-54 it is generally accepted that 5 years of adjuvant therapy is an appropriate duration.

The success of tamoxifen as a safe long-term therapy for breast cancer resulted in the evaluation of the drug as a preventive for breast cancer. The initial pilot study was planned to determine whether women at high risk would volunteer to test the concept and whether volunteers, once recruited, would remain compliant. The study was conceived in 1986 at the Royal Marsden Hospital 55 based on 2 critical scientific observations. First, tamoxifen prevents the development of rat mammary cancers if administered simultaneously with the carcinogen 56,57 or after the carcinogen during the promotional phase of mammary carcinogenesis. 58-6° Second, tamoxifen was found to reduce the incidence of contralateral breast cancer in women. 61 Indeed, this observation has subsequently been investigated in great detail, and it is clear that, based on the contralateral breast cancer data (Table 4), long-term tamoxifen treatment has the potential to reduce the breast cancer risk by up to 40%.

Curr.Probl Surg, March 1999 175

TABLE 4. The 1992 Oxford Overview Analysis 4° demonstrated a significant reduction in the incidence of contralateral breast cancer with tamoxifen use

Tamoxifen/control

No. of contralateral breast cancers observed 122/184 Reduction in incidence (%) 39 + 9

P value <.00001 Reduction in incidence with durations (%)

<2 Yrs 26:1:21 2 Yrs 37:1:13 >2 Yrs 54 + 16

Before the national prevention studies could start, an important safety issue had to be addressed. Estrogen is essential to reduce the risk of coronary heart disease in women and to prevent osteoporosis. Tamoxifen is classified as an antiestrogen so, in the mid 1980s, there was every possibility that the long-term administration of an "antiestrogen" would increase the risk of coronary heart disease and precipitate premature osteoporosis. However, tamoxifen is not a pure antiestrogen and has a mixture of estrogenic and antiestrogenic properties in laboratory animals.62 Studies in ovariectomized r a t s , 4x,43 initially demonstrated the clinical potential of tamoxifen to preserve rather than to decrease the bone density in patients. This discovery translated from the laboratory to the clinic with the finding that tamoxifen maintains the bone density in the postmenopausal patient. 63 Similarly, tamoxifen reduces circulating cholesterol levels, 64,65 and there is a suggestion that tamoxifen could reduce the risk of coronary heart dis- e a s e . 66-68 Clearly, the ability of tamoxifen to express estrogen-like effects selectively provides an added benefit for the postmenopausal patient.

Based on these findings, 3 large clinical trials were started in the early 1990s to test the utility of tamoxifen as a preventive for breast cancer. Although a total of 14,000 volunteers have been randomized to tamoxifen or placebo in clinical studies in the United Kingdom and Italy, the princi- pal study, conducted by the National Surgical Adjuvant Breast Project (NSABP), in North America has completed the accrual of 13,000 high- risk patients (Fig 5). Both premenopausal and postmenopausal women have volunteered, but premenopausal women must have a 5-year anticipated risk of the development of breast cancer equivalent to that of a 60- year-old woman. The risk was calculated with the Gall model, 69 and women meeting the entry criteria were then randomized to receive either tamoxifen or placebo for 5 years. In fact, the overall risk of the women who have volunteered was higher than originally anticipated so the recruit- ment goal of 16,000 was reduced to 13,000. The initial results of the pre-


Potential Participants

>60 years old - w i t h / w i t h o u t r i sk factors 35-59 years old - w i t h r i sk factors

•LCIS

• lO re la t ive w i t h breast cancer

• Breast biopsies

• a typical h y p e r p l a s i a

• Over 25 years old before b i r t h of first ch i ld

• no children

• menarche before age 12

~ Placebo

R A N D O M I Z E 1 3 , 0 0 0 ~

Tamoxifen 20mg/day

5 yea r s

FIG ,5. The entry criteria and clinical trial plan of the prevention trial testing the benefit of tamoxifen in high-risk women.

TABLE 5. Initial results of the NSABP Breast Cancer Prevention Trial 7°

No. of events Rate per 1000

Age (yr) Placebo Tamoxifen Placebo Tamoxifen Relative risk

95% Confidence

interval

_<49 59 38 6.33 4.11 0.65 0.4343.98 50-59 46 24 6.31 3.26 0.52 0.32-0.85 _>60 49 23 6.88 3.22 0.47 0.29-0.77

Total 154 85 6.4g 3.58 0.55 0.42-0.72

vention trial have been reported with a mean follow-up of 3.6 years.* There was a 45% reduction in the number of invasive breast cancers in the tamoxifen-treated group. This benefit was observed for all age groups (Table 5). A significant reduction in the rate of intraductal cancer was also observed in the tamoxifen-treated women (57 vs 31 cases; P = .002). 7°

This trial is clearly pivotal for the prospects for prevention of breast cancer in a targeted population at risk. In addition to the reduction in breast cancer incidence, women treated with tamoxifen had a 35% reduction in the risk of fractures of the hip, spine, and wrist (P = 0.013). To date, no

"Readers are referred to Fisher B, et al., Tamoxifen for prevention of breast cancer: report of the

National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371-88,

for a detailed, updated discussion.

Curr Probl Surg, March 199g 177

differences have been observed between treatment groups in the incidence of ischemic heart disease.

For the first decade (1977-1987) that tamoxifen was available in the United States for the treatment of breast cancer, there was no evidence to suggest that tamoxifen could be associated with an increased risk of endometrial cancer. Again, based on results from studies in the laboratory that tamoxifen might increase the growth of preexisting endometrial cancer, 42 clinical trial groups examined their databases to determine whether increased numbers of endometfial cancer were identified in tamoxifen treatment arms. This is difficult in retrospective analyses because the incidence of endometrial cancer is extremely low and the study design of retrospective data collection introduces biases. Nevertheless, it is now possible a decade later to provide a realistic estimate of the risk of the development of endometrial cancer. The risk of invasive endometrial cancer was increased approximately 2.5 times in the tamoxifen-treated women in the prevention trial. All of the excess risk was observed in women older than 50 years. 7° Unfortunately, the concern about endometrial cancer in patients has been linked with the ability of tamoxifen to produce DNA adducts and induce liver cancer in rats. 7~,72 This has produced undue concern in the treatment population despite the fact that tamoxifen does not produce DNA adducts in human liver, 73 that the known metabolic pathways in rats and humans are different, 74 and that there is no reported increase in hepatocellular carcinoma in patients. 75

The International Agency for Research on Cancer has reviewed all of the laboratory and clinical databases. 76 This evaluation resulted in the classifi- cation of tamoxifen as a carcinogen but with the statement that no woman should consider stopping tamoxifen because of the 2- to 3-fold increased risk of endometrial cancer. The benefits of tamoxifen outweigh the risks. The increased risk of endometrial cancer translates into 2 to 3 new cases per 1000 women per year. The disease is the same stage and grade as that encountered in women not taking tamoxifen, 77 and the American College of Obstetrics and Gynecology has not issued special guidelines to monitor women treated with tamoxifen. 7s However, any woman who experiences spotting or bleeding should be evaluated immediately.

Roloxifene to Prevent Osteoporosis Raloxifene (initially referred to in the literature as LY 156750 and keoxifene) was originally designed as an agent to treat breast cancer. However, in the mid 1980s there were no perceived advantages over tamoxifen that would encourage the development of a competitor drug. Nevertheless, the discovery of SERM was a stimulus for the development of similar drugs


TABLE 6. Breast cancer incidence in raloxifene trials 81

Interval to 95% diagnosis No. of events Rate per 1000 Confidence (too) Placebo Tamoxifen Placebo Tamoxifen Relative risk interval

>1 25 20 0.74 0.28 0.38 0.22-0.68 >6 23 15 0.68 0.21 0.31 0.17-0.58 >12 23 12 0.68 0.17 0.25 0.130.48 >18 17 8 0.50 0.11 0.23 0.10-0.49

for alternate uses. Raloxifene maintains bone density in laboratory rats, 41,79 reduces cholesterol, 79 and, most importantly, has a reduced estro- genicity in the rodent uterus. 8° Based on this profile, raloxifene has been developed as a preventive for osteoporosis. Clinical trials of 12,000 women have demonstrated that raloxifene can maintain bone density and has a low incidence of side effects. 47 Although there should be vigilance about uterine safety issues, the present data indicate that the uterus is atrophic, with no increase in endometrial thickness. 47 Similarly, raloxifene has a positive effect on circulating cholesterol. Low-density lipoprotein cholesterol is reduced whereas the high-density lipoprotein cholesterol remains elevated. 47 The early results of the effects of raloxifene on breast cancer incidence are available from women in placebo-controlled osteoporosis trials. 8~ The incidence of breast cancer in the raloxifene arm was 0.33%, compared with a 0.77% incidence in the control arm, a 58% reduction in risk. As the time from randomization increased, the beneficial effects of raloxifene increased (Table 6). The reduction in breast cancer incidence was confined to estrogen receptor-positive tumors. The incidence of estrogen receptor-negative tumors was unchanged. The drug is approved by the Food and Drug Administration for the prevention of osteoporosis. However, based on the encouraging initial results with raloxifene, there is an ongoing trial to compare and contrast tamoxifen and raloxifene for the prevention of breast cancer (the Study of Tamoxifen and Raloxifene [STAR]).

