Initially Metastatic Breast Carcinoma Has a DistinctDisease Pattern but an Equivalent Outcome Comparedwith Recurrent Metastatic Breast Carcinoma

Antonio Jimeno, M.D., Ph.D.1

Marıa Luz Amador, M.D., Ph.D.1

Lucıa Gonzalez-Cortijo, M.D.1

Marıa Victoria Tornamira, M.D.1

Santiago Ropero, Ph.D.1

Vicente Valentın, M.D.1

Javier Hornedo, M.D.1

Hernan Cortes-Funes, M.D., Ph.D.1

Ramon Colomer, M.D., Ph.D.1,2

1 Department of Medical Oncology, Hospital Uni-versitario 12 de Octubre, Madrid, Spain.

2 Department of Medical Oncology, Institut Catalad’Oncologia, Hospital Universitari Dr. Josep Trueta,Girona, Spain.

Dr. Jimeno’s current address: The Sidney KimmelComprehensive Cancer Center, Johns HopkinsUniversity, Baltimore, Maryland.

Address for reprints: Antonio Jimeno, M.D., Ph.D.,The Sidney Kimmel Comprehensive Cancer Center,Johns Hopkins University, 1650 Orleans St., Room162A, Baltimore, MD 21231; Fax: (410) 614-9006;E-mail: ajimeno1@jhmi.edu

Received January 8, 2004; revision received Feb-ruary 3, 2004; accepted February 12, 2004.

BACKGROUND. To date, the clinical features and outcomes of patients with initially

metastatic breast carcinoma (IMBC) have not been compared with the corre-

sponding characteristics in patients with recurrent metastatic breast carcinoma

(RBC). This issue may be particularly relevant to clinical research, as it may shed

light on a potential bias with respect to the selection of patients for clinical trials.

METHODS. A retrospective analysis of the medical records of 1350 patients with

breast carcinoma was performed. Outcome variables included overall survival,

response rate, and progression-free survival.

RESULTS. One hundred nineteen of 370 patients with metastatic breast carcinoma

had IMBC, whereas the remaining 251 had RBC. The median follow-up duration

was 39.4 months, and the median overall survival duration was 24 months. With

regard to clinical characteristics, patients with IMBC were older than patients with

RBC (61.7 years vs. 58.1 years; P � 0.001) and had a higher incidence of lobular

carcinoma (15.9% vs. 7.7%; P � 0.018), a greater proportion of T3– 4 tumors (58.8%

vs. 27.9%; P � 0.001), a higher incidence of bone as the dominant metastatic site

(41.2% vs. 21.5%; P � 0.001), a lower incidence of soft tissue as the dominant

metastatic site (10.1% vs. 26.7%; P � 0.001), and a similar incidence of the viscera

as the dominant metastatic site (48.7% vs. 51.8%; P � 0.78). Median overall survival

duration was similar for patients with IMBC (25.1 months) and patients with RBC

(23.3 months; P � 0.81). Statistical analyses also revealed nonsignificant differ-

ences between patients with IMBC and patients with RBC in terms of response rate

(40.7% vs. 35.2%, respectively; P � 0.35) and median progression-free survival

duration (10.2 months vs. 9.0 months, respectively; P � 0.58).

CONCLUSIONS. Although patients with IMBC and patients with RBC exhibit distinct

histologic and clinical characteristics, similar treatment efficacy results and sur-

vival outcomes are observed in these two groups. Cancer 2004;100:1833– 42.

© 2004 American Cancer Society.

KEYWORDS: prognosis, initially metastatic, recurrence, breast carcinoma.

Breast carcinoma is the second most common cause of malig-nancy-related death among women in the Western world.1 De-

spite improvements in the diagnosis of this malignancy, up to 10% ofpatients with breast carcinoma have metastatic disease at the time ofpresentation.2– 4 In addition, more than 40% of patients with early-stage breast carcinoma eventually will experience recurrence.5 Thus,up to 1 in 30 women will develop metastatic breast carcinoma at somepoint during life.

Metastatic breast carcinoma exhibits a great deal of heterogeneityin its clinical presentation and behavior. Due to the wide array oftherapeutic alternatives that currently are available, prognostic clas-

1833

© 2004 American Cancer SocietyDOI 10.1002/cncr.20204Published online 2 April 2004 in Wiley InterScience (www.interscience.wiley.com).

sification of metastatic breast carcinoma is necessaryfor the identification of optimal therapeutic ap-proaches. Although numerous studies have evaluatedpotential prognostic factors in early-stage breast car-cinoma, only a limited number of reports have exam-ined this issue in the metastatic setting. These reportshave indicated that a number of factors, includingage,6 axillary lymph node status at diagnosis,7–9 dis-ease-free interval (DFI) from the time of diagno-sis,6,8 –10 estrogen receptor (ER) status,8 –12 progester-one receptor (PgR) status,6 Bcl-2 status,6 and site andnumber of metastases,6,8 –12 exhibit prognostic impactwith respect to survival after the diagnosis of meta-static breast carcinoma.