The Prevention of Breast Cancer With SERMs The proposed use of tamoxifen as a preventive in high-risk women is a valuable application of a successful cancer therapy, but the key to the success of this strategy is the identification of high-risk women. Unfortunately, approximately 50% of women in whom breast cancer develops cannot be classified as "high risk," so a broader strategy must be developed to impact successfully on public health. In the late 1980s, it was proposed 41,45 that drugs should be targeted to prevent osteoporosis in


Tamoxifen Raloxifene

Prevents Mammary , Mammary Carcinogen, :mogenes,s

Ago.nist Act ~w A.gonist in Uterus y in Uterus

Maintains ~tains Bone Bone Density Density

FIG 6. Similarily of the pharmacologic properties of tamoxifen and raloxifene in the rat.

healthy women after menopause with the beneficial side effect of preventing breast and endometrial cancer. A comparison of the known pharmacologic action of tamoxifen and raloxifene in the rat (Fig 6) demonstrates the similarity of the agents. Both agents prevent bone lOSS, 41 and both agents prevent rat mammary carcinogenesis. 44 Taking the argument 1 step further, the pharmacologic action of tamoxifen is well established in women after menopause ,'Fig 7), and the multifaceted actions of raloxifene are being documented. There is every reason to anticipate that raloxifene will reduce the risk of breast cancer, based on its known pharmacologic features as a targeted antiestrogen. Breast safety was a critical issue for the approval of raloxifene for the prevention of osteoporosis, and there was no evidence from the clinical studies that raloxifene increased the breast cancer risk. It is not an estrogen in the breast. However, further evaluation will be necessary to prove that raloxifene consistently reduces the breast cancer risk.

Conclusion and Prospects for the Future It is now more than 60 years since Lacassagne 36 suggested that an antagonist to block the sensitivity of the breast to estrogen could be used as a preventive for breast cancer. By a strange coincidence, 1998 was the 40th anniversary of the "estrogen receptor hypothesis" and the report of the first nonsteroidal antiestrogen. 3s,82 More details of the evolution of these seminal discoveries are reported elsewhere. 83,84

At present, we are poised to apply a practical intervention for risk reduc-


Tamoxifen i Raloxifene tandard Endocrine Therapy ~ Preventive for r Breast Cancer ' ~ , ~ Osteoporosis

Prevents I - - Contralateral Breast Cancer I ~ _ e - f

•

Decreases Circulating ~ Decreases Circulating Cholesterol Cholesterol Increases . . . . No Increase in Endometrial Endometrial Thickness ~ ~ Thickness Maintains _ ~ ~ - ' ~ i ' Maintains Bone Density " ~ / Bone Densily

FIG 7. Similarity of the actions of tamoxifen and raloxifene to produce selective estrogen receptor modulation in the postmenopausal woman. Although there is every reason to expect that raloxifene will reduce the risk of breast cancer, only large-scale clinical studies will prove the point unequivocally.

tion in breast cancer. Tamoxifen prevents breast cancer in high-risk women. Additionally, we will soon have information about whether tamoxifen can reduce the breast cancer risk in BRCA-1 and BRCA-2 carriers. All of these results come from the NSABP prevention trial. Perhaps more important, a new public health strategy for the woman after menopause is in place. The SERMs will be used as a prevention and maintenance treatment for well women with diverse risk factors in 3 major diseases: osteoporosis, coronary heart disease, and breast cancer. A laboratory idea conceived a decade ago will have revolutionized women's health. 41'45,46

Controversies Related to the Use of Primary Chemotherapy

Chemotherapy before local therapy of the breast has been used for locally advanced breast cancer (LABC) for over 20 years. 85-87 Chemotherapy administered as an initial therapy has been referred to by several different terms including neoadjuvant chemotherapy, preoperative chemotherapy, induction chemotherapy, and primary chemotherapy. Primary chemother-


TABLE 7. Criteria for stage III breast cancer according to the American Joint Commiltee on Cancer

Stage IliA All T, N2, MO T3, N1 or N2, MO

Stage IIIe T4, any N, MO Ar~ T, N3

T3 Tumor > 5 cm T4 T4a Extension to chest wall

T4b Skin involvement (includes peau d'orange, ulceration, satellite nodules)

T4c Both chest wall and skin involvement T4d Inflammatory cancer

N2 Ipsilateral axillary lymph nodes fixed to one another or to other structures

N3 Ipsilateral internal mammary lymph nodes

apy is the term that most accurately captures the intent of chemotherapy that is administered as the initial treatment before local therapy with operation and/or radiation therapy.

The use of primary chemotherapy for LABC was introduced as a treatment strategy in the early 1970s. At 1 time LABC accounted for up to 15% of all newly diagnosed breast cancer cases in the United States; but with the introduction and widespread use of screening mammography, LABC accounts for a smaller fraction of all newly diagnosed breast cancer because earlier stages of disease predominate. 88 More recently, primary chemotherapy has been evaluated in patients with breast cancer who are technically operable at the time of diagnosis.

The use of primary chemotherapy for LABC is well established, but the definition of what constitutes LABC is not easily agreed on. As a result, clinical trials designed to evaluate new treatment strategies for patients with LABC contain a heterogeneous patient population, with very different prognoses. As a result, the objective assessment of treatment efficacy is difficult. For purposes of this discussion, LABC will be defined as (1) tumors greater than 5 cm (T3 lesion), (2) tumors that extend to the chest wall or skin (T4 lesion), and (3) tumors with fixed ipsilateral axillary lymph nodes or ipsilateral internal mammary lymph nodes (N2/N3). 8587 These definitions most readily correspond to the American Joint Committee on Cancer criteria for stage lII breast cancer as summarized in Table 7. A subset of LABC is inflammatory breast cancer (IBC), which accounts for 1% to 3% of all newly diagnosed breast cancers. 8s-87 IBC is characterized clinically by erythema, edema, and ridging of the skin (T4 lesion). Pathologically, IBC is often associated wi thdermal lymphatic invasion, but this feature is not required to establish the diagnosis. 87,89


TABLE 8. Combined treatment modality strategies for LABC

CTx -->S-->CTx ° CTx-->S~CTx "--)RT CTx -)RT--)CTx" CTx--) RT--)S---)CTx * CTx+RT--)CTx" CTx+RT---)S--)CTx *

CTx, Chemotherapy; S, surgery; RT, radiation therapy. "Followed by tamoxifen, if hormone-receptor positive.

Biologically, IBC is usually hormone receptor-negative and has a high proliferative index. Clinically, these features are manifested by rapidly progressive disease that is often metastatic at the time of diagnosis. 85-87

Evolution of Multimodality Therapy The introduction of multimodality therapy for patients with LABC has had an impact on patient survival. Physicians at the Middlesex Hospital in London, between 1805 and 1933, documented the natural history of patients with untreated LABC. 9° Of the 250 recorded cases, most were accounted for by LABC, with a median survival of 2.7 years. The reports of single-modality therapy (eg, radiotherapy or operation) in patients with LABC/IBC describe uniformly poor patient outcomes.85-87 The 5-year survival rates for patients with LABC/IBC treated with operation alone, radiotherapy alone, or a combination of operation and radiotherapy are 36% and 2%, 29% and 3%, and 35% and 5%, respectively. 85-87 These poor results are accounted for by the inevitable development of metastatic disease, even after optimal local therapy. In addition, locoregional failure was common in most of these early trials. 85-87

The observation that local therapies failed to prevent the development of distant metastases led to the introduction of systemic chemotherapy into the multimodality treatment approach for L A B C ] I B C . 85-87 A variety of different treatment modality sequences have been evaluated (Table 8), but the generally accepted approach uses primary chemotherapy as the initial treatment modality followed by operation, if technically feasible, followed by adjuvant radiation therapy and possibly additional adjuvant chemotherapy and hormonal therapy. 85-87

The impact of systemic chemotherapy on the outcome of patients with LABC/IBC has been demonstrated consistently in phase II trials in which the overall survival rate has improved significantly compared with historical controls. 85-87 One of the largest single-institution experiences in treating patients with LABC/IBC with a multidisciplinary approach comes from the MD Anderson Cancer Center, where more than 800 patients have been


TABLE 9. LABC: Response rates after induction chemotherapy 8s'87

IndueUon CTx Response rate (%) CR (%)

AV x 3-4 53-86 15 FAC x 34 83-87 8-15 DES-FAC x 3 72 15 CA'FPMFL x 3-11 90 52 CMFT x 4 47 8 VbTMAF Pr x 2-4 91 23 AMC/CMF 63 2 FACV x 4 55 10

CTx, Chemotherapy; CR, complete response; A, doxorubicin; V, vincristine; F, 5-fluorouracil; C, cyclophosphamide; DES, diethylstilbestrol; T, tamoxifen; P, prednisone; M, methotrexate; L, leucovorin; Vb, vinblastine; Pr, progestin.

enrolled in 5 consecutive clinical trials, including those evaluating the efficacy of doxorubicin-based primary chemotherapy regimens. 91-93 After primary chemotherapy, complete clinical responses (CRs) and partial responses (PRs) were achieved in 5% to 20% and 60% to 80% of patients, respectively. With maximum follow-up now reaching 20 years, the median survival for patients with stage llla disease has not been reached and for patients with stage UIb disease is 37 months. The 10-year overall survival rates for patients with stage l/Ia and stage IIIb disease are 56% and 26%, respectively. 91-93 Other investigators have reported similar results. 85-87 Overall, 50% to 95% of patients treated with primary chemotherapy achieved an objective response, including up to 50% clinical CR. The collective experience reported in the medical literature strongly supports the use of primary chemotherapy as an integral component of the multimodality treatment for LABC/IBC. Standard practice guidelines now uniformly recommend primary chemotherapy, usually doxorubicin-based, before local therapy in patients with inoperable stage IT[ tumors. 94

One of the fundamental goals of administering primary chemotherapy is to reduce the size of the primarytumor, making inoperable tumors operable. 85-87 Ideally, primary chemotherapy will cause complete tumor regression before local therapy (eg, CR). A variety of primary chemotherapy regimens and schedules have been evaluated. The most effective regimens, as judged by objective response criteria, usually contain doxorubicin and are administered for 3 to 4 cycles before patients have local therapy. Most reports indicate that response rates of 50% to 90% (Table 9) can be achieved with such regimens. Only 20% of patients experience CR, and only rarely is the pathologic specimen free of all tumor (eg, pathologic CR). 85-87,91-93

Although the administration of 3 to 4 cycles of primary chemotherapy is viewed as a convention, longer durations of primary chemotherapy have


been reported to improve the CR rate and possibly to improve the breast conservation rate. Swain and colleagues 95 treated 76 patients at the National Cancer Institute with CAMFL (cyclophosphamide, 500 mg/m z, day 1; doxorubicin, 30 mg/m 2, day 1; methotrexate 300 mg/m z, day 8; 5- fluorouracil, day 8; leucovorin 10 mg/m 2 x 6, day 9) and attempted hormonal synchronization of the tumor cells using tamoxifen and conjugat- ed estrogens. Patients whose disease achieved a CR, determined by a negative repeat biopsy, generally received radiation therapy, whereas patients with residual disease received a debulking operation before radiation therapy. The overall response rate to primary chemotherapy was 93%, with 43% CR, 44% PR, and 7% of patients experiencing no change. 95 The median number of cycles to achieve a CR or PR were 5 and 3, respectively.

More recently, the University of Michigan reported their experience using prolonged treatment with primary chemotherapy in 89 patients with stage III disease. 96 Patients received nine 21-day cycles of CAMF-PT (cyclophosphamide, 750 mg/m 2, day 1; doxorubicin, 30 mg/m 2, day 1; methotrexate, 40 mg/m 2, day 8; 5-fluorouracil, 500 mg/m 2, day 8; conju- gated estrogen 0.625 mg, orally, days 6 through 8; tamoxifen, 20 mg, days 9 through 14) before undergoing reassessment of the tumor response with a breast biopsy. Patients with a negative biopsyfinding received radiation only, whereas those with residual disease underwent a modified radical mastectomy and postoperative radiation. The clinical response rate to primary chemotherapy with CAMF-PT was 97%, with 28% of patients having a negative biopsy after 9 cycles of primary chemotherapy. 96 These findings suggest that the prolonged administration of primary chemotherapy may result in enhanced tumor regression, allowing for breast preservation in many patients with LABC.

One of the controversies regarding the administration of primary chemotherapy is the ability to judge accurately the clinical response to t r ea tment . 85-87,91-93,95,96 The clinical examination is not precise, given the small percentage of CR that is actually determined to be pathologic CR at the time of operation. Other methods for evaluating the response to primary chemotherapy include mammography, ultrasound, and biopsy of the primary site within the breast. Each of these methods has limitations, and their use results in either overestimation or underestimation of the actual response to treatment with primary chemotherapy. Mammographic evaluation of tumor response to primary chemotherapy has had mixed results. In a study by Semiglazov and colleagues, 97 the pathologic CR rate corresponded more closely to the mammographic findings than to the assessment by physical examination. In contrast, in a study of chemoendocrine


therapy, Powles and colleagues 98 reported that mammography did not accurately characterize tumor response because of an inability to define the margins of the tumor and the persistence of architectural distortion on the mammogram. Only 50% of patients had a reduction in tumor size by mammography, whereas 88% had tumor shrinkage demonstrated by ultrasound, which more closely corresponded to the clinical response rates. 98

More recently, magnetic resonance imaging (MRI) has been investigated as a method to evaluate the response to treatment with primary chemotherapy. Although MRI remains an investigational tool for assessing breast tumors, preliminary results from several groups suggest that it may prove useful. Abraham and colleagues 99 reported that MRI accurately estimates residual disease after the administration of primary chemotherapy in 97% of cases and does so better than the clinical examination or mammography. Cross and colleagues ~°° also reported that assessment by postchemothera- py MRI demonstrated a reduction in tumor burden enhancement and cor- related with the extent of disease determined by pathologic examination. The use of MRI as a means of assessing the response to primary chemotherapy may allow more women to undergo breast conservation without compromising local control or cosmesis. Issues related to cost and availability of the technology will determine how useful MRI becomes as a method to assess response to primary chemotherapy.

Theoretic Advantages and Disadvantages Associated With Primary Chemotherapy

Reducing the primary tumor size to allow for an operation, for patients with otherwise inoperable LABC/IBC has been demonstrated convincingly with the use of primary chemotherapy programs, but primary chemotherapy is now being administered more commonly in patients with early-stage, operable breast cancer. The theoretic rationale for considering the use of primary chemotherapy in this group of patients is multifaceted. The local recurrence rate within the breast in patients undergoing breast-conserving therapy does not appear to be related to the size of the primary tumor (T1 or T2). I°I,1°2 Decreasing the size of the primary tumor with primary chemotherapy may improve cosmesis by limiting the amount of tissue that needs to be removed from the breast (eg, size of the lumpectomy).

The breast of a patient receiving primary chemotherapy serves as an in vivo assay for the tumor's chemosensitivity to the effects of the therapy administered. As such, it may provide useful information regarding the use of the same treatment program in the postoperative adjuvant setting. If the tumor decreases in size, it would be reasonable to continue treat-


ment, whereas tumors that do not respond to primary chemotherapy may have developed drug resistance. As a result, an alternative, non-cross- resistant chemotherapy program should be considered in the postoperative, adjuvant setting.