To date, the clinical features and outcomes ofpatients with initially metastatic breast carcinoma(IMBC; any T, any N, M1, according to the TNM clas-sification) have not been compared with the corre-sponding characteristics in patients with recurrentmetastatic breast carcinoma (RBC; rM1, according tothe TNM classification). This issue may have specialrelevance with respect to clinical research, as the pro-portion of patients with IMBC in Phase II and IIIclinical trials is highly variable, ranging from 10% to31%.10,13–16

In the current study, we have compared the clin-ical characteristics and outcomes of patients withIMBC and patients with RBC. In addition, we haveanalyzed the prognostic factors influencing overallsurvival in the current series of patients with meta-static breast carcinoma (initial or recurrent).

MATERIALS AND METHODSPatientsThe computer-based files of patients with breast car-cinoma who were treated at the Hospital Universitario12 de Octubre (Madrid, Spain) between 1992 and 1998were reviewed. Patients with diagnoses of metastaticbreast carcinoma were eligible for the current analysis.The full medical records of patients selected for theanalysis were reviewed. Standard staging proceduresperformed at our institution included chest X-ray,bone scan, abdominal ultrasound evaluation, a panelof hematologic tests, and liver function assays. Pa-tients were considered to have IMBC if systemic dis-ease was evident within 3 months of the initial diag-nosis of breast carcinoma. Patients were considered tohave RBC if metastases had developed during follow-up for localized breast carcinoma. For patients withRBC, the disease-free interval (DFI) was calculatedfrom the time of diagnosis of breast carcinoma to thetime at which recurrence was documented. Patientswith metastatic breast carcinoma at the time of diag-nosis were considered to have a DFI of zero. Patients

were considered to be postmenopausal if the lastmenses had taken place at least 1 year before thediagnosis of metastatic breast carcinoma. Metastaseswere individually recorded by site (skin, lymph nodes,bone, pleura, lung, liver, or central nervous system[CNS]), and for each patient, metastases were classi-fied as predominantly affecting the soft tissue, bone,or viscera.11 Response was evaluated according to theWorld Health Organization criteria. Patients with lo-coregional recurrences who were free of disease fol-lowing surgery were classified as complete respond-ers. Progression-free survival (PFS) was defined as thetime from diagnosis of metastatic disease to last con-tact or disease progression. Overall survival (OS) wasdefined as the time from diagnosis of metastatic dis-ease to last contact or death.

The demographic, histologic, and clinical vari-ables that were examined included age and meno-pausal status at the time of diagnosis of metastaticbreast carcinoma, body mass index, tumor size at thetime of initial diagnosis of breast carcinoma, numberof positive lymph nodes, histologic type, tumor grade,ER and PgR status, year of initial diagnosis of disease,adjuvant treatment received, DFI, number of recur-rence sites, dominant site of metastasis, response tofirst-line therapy for metastatic disease, and allocationto the IMBC or RBC group. The study protocol wassubmitted for review, and approval was granted by theinstitutional review board (IRB) at our institution. Inaccordance with national laws and in light of the non-interventional, retrospective nature of the currentstudy, informed consent was obtained from living pa-tients, and a waiver allowing the use and analysis ofnon-identifing information from patients who haddied was furnished by the IRB.

Statistical AnalysisComparisons involving categoric and continuous vari-ables were performed using the chi-square test andthe Mann–Whitney test, respectively. Univariate anal-yses of survival were performed by calculatingKaplan–Meier survival curves and comparing subsetsof patients using log-rank tests. Multivariate analysisof potential prognostic factors was performed to gen-erate a Cox proportional hazards model. All tests weretwo-sided, with P � 0.05 being taken as an indicator ofsignificance. The SPSS statistical package (Version10.0; SPSS Inc., Chicago, IL) was used for all statisticalanalyses.

RESULTSOut of a total of 1350 patients who were diagnosedwith breast carcinoma during the 7-year study period,392 (29%) were identified as having metastatic breast

1834 CANCER May 1, 2004 / Volume 100 / Number 9

carcinoma. One hundred twenty patients (8.9%) pre-sented with metastatic disease at the time of the initialdiagnosis, whereas 272 patients experienced diseaserecurrence following a case of localized breast carci-noma. Twenty-two patients were not included in theanalysis for the following reasons: loss of patient tofollow-up (n � 13), insufficient histologic data (n � 6),and equivocal disease staging (n � 3). Complete datawere available for the remaining 370 patients, whosecharacteristics are summarized in Table 1. Age at di-agnosis of metastatic disease exhibited a unimodaldistribution. The overall median follow-up durationamong patients with metastatic disease was 39.4months, and the median OS from the time of diagno-sis of metastatic disease was 24 months (95% confi-dence interval [CI], 20.7–27.3 months). The estimated5- and 10-year survival rates were 24.0% and 11.5%,respectively. At the time of the analysis, 113 patientswere alive, including 47 who had no evidence of dis-ease progression. Two deaths in the current studycohort were not malignancy related; one was due toacute myocardial infarction, and the other was due tostroke. The median PFS duration was 9.6 months (95%CI, 8.1–11.1 months).