Primary chemotherapy may also have an effect on the systemic control of micrometastases. Unfortunately, standard chemotherapy or even high- dose chemotherapy cures few patients with grossly metastatic disease. 1°3 The advantage of treating patients when the tumor burden is much smaller (ie, adjuvant setting) has been confirmed in multiple randomized, clinical trials evaluating chemotherapy and tamoxifen. 4° The basis for this effect is explained by the Goldie-Coldman hypothesis, which states that as a tumor-cell population increases in size, the probability that drug- resistant tumor cells will arise by spontaneous mutation increases. ~°4 The clinical implication is that initiating systemic therapy at the earliest possible opportunity (ie, small tumor burden) may minimize the probability of the development of chemoresistance.

Furthermore, Skipper 1°5 suggested that removal of the primary tumor may affect the growth characteristics of any residual micrometastases. Experimental animal models of malignancy have supported the latter theory. Fisher and colleagues 1°6 and Gunduz and colleagues 1°7 demonstrated that the removal of a C3H adenocarcinoma resulted in an increase in the labeling index of distant metastases within 24 hours after the removal of the primary tumor, and the effect lasted for up to 10 days. This observation was thought to be the result of noncycling tumor cells being moved from a dormant pool to an actively proliferating pool of tumor cells. More recently, O'Reilly and colleagues 1°8 have demonstrated that primary tumors are capable of secreting a substance that inhibits the growth of micrometastases. In mice that received a transplant with the Lewis lung carcinoma, vascular micrometastases develop in the lungs of the animals in which the primary tumor has been removed much more quickly compared with animals in which the primary tumor remains intact. Subsequent experiments identified a compound secreted by the primary tumor, angiostatin, that is a potent inhibitor of tumor angiogenesis. Holmgren and colleagues 1°9 were able to show that the inhibition of angiogenesis limits tumor growth by inducing apoptosis, although removal of the primary tumor removes the source of angiostatin and allows for the growth of lung metastases in the animals (ie, negative reg- ulator removed). The clinical implication of these observations, as they relate to primary chemotherapy, may be that earlier administration of chemotherapy may affect tumor cells in different phases of the cell cycle and also exert an angiosuppressive effect.


There are several potential disadvantages associated with the administration of primary chemotherapy in patients with operable breast cancer. The most serious concern relates to the accuracy of the diagnosis of invasive breast cancer based on a core biopsy or fine-needle aspiration biopsy (FNAB) of the breast lesion. The accuracy of FNAB is dependent on the skill of the individual performing the FNAB and the experience of the pathologist interpreting the material obtained. The sensitivity and speci- ficity of FNAB varies widely in the medical literature, with sensitivities varying between 65% and 98% and specificities ranging from 34% to 100%. 11° More recently, false-negative rates have ranged from 0% to 4% ln,112 and appear to occur more commonly in well-differentiated tumors. 113 The most serious concern is a false-positive rate of up to 18%, 113'114 which may result in a patient without cancer or with noninvasive cancer (eg, DCIS) receiving primary chemotherapy unnecessarily. Finally, the quantity of tissue obtained by FNAB limits the number of biologic indices that can be evaluated (ie, hormone receptors, c-erB-2). As a result, information that potentially could guide the choice of therapy or provide information regarding prognosis is not available.

The single most important prognostic factor in early-stage breast cancer remains the status of the axiUary lymph nodes. If an axillary lymph node dissection is not performed before primary chemotherapy is initiated, the information related to the status of the axilla is potentially lost. Medical oncologists have incorporated the nodal status of the axilla (eg, node-positive or node-negative, number of involved nodes) into the decision about which type of adjuvant therapy should be recommended. For example, the exceedingly poor prognosis of patients with more than 10 involved axillary lymph nodes has generated considerable interest in high-dose chemotherapy approaches for patients at high risk for recurrence. 1°3 Such patients may not be identified because primary chemotherapy may affect the primary tumor and the involved lymph_ nodes within the axilla. Alternatively, patients with a particularly good prognosis (ie, small tumor size, negative axiUary lymph nodes) may not have received a recommendation for chemotherapy or hormonal therapy had these parameters been known. To counter such arguments, data are now available that suggest that the axillary nodal status after primary chemotherapy conveys the same prognostic information compared with having the information before postoperative adjuvant therapy is administered. ~15 Furthermore, outside of a clinical trial (eg, the majority of all patients with breast cancer) most of the patients with early-stage breast cancer receive a recommendation for some form of adjuvant therapy. Generally, only patients with the smallest lymph node-negative tumors (<1 cm) avoid adjuvant therapy.


Clinical Trial Results Several nonrandomized clinical trials have reported the efficacy of primary chemotherapy in patients with operable breast cancer. JacquiUat and colleagues H6 administered primary chemotherapy with vinblastine, thiotepa, methotrexate, 5-fluorouracil, and prednisone with or without doxorubicin and breast irradiation in 250 patients with various stages of disease. All patients were reported to have achieved a response to primary chemotherapy (100%), and breast conservation was achieved in 96% of patients. Bonadonna and colleagues 117 and Veronesi and colleagues 118 at the Milan Cancer Institute evaluated 5 different primary chemotherapy regimens, each administered for 3 to 4 cycles, in patients with tumors larger than 3 cm in diameter. The primary chemotherapy regimens included cyclophosphamide, methotrexate, and 5-fluorouracil (CMF); 5-fluorouracil, epirubicin or doxorubicin, cyclophosphamide (FAC); 5-fluorouracil, mitoxantrone and cyclophosphamide; or doxorubicin. Patients underwent local therapy with either mastectomy or quadrantectomy followed by breast irradiation. Patients with positive axillary lymph nodes or estrogen-receptor negative tumors received additional chemotherapy after completing the local therapy. With a median follow-up of 4 years, the response to primary chemotherapy was 78%, and local control has been maintained in 94% of all patients. H7,118 Although most of the patients (91%) in these trials were able to undergo breast-conserving therapy, the trial results have been criticized in the United States because most of the patients were initially judged to have tumors measuring less than 5 cm in diameter and as such were candidates for breast-conserving therapy even without receiving primary chemotherapy.

Calais and colleagues 119 reported the results of a trial with primary chemotherapy consisting of mitoxantrone or epirubicin, vindesine, cyclophosphamide, and 5-fluorouracil, administered to patients with tumors measuring more than 3 cm in diameter. The patients' response to primary chemotherapy dictated subsequent locoregional therapy and adjuvant chemotherapy. Patients attaining an objective response (eg, PR, CR) received therapy with breast-conserving surgery, adjuvant radiation therapy, and 6 cycles of additional chemotherapy. Breast conservation was achieved in 49% of patients. Nonresponders were treated with a mastectomy, radiation therapy, and 6 cycles of an alternative chemotherapy regimen consisting of teniposide, mitomycin-C, and methotrexate. The 5- year survival rate for patients who responded to primary chemotherapy was superior (90%) to patients who did not respond (57%). 119 Several other priot studies that used different primary chemotherapy combinations in patients with tumor characteristics variably described as T1-3 lesions, "requiring a mastectomy," have reported similar resultsJ 2°-124


Several randomized clinical trials have been reported that compare primary chemotherapy with standard postoperative adjuvant chemotherapy. Mauriac and colleagues 125 reported on 272 patients with tumors larger than 3 cm in diameter who were randomized to mastectomy with axillary dissection or primary chemotherapy consisting of 3 cycles of epirubicin, vincristine, and methotrexate followed by 3 cycles of mitomycin, tlfiotepa, and vindesine. The patients who initially received local surgical therapy and who had positive axillary lymph nodes or tumors that were hormone receptor-negative received the same chemotherapy after the operation. Patients who received primary chemotherapy and were deemed to have attained a clinical CR (33%) received local therapy consisting of radiation therapy alone, whereas patients attaining only a clinical PR underwent breast-conserving therapy followed by breast irradiation. All other patients received local therapy consisting of a modified radical mastectomy. With a follow-up of 4 years, there was no difference in the relapse-free survival rate between the 2 treatment arms (57% vs 61%), and the overall survival rate appears to be similar in patients who received primary chemotherapy (78%) compared with standard therapy (81%). Sixty-three percent of patients who received primary chemotherapy were able to undergo breast-conserving operations. 125

Scholl and colleagues, 126 at the Institut Curie, reported on 390 premenopausal women who had tumors measuring a median of 4.5 cm in diameter and who were considered unacceptable candidates for breast-conserving therapy (T1-3, N0-1b). These women were randomized to primary chemotherapy consisting of 4 to 6 FAC treatments, followed by radiation therapy or radiation therapy alone. Operation was performed in both groups of patients after the maximal tumor response, and patients randomized to primary radiation therapy received the identical chemotherapy after operation. With a median follow-up of 66 months, the 5-year survival rates were 84% in the primary chemotherapy group and 78% in the primary radiation group. The objective response rate achieved with primary chemotherapy was 82%. The CR rate increased to 61% in the primary chemotherapy group after radiation therapy, compared with a 41% CR rate in the primary radiation therapy group. The 5-year local recurrence-flee rates were 73% and 81% in the primary chemotherapy and radiation group, respectively. The 5-year breast preservation rate was identical in the primary chemotherapy and primary radiation therapy group (61% vs 63%). 126

In 1995, Powles and colleagues 98 reported on 200 patients younger than 70 years who were randomized to primary chemotherapy consisting of methotrexate, mitoxantrone, mitomycin x 4, and tamoxifen; local surgical therapy (breast-conserving operation and radiation therapy or mastecto-


my); and 4 additional cycles of the same chemoendocrine adjuvant therapy or breast-conserving therapy or mastectomy followed by 8 cycles of adjuvant chemoendocrine therapy. Mitomycin was eventually deleted from the treatment program because of unexpected toxicity with tamoxifen. The primary chemoendocrine program produced an objective response rate of 85%, including 19% with a clinical CR and 10% with a pathologic CR. The breast-conserving rate was superior for patients who received primary chemoendocrine therapy (88%) compared with patients who received postoperative chemoendocrine therapy (77%). 98

In 1988, the NSABP initiated a large randomized clinical trial in patients with operable breast cancer in an effort to compare primary chemotherapy versus standard postoperative adjuvant chemotherapy. 127,~28 Patients were stratified according to age, clinical tumor size, and axillary nodal status. Between 1988 and 1993, 1523 patients were randomized to receive either an operation (lumpectomy or modified radical mastectomy) followed by 4 cycles of AC chemotherapy or primary chemotherapy with 4 cycles of AC followed by an operation. All patients undergoing a lumpectomy received adjuvant radiation therapy, and all patients 50 years of age or older received tamoxifen (20 mg/day) for 5 years after the completion of adjuvant chemotherapy. The overall response rate to primary chemotherapy was 79%, with 36% CR and 43% PR.I. 27,128 Of those patients achieving a complete clinical response to primary chemotherapy, 25% of patients (or 9% of all patients who received primary chemotherapy) actually had a complete pathologic response at operation. Furthermore, 10% of patients with a complete clinical response after primary chemotherapy only had noninvasive cancer (DCIS) in the surgical specimen.~27'128 A secondary aim of this trial was to determine whether the administration of primary chemotherapy resulted in down-staging of the axilla. Fifty-eight percent of the patients who received postoperative chemotherapy were found to have positive axillary lymph nodes at operation, compared with 40% of patients who received primary chemotherapy. These findings demonstrate that primary chemotherapy was able to down-stage the axilla in 18% of patients or 31% of patients who were thought to have positive axillary lymph nodes before treatment. 127,12s There was also evidence that suggested that primary chemotherapy was able to improve the breast conservation rate because 68% of patients who received primary chemotherapy underwent lumpectomy versus 60% of patients who received postoperative adjuvant chemotherapy (an increase of 13%). 127,128 In terms of outcome, there was no difference in the disease- free survival rate, the distant disease-free survival rate, or the overall survival rate between the 2 groups. The results from this trial also suggested


TABLE 10. Ongoing primary chemotherapy trials

Study Description

Overview of results

Efficacy Safety

Docetaxel primary/adjuvant studies: sequential RPR ( n = 3 3 ) T--)Surgery--)AC--)RT RR: 85% 13~

CR: 18% NSABP AC(x4)--)Surgery vs Ongoing

(n=2400 planned) AC(x4) -~T(x4) -~Su rger y vs AC(x4) -~Su rger y-~T(x4)

Institutional trial A(90)-~T(lOO)-~Surgery Ongoing Institutional trial T(100) --)A(80)--~

C(2.5)--)Surgery Ongoing Docetaxel primary/adjuvant studies: combination Institutional trial AT(50/75)--)Surgery Institutional trial AT(60/60) ~Surgery Institutional trial TAC(75/50/500+

ciprofloxacin)--~Surgery Institutional trial T(lOO)--)Surgery

Neutropenia main toxicity, manageable

Ongoing

Ongoing

Ongoing

Ongoing Ongoing Ongoing Ongoing Ongoing Ongoing

Ongoing Ongoing

Patients Design

Pacitaxel primary/adjuvant studies: combination

CALEG 9141 European multicenter

Italian

Italian

Stage II/lll Stage II/111

Early stage

T > 2 c m

Surgery-~AC( x5)q 3 wk +G-CSF -~TL(x4) Surgery--~A-~CM F vs Surgery-~A-~TL-~

CMF vs A-~TL-~CMF Surgery Surgery--~ATL(x4)--~CMF(x4)+RT and TAM

vs ATL(x4)--)Surgery Surgery--~A(x4)--~CMF(x4)+RT and TAM vs

Surgery--~ATL(x4)--~CMF(x4):l:RT and TAM vs ATL(x4)--)CMF(x4)-~Surgery_+RT and TAM

RPR, (Rhone Poulenc Rhorer; 7", docetaxel; A, doxorubicin; C, cyclophosphamide; RT, radiation therapy; RR, response rate; CR, complete response; G-CSF, granulocyte colony-stimulating factor; TL, paclitaxel.

that those patients who achieved a pathologic CR to primary chemotherapy had a statistically significant improvement in the disease-free and overall survival rates. 127,128

Future Directions The results from these trials stimulate continued interest in primary chemotherapy for operable breast cancer. Data from the NSABP B-18 trial suggest that the response to primary chemotherapy correlates with patient outcome, and as a result, the response to primary chemotherapy serves as an intermediate endpoint for the evaluation of new chemotherapy drugs or


biologic agents or combinations containing new agents. Investigational strategies that use primary chemotherapy that lead to an increase in the pathologic CR rate are warranted. New chemotherapy drugs are now in clinical trials to assess their contribution to primary chemotherapy regimens. The most recent drugs approved for the treatment of metastatic breast cancer are the taxanes (eg, paclitaxel and docetaxel). As single agents, both drugs are very active as first-line therapies for metastatic breast cancer. Paclitaxel, using administration schedules that vary from 3 to 24 hours and a dose range from 175 to 250 mg/m 2, produces response rates of 29% to 63%. 129 Docetaxel, administered at 100 mg/m 2 as a 1-hour infusion, produces response rates of 48% to 68%. 129-135 Although most responses in these trials were partial, the significant activity of the taxanes provided opportunities to assess combination regimens, especially with doxorubicin in the metastatic disease setting. These trials have confirmed the activity of the taxane/anthracylcine combination and provide the rationale to evaluate the combination as primary chemotherapy. 136-138

Table 10 summarizes several of the ongoing primary chemotherapy trials that include anthracyclines and taxanes in their design. 139 The immediate preoperative period also provides an opportunity to design clinical experiments that generate and validate hypotheses between prognostic or predictive factors related to the tumor (ie, hormone receptors, p53, c-erB- 2, vascular density, proliferation indices, ploidy) and response to a particular primary chemotherapy program. The next generation of primary chemotherapy strategies will hopefully lead to an improved outcome for patients with operable breast cancer and a better understanding of the biologic features of this disease.

Postmastectomy Radiotherapy Revisited: Implications for Improved Breast Cancer Survival

Few topics in cancer management have generated the same degree of controversy as the use of postmastectomy radiotherapy. Although this was once an established therapy in the treatment of early-stage breast cancer, reports of cardiac death related to its use and the possibility that the routine use of systemic therapy would provide rates of locoregional control comparable to those achieved with radiotherapy have led many physicians to abandon the routine use of adjuvant radiotherapy after mastectomy. Recent data have emerged, however, that have brought this topic again to the forefront for discussion. These data strongly suggest an improvement in the overall breast cancer survival rates because of maximal locoregional control by the addition of postmastectomy radiotherapy.