Two hundred forty-two patients in the RBC group(96.4%) had received some form of adjuvant treat-ment. Ninety-one patients (36.1%) had received an-thracycline-based chemotherapy; 25 (9.9%) had re-ceived high-dose chemotherapy; and 54 (21.5%) hadreceived the cyclophosphamide, methotrexate, and5-fluorouracil (CMF) chemotherapy regimen. Onehundred fifty-two patients in the RBC group (60.5%)had received adjuvant hormonal therapy; tamoxifenwas used as the endocrine agent for 146 of thesepatients. Finally, 149 women in the RBC group (59.4%)had received adjuvant radiotherapy.

Comparison of the IMBC and RBC GroupsClinical characteristics and therapyOf the 370 patients with metastatic breast carcinomain the current study, 119 had IMBC, and the remaining251 had RBC. The characteristics of these two patientgroups are summarized in Table 1. Patients with IMBCwere significantly older than patients with RBC (61.7years vs. 58.1 years; P � 0.001), and the proportion ofpostmenopausal patients was greater in the IMBCgroup than in the RBC group (77.3% vs. 70.5%; P� 0.02). The IMBC group also had a higher proportionof T3– 4 tumors (58.8% vs. 27.9%; P � 0.001), a lowerproportion of N0 tumors (11.4% vs. 30.2%; P � 0.002),a higher percentage of patients with � 10 positivelymph nodes (34.3% vs. 21.0%; P � 0.02), and a higherpercentage of patients with unknown axillary lymphnode status (41.2% vs. 1.2%; P � 0.001). Analysis of

histologic characteristics revealed a significant differ-ence in the incidence of lobular carcinoma betweenthe IMBC group and the RBC group (15.9% vs. 7.7%,respectively; P � 0.018). There was no difference be-tween the two groups in terms of grade of tumordifferentiation, ER status, or PgR status.

With regard to clinical characteristics, the per-centage of patients who had multiple metastatic siteswas similar in both groups; 47.1% and 39.9% of pa-tients in the IMBC group and the RBC group, respec-tively, had 2 or more metastatic sites (P � 0.21). Com-pared with the RBC group, the IMBC group containeda smaller proportion of patients whose metastasespredominantly affected soft tissue (10.1% vs. 26.7%; P� 0.001), a larger proportion of patients whose metas-tases predominantly affected bone (41.2% vs. 21.5%; P� 0.001), and a similar proportion of patients whosemetastases affected the viscera (48.7% vs. 51.8%; P� 0.78). Comparison of incidence rates for metastasesat specific sites revealed that bone metastases weresignificantly more common in the IMBC group (69.7%vs. 38.2%; P � 0.001), whereas skin metastases wereless common (10.1% vs. 33.1%; P � 0.001). Lymphnode, pleural, lung, liver, and CNS metastases wereequally common in both groups.

Data on therapeutic decisions revealed that pa-tients with IMBC were treated more aggressively. Theproportion of patients in the IMBC group who re-ceived combined chemoendocrine treatment (con-comitantly and/or sequentially) was significantlygreater than the corresponding proportion in the RBCgroup (29.4% vs. 12.3%; P � 0.001). The percentage ofpatients who received any chemotherapy also washigher in the IMBC group (63.9% vs. 54.9%; P � 0.044),as was the percentage of patients who received anyendocrine therapy (65.5% vs. 57.4%; P � 0.041). Fur-thermore, the types of chemotherapy and endocrinetherapy that were used differed between groups.Whereas patients with IMBC were treated primarilywith anthracycline-based chemotherapy (75.0%) orCMF (13.1%), most patients with RBC were treatedwith taxanes (41.8%), anthracycline-based chemother-apy (24.6%), or vinca alkaloid– based chemotherapy(18.0%). Tamoxifen was used as the first-line endo-crine agent for 97.4% of patients in the IMBC group,compared with only 35.0% of patients in the RBCgroup. Aromatase inhibitors (42.9%) were the mostcommonly used endocrine agents in the RBC group.

OutcomeThe overall rates of response to first-line therapy weresimilar in the IMBC group and the RBC group (40.7%vs. 35.2%, respectively; P � 0.35). The complete re-sponse rates in these two groups were 12.7% and

MBC Prognosis Is Unrelated to Presentation/Jimeno et al. 1835

TABLE 1Patient Characteristics, with Comparison of Clinical Characteristics