Historical Perspective of Postmastectomy Radiotherapy Numerous randomized trials have been conducted from the 1940s through the late 1970s that compared local control and overall survival rates in women treated with radical mastectomy, modified radical mastectomy, or total mastectomy followed by either postmastectomy radiotherapy or observation. 14°-148 These trials have been discussed in previous reviews. 149,15° Factors common to many of these trials have affected their long-term results. Specifically, the chest wall was often omitted from the radiotherapy target volume, leaving only the regional lymph nodes in the treatment field. Studies of patterns of failure after mastectomy alone have repeatedly shown the chest wall to be the most common site of locoregional failure, with 1 review noting chest wall involvement in 60% to 85% of all isolated locoregional recurrences.IS1 Thus omission of the chest wall from the treatment field would be expected to result in increased locoregional recurrence. Many of these trials were conducted in the early years during which only orthovoltage equipment was available to deliver the radiotherapy dose that, because of depth-dose limitations, prevented the delivery of a uniform therapeutic dose throughout the target volume.

One of the greatest limitations to the interpretation of the data generated from these trials was the inclusion criteria for the women randomized. These trials often included women with small primary lesions and negative lymph nodes whose risk of locoregional failure was so low that chest wall and nodal prophylaxis was not warranted. Inclusion of these low-risk women reduced the perceivable benefit from radiotherapy in women at significant risk for locoregional failure, such as patients with large primary tumors, positive axiUary lymph nodes, and pectoralis fascia involvement.

The consequences of the fractionation schemes used in many of the early trials and the incorporation of cardiac structures in the treatment volumes have also significantly affected the long-term results of these studies. Although not known at the time, large daily fractions, as often used in the early years of fractionated radiotherapy, result in less normal tissue repair and a higher incidence of chronic tissue damage and long-term sequelae. Photon beams were often directed over the internal mammary lymph node regions, which included substantial volumes of the heart in the radiotherapy beam. As a result, increasing rates of cardiac death were encountered in long-term survivors of breast cancer. In the overview of the randomized trials of radiotherapy after either simple or radical mastectomy by Cuzick and colleagues, ~s2 no differences were detected in the survival rates in patients treated with or without radiotherapy in the first 10 years of follow-up. With follow-up beyond 10 years, however, an excess of deaths was observed among the patients treated with radiother-


apy~ A follow-up report by Cuzick and colleagues 153 of the long-term cause-specific mortality rates in patients treated in these randomized trials identified an excess of cardiac deaths in the patients who had received radiotherapy, most strongly influenced by patients randomized in the earlier radical mastectomy trials. A study of cardiovascular mortality rates in the Stockholm trial, in which techniques were consistent throughout the study, also demonstrated that, in patients who received the highest doses of radiotherapy to the myocardium, significantly increased rates of death from ischemic disease were observed relative to operative controls.l¢3

Reanalysis of the Postmastectomy Randomized Trials Despite the limitations of these postmastectomy trials, every trial demonstrated an improvement in locoregional control with the addition of radiotherapy. Therefore, even with inadequate techniques and doses, some degree of reduction in locoregional failure was observed. However, survival rates were not improved by the addition of radiotherapy, and as noted in the first overview analysis by Cuzick and colleagues, 159 patient survival was impacted negatively by adjuvant treatment. However, reanalysis of the data with increased follow-up resulted in important observations. In the 1994 update of all patients entered into randomized trials for postmastectomy radiotherapy before 1975, information regarding the cause of death was sought for all patients who died more than 10 years after entry into the trial. 153 The mortality rate was no longer significantly greater for patients who had received radiotherapy. Although there was still a negative survival trend overall, it was primarily due to the contribution of patients treated in the earliest trials. With maturation of the data from the more recent trials, an overall survival benefit emerged in favor of radiotherapy. Although an excess of cardiac deaths was seen primarily from patients from the earlier trials, this was offset by a reduction in the number of breast cancer-specific deaths, specifically from the Stockholm, the Manchester Regional, the Cancer Research Campaign, and the NSABP B-04 t r ials . 143"146 The standardized mortality ratio was especially favorable in the Stockholm trial, in which this ratio after radiotherapy versus no radiotherapy was 0.39.143

A further update of the meta-analysis was published in 1995 by the Early Breast Cancer Trialists' Collaborative Group.154 Mortality data were available from 36 trials that compared radiotherapy plus operation with operation alone. Included in these trials were some women treated with breast-conserving therapy. As expected, the addition of radiotherapy to operation reduced the rate of local recurrence, with a 67% reduction in the rate of locoregional relapse compared with operation alone. Patients treat-


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ed with radiotherapy also experienced a 6% reduction in the mortality rate from breast cancer, with an odds ratio of 0.94.

Arriagada and colleagues 155 performed a reanalysis of the event-free survival rates in the Stockholm radiotherapy trial with more than 15 years of follow-up information. In the patients with negative lymph nodes, local failures were reduced 10-fold in the radiotherapy group, but there was no significant difference in the rate of distant metastasis. In the group with positive lymph nodes, however, a 5-fold reduction in local failure was observed after radiotherapy, as well as a significant decrease in distant metastases, with a relative risk of 0.63. Furthermore, when local recurrence was introduced into a Cox model as a time-dependent covariate, it was found to increase the risk of metastases by a factor of 6. Therefore this analysis provided strong evidence that postmastectomy radiotherapy could decrease the rate of distant metastases by preventing local failure and preventing a source for distant dissemination.

In summary, the reanalyses of these trials have demonstrated a reduction in death from breast cancer associated with the use of adjuvant radiotherapy. They also demonstrated the importance of careful treatment planning to minimize cardiac morbidity, such that an even greater survival benefit can be realized after adjuvant radiotherapy.

Postmastectomy Trials With Adjuvant Chemotherapy With or Without Radiotherapy

With the widespread use of chemotherapy in women at risk for systemic recurrence, some physicians have again questioned the role for locoregional radiotherapy after mastectomy. Although retrospective reviews have identified predictors for isolated locoregional failure after mastectomy and systemic therapy to include the number of positive axillary lymph nodes, tumor size, pectoralis fascia involvement, and stage llI disease, 156-159 randomized trials with and without radiotherapy have proved the locoregional benefit with the addition of radiotherapy, t6°-168 As with the trials randomizing women to receive radiotherapy that did not include chemotherapy, every trial has shown a benefit in locoregional control with the addition of radiotherapy to chemotherapy. On the basis of these findings, delivery of chemotherapy alone does not result in maximal locoregional control. The impact of radiotherapy on survival, however, has been the major endpoint of these trials. The largest of the studies are presented in Table 11.

The Mayo Clinic trial was initially designed to compare the outcome after mastectomy alone; mastectomy and postoperative radiotherapy; mastectomy and cyclophosphamide, 5-fluorouracil, and prednisone (CFP); and


mastectomy, CFP, and postoperative radiotherapy in high-risk patients. 16° Later, an additional arm was opened for phenylalanine mustard (L-PAM) alone. The patients eligible for this study included women with positive lymph nodes and/or the presence of unfavorable local signs such as skin, muscle, fascia, or nipple invasion with tumor. As evidence emerged that suggested the benefit of polychemotherapy in premenopausal women with these high-risk characteristics, the study evolved to a 2-arm trial of CFP with or without radiotherapy for premenopausal women and the 2 CFP arms plus the L-PAM arm for postmenopausal women. For patients randomized to receive radiotherapy, only the regional lymph nodes were irra- diated. The chest wall was not included in the target volume unless there was evidence of skin involvement or invasion of the muscle or fascia. Follow-up ranged from 4 to 10.8 years. As expected, the locoregional control was superior in the presence of radiotherapy, with crude rates of control of 74%, 70%, and 90% for patients randomized to L-PAM (arm A), CFP (arm B), and CFP with radiotherapy (arm C), respectively. The 5-year survival rates were 56%, 66%, and 68%, and the 5-year disease-free survival rates were 34%, 48%, and 53% for arms A, B, and C, respectively. A positive trend in the disease-free survival rate was noted in the patients who received both locoregional radiotherapy and systemic treatment.

In the Glasgow study, women with positive axillary lymph nodes were randomized after simple mastectomy and axillary clearance to radiotherapy alone (regimen A); CMF (regimen B); and radiotherapy followed by CMF (regimen C). 161 Radiotherapy was administered with orthovoltage equipment, delivering approximately 250 cGy per day for 15 fractions. With a 63-month median follow-up, crude rates of locoregional recurrence as either isolated failure or simultaneous locoregional and distant failure were 17%, 31%, and 12% for regimens A, B, and C, respectively. The disease-free survival rate was significantly improved in the patients who received both radiotherapy and systemic chemotherapy, with a 5-year disease-free survival rate of 40% with regimen A, 43% with regimen B, and 51% with regimen C (P = .005). A benefit was detected in patients with 3 or fewer and with more than 3 positive lymph nodes, with 5-year disease-free survival rates of 44%, 54%, and 63% in women with 3 or fewer positive l~;mph nodes, respectively (P = .01), and 25%, 22%, and 33% in women with more than 3 positive lymph nodes, respectively (P = .006). In the subgroup with more than 3 lymph nodes, there was a significant benefit in the disease-specific survival rate with combined locoregional and systemic therapy, with 5-year survival rates of 35% after radiotherapy alone, 46% with chemotherapy only, and 54% with both CMF and radiotherapy. This trial demonstrated that, although radiotherapy after


mastectomy decreased the rates of locoregional recurrence, maximal locoregional benefit and disease-specific survival rates were seen with the combination of systemic chemotherapy and radiotherapy.

A similar result was found in the Southwestern Cancer Study Group trial. 165 Patients with 4 or more positive lymph nodes were randomized between CMF for 6 cycles (regimen A), CMF for 12 cycles (regimen B), or locoregional radiotherapy followed by 6 cycles of CMF (regimen C). With a median follow-up of 10 years, a benefit of borderline significance for locoregional control was found for patients who received radiotherapy, with rates of locoregional failure as first failure of 25% for regimen A, 20% for B, and 13% for regimen C (P = .067). Crude rates of relapse were less with the combination of radiotherapy and chemotherapy versus CMF alone, with relapse rates of 61% with arm A, 63% with arm B, and 49% with ann C. The disease-free survival rate was improved for patients on arm C of the trial compared with arm A (P = .07). The overall mortality rate was also less with the combination of radiotherapy and CMF compared with CMF alone, but the differences were not statistically significant.

The MD Anderson trial yielded results that differed from those obtained in the previous trials. 166 This may be, in part, explained by the inclusion of patients with stage 111 disease in the trial, who would have a higher sys~ temic tumor burden compared with patients with stage II disease. This was a study in which patients with technically operable breast cancer were randomized to receive FAC alone or FAC with bacillus Calmette-Guerin. Patients who had not received radiotherapy at the time of referral also were randomized to receive postoperative radiotherapy. Although 238 patients were registered for the study, only 94 women were randomized to receive radiotherapy, and 49 women did not receive radiotherapy. With a median follow-up of 155 months, a benefit in locoregional control was noted with radiotherapy, with a 2% incidence of locoregional failure with radiotherapy versus 14% in the absence of radiotherapy. Radiotherapy had no effect on the disease-free and overall survival rates, with disease-free survival rates of 41% and 48%, with and without radiotherapy at 12 years (P = .74) and overall survival rates of 41% and 51%, respectively (P = .12).

The British Columbian trial and the Danish trial represent the largest and the most recently reported of the randomized trials. ~67,168 The British Columbian trial randomized 318 premenopausal women with lymph node-positive breast cancer treated by modified radical mastectomy and CMF to receive radiotherapy or no radiothrerapy. 167 The radiotherapy consisted of 37.5 Gy delivered in 16 fractions to the chest wall and regional lymph nodes, administered between cycles 4 and 5 of CMF. The chemotherapy consisted of cyclophosphamide (600 mg/m2), methotrexate


(40 mg/m2), and fluorouracil (600 mg/m 2) administered every 21 days intravenously initially for 12 months and after 1981, for 6 months. With a median follow-up of 150 months, the rate of locoregional recurrence was reduced by 56% with the addition of radiotherapy, with the 15-year survival rate free of locoregional disease of 87% with the combination of CMF and radiotherapy versus 67% with CMF only (P = .003). A 33% reduction in the rate of recurrence of breast cancer was noted with CMF plus radiotherapy, for a difference in 15-year disease-free survival rates of 50% versus 33% in favor of combined therapy (P = .007). A 29% reduction in the breast cancer-specific mortality rate was noted with CMF and radiotherapy (P = .05). At the time of publication, a borderline significant benefit in the overall survival rate was seen in the CMF and radiotherapy arm, with survival increased from 46% with CMF to 54% with CMF and radiotherapy (P = .07). The authors noted, however, that more patients in the CMF-alone arm are currently alive with metastatic disease than in the CMF plus radiotherapy arm, so survival differences were likely to increase. When the data were analyzed by the number of positive lymph nodes, the reduction in systemic recurrence was almost identical in the 1 to 3 positive lymph node group (35%) to the 4 or more positive lymph node group (36%). This trial strongly supports a benefit in disease- specific survival because of maximal locoregional control with the addition of comprehensive locoregional radiotherapy to systemic therapy.

Finally, the Danish Breast Cancer Cooperative Group 82b trial randomized 1708 premenopausal women primarily with pathologic stage 11 disease to 8 cycles of CMF and radiotherapy versus 9 cycles of CMF after mastectomy.168 Patients were eligible for the study if the axiUary lymph nodes were involved, the tumor size exceeded 5 cm, or the cancer invaded the skin or pectoralis fascia. Operation consisted of a total mastectomy with a limited axiUary dissection, with a median of 7 lymph nodes removed. The radiation therapy was delivered to the chest wall and regional lymph nodes, administering 50 Gy or its equivalent, usually with megavoltage equipment. Adjuvant chemotherapy consisted of cyclophosphamide (600 mg/m2), methotrexate (40 rag/m2), and fluorouracil (600 mg/m 2) administered intravenously every 4 weeks for 8 cycles for patients randomized to receive radiotherapy and 9 cycles for patients who received chemotherapy alone. For patients assigned to receive radiotherapy, treatment was administered between cycles 1 and 2 of CMF. With a median follow-up of 114 months, the relative risk of locoregional recurrence as a first event was 3.7 among patients treated with CMF, with absolute rates of recurrence of 32% with CMF alone versus 9% with radiotherapy. The 10-year disease-free survival rate was 48% after CMF and radiotherapy compared with 34% with CMF


only (P < .001), and the 10-year overall survival rates were 54% and 45%, respectively, strongly in favor of radiotherapy (P < .001).

When survival rates were compared between patients with tumors of similar size, nodal status, and grade, the addition of radiotherapy was beneficial in all subgroups. Unfortunately, because of the limited nature of the axillary dissections, the magnitude of the benefit of radiotherapy in women with 1 to 3 positive lymph nodes versus 4 or more cannot be determined from this trial. Multivariate analysis for any type of recurrence or death from any cause demonstrated that there was a beneficial effect for radiotherapy regardless of the tumor size, number of positive lymph nodes, or tumor grade. With the number of patients entered into the Danish trial and the duration of follow-up, this study had the power to demonstrate the impact of a locoregional modality on survival. It is important to note that although radiotherapy was the factor that led to the benefit in survival, it was delivered in conjunction with systemic therapy. It appears that, with the administration of systemic therapy to reduce and/or eliminate micrometastatic disease, the benefit of locoregional therapy can be realized.

Critiques of the British Columbian and Danish Breast Cancer 82b Trials

After the simultaneous publication o f the 2 trials, 167,168 considerable debate has ensued regarding the applicability of the data to centers in the United States and whether adjuvant radiotherapy can impact survival rates in the presence of "adequate" systemic therapy. The controversies center around the overall rate of locoregional failure in both studies, the rate of axillary failure, especially in the Danish study, and the dose intensity of the CMF regimens in both trials. The 10-year rate of locoregional failure either as the only site of failure or as a component of fai.'lure in the Danish trial was 32% with CMF alone versus 9% with CMF and radiotherapy. At 10 years in the British Columbian study, the rates of locoregional failure were 25% and 13%, respectively.

Although the rates of locoregional failure are higher than rates reported after mastectomy in the US trials randomizing women with early-stage breast cancer between mastectomy and breast-conserving therapy, the US studies included a majority of women with negative lymph nodes compared with the number of women with positive lymph nodes in the British Columbian and Danish trials. ~°1,169 The absolute rates of locoregional recurrence do not detract from the comparative benefit of the addition of radiotherapy.

In an earlier report of the Danish trial, patterns of failure were presented that indicated that the axilla was the second most common site of locore-


gional failure, with 44% of the locoregional failures having an axiUary component and a 5% axillary failure rate in the overall patient cohort as a site of first failure) 7° The report does state that the median number of axillary lymph nodes dissected was 7. This is less than typically encountered in the United States, where a level I and II dissection represents the standard of care, often yielding 10 or more lymph nodes. As a result of a more thorough dissection, rates of axillary failure are generally less than 3%. 17! Although this may represent a shortcoming in the identification of which patients were truly in the group with 1 to 3 positive lymph nodes in the Danish study, it does not detract from the interpretation of the trial. If a portion of the survival benefit is due to the radiotherapeutic treatment of an inadequately dissected axiUa, then that strengthens the argument that maximal locoregional therapy impacts the survival rate. As we have seen in every trial in which women have been randomized to receive radiotherapy after mastectomy and adjuvant chemotherapy, radiotherapy improved locoregional control beyond that which could be obtained with mastectomy and chemotherapy alone. Therefore, if the only residual disease is in a locoregional site, it is logical that radiotherapy would impact the survival rate.

The CMF regimens used in both of the trials were not equal to the dose intensity of the classic CMF regimen reported by Bonadonna and colleagues.172 However, there are no data to suggest that classic CMF would have altered the rate of locoregional failure. In fact, there are data to suggest the contrary. In the 20-year update of the Milan trial in which women with positive lymph nodes were randomized to receive CMF, a 13% rate of locoregional failure as first failure was noted with CMF versus 15% in the control group. 173 In a relrospective review of women prospectively entered on Cancer and Leukemia Group B trial 8782 for bone marrow transplantation, 3 of the first 9 women entered who did not receive postmastectomy radiotherapy experienced a locoregional failure despite ablative doses of chemotherapy. 174 This can be compared with only. 1 subsequent failure in 34 patients who received locoregional radiotherapy. It appears that regardless of the chemotherapy regimen, as long as chemotherapy is unable to sterilize residual locoregional disease, the principles of these randomized studies hold true.

Further Support of the Importance of Locoregional Control • on Survival

A recent review of the outcome of 857 patients with 10 or more positive lymph nodes was presented by Diab and colleagues 175 from San Antonio. Thirty-five percent of these women received adjuvant-radiotherapy to the chest wall. With a median follow-up of 6 years, a multivariate analysis


TABLE :1.2. Recommendations for postmastectomy radiotherapy

Lymph node-positive disease Premenopausal women

1-3 Positive lymph nodes > 4 Positive lymph nodes

Postmenopausel women ??? 1-3 Positive lymph nodes >4 Positive lymph nodes

T size > 5 cm Stage III disease Positive mastectomy margins

demonstrated that the improvement in local control by radiotherapy was an independent predictor of disease-free (P = .03) and overall survival rates (P = .001). These significant improvements in disease-free and overall survival rates were evident only in patients who had received adjuvant chemotherapy. This is additional evidence that patients who receive chemotherapy are the patients most likely to realize a survival benefit by the addition of locoregional radiotherapy.

Current Recommendations for Treatment The current treatment policies at the University of Michigan for postmastectomy radiotherapy have incorporated the outcomes of the recent randomized trials and are summarized in Table 12. For premenopausal women, we recommend treatment of all patients with positive lymph nodes. Although the absolute locoregional benefit is less in patients with 1 to 3 positive lymph nodes compared with 4 or more, the reduction in the relative risk of a recurrence was comparable between groups in the British Columbian study. In postmenopausal patients, we continue to recommend adjuvant radiotherapy in women with 4 or more positive lymph nodes, based on improvements in locoregional control and the disease-free survival rate. An update is expected soon of trial 82c from Denmark randomizing postmenopausal women with positive lymph nodes who are undergoing tamoxifen therapy to receive radiotherapy or not after mastectomy. This trial may have implications for treatment recommendations for women with 1 to 3 positive lymph nodes. We also recommend treatment in cases of tumors larger than 5 cm, positive surgical margins after mastectomy, and stage m disease.

Radiotherapy Considerations The technique used for the administration of postmastectomy radiotherapy is critical for minimizing the cardiac (and pulmonary) morbidity and mortality rates, especially for left-sided breast cancers. Although it is


FIG 8. Location of internal mammary lymph nodes with respect to cardiac structures and the lungs.

beyond the scope of this monograph to provide specific radiotherapeutic details in treatment planning, interested readers are referred to sources dedicated specifically to technique) 76 Important considerations will be outlined here, however, as a guide when reviewing the literature.

Failure patterns in the absence of radiotherapy have identified the anatom- ic regions requiring postmastectomy prophylaxis. As noted in patients with positive axillary lymph nodes, the chest wall is the most common site of locoregional failure, followed by the supraclavicular region) 5t The axilla and the internal mammary nodal_ regions have not been common sites of failure and, on the basis of failure patterns, have not been treated routinely. However, the recent publications of the Danish and Canadian trials have brought into question whether these regional sites should be included in the radiotherapy field. The Danish trial identified the axilla as the second most common site of locoregional failure in patients randomized not to receive radiotherapy. The median number of lymph nodes removed was 7, which undoubtedly affected the rate of axillary recurrence. Because the rate of axillary recurrence in most series in the United States has generally not exceeded 3% with the dissections conarnonly used, 17t the addition of a radiation field to treat the axilla specifically does not appear to be warranted.

The recent trials incorporated the internal mammary lymph nodes in the


FIG 9. An example of a radiation beam arrangement to encompass target volume that includes the internal mammary lymph node region and to minimize cardiac and pulmonary toxicity.

treatment field. It is impossible to know whether treatment of these lymph nodes contributed significantly to the survival advantage documented by these trials. Although previous randomized studies that did not include systemic therapy have not demonstrated a survival benefit with the resection or irradiation of these lymph nodes in the overall patient groups, 153'177 subset analyses have suggested that patients with medial lesions and positive axillary lymph nodes may derive a benefit from internal mammary lymph node treatment. Conceptually, it is understandable that treatment to these lymph nodes could improve survival because they represent a locoregional site with documented involvement in patients with axillary lymph node-positive disease. The ultimate question of whether treatment to the internal mammary lymph nodes with radiotherapy, in the presence of chemotherapy, will impact survival is currently being tested in a randomized trial being conducted by the European Organization for Research on the Treatment of Cancer (EORTC trial 22922). If, in the meantime, the decision is made to treat these lymph nodes, it is important to develop a treatment plan for each patient indi- vidually, with the aid of computed tomographic planning, given the critical location of the lymph nodes with respect to the heart and lungs 178 (Fig 8).

One example of beam arrangements that can be used is shown in Fig 9. Photon tangent fields, which traverse the full thickness of the tissue, are


used to treat the lateral portion of the chest wall, and electrons, which only travel a prescribed depth, can treat the medial chest wall and internal mammary lymph nodes. As a result, the heart and lungs can be spared a considerable dose. This is particularly important because most women with positive lymph nodes will receive a doxorubicin-based regimen at some point in their management. It should be emphasized that beam arrangements will vary depending on the patient anatomy, and computed tomographic planning is strongly encouraged because it allows individualized treatment planning. The dose prescribed to the chest wall is typically 50 Gy over 5 weeks, with tissue-equivalent material applied to the skin every other day to decrease the skin-sparing effect of megavoltage therapy. For patients with a positive margin or stage III disease, the scar is generally boosted with an additional 10 Gy, for a total dose of 60 Gy. The supraclavicular lymph nodes are commonly treated with 46 to 50 Gy with pho- tons, prescribed to the depth of the lymph nodes, generally to 3 cm.

Future Directions The recent randomized trials, in conjunction with the reanalyses of the earlier studies, have provided a strong basis with which to recommend the routine use of postmastectomy radiotherapy to premenopausal women with positive lymph nodes. Some, however, still question the magnitude of the benefit, particularly in the 1- to 3-lymph node group and in the presence of doxorubicin-based chemotherapy regimens. This question may, again, be put to the test, this time in an American cooperative group study. Data will be forthcoming from the Danish Breast Cancer trial 82c for postmenopausal patients with positive lymph nodes, which will help to establish treatment guidelines for postmastectomy radiotherapy for postmenopausal women. The EORTC trial on internal mammary irradiation will provide valuable information on the importance of including the internal mammary lymph nodes in the radiotherapy treatment fields in patients who are receiving systemic therapy. In the meantime, studies in treatment planning will continue to generate information about the safe administration of radiotherapy to the locoregional target volumes at risk.

We (M.M., V.C.J., H.T., W.J.G.) thank the Lynn Sage Breast Cancer Foundation of Northwestern Memorial Hospital for the continuing support.

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Current controversies in breast cancer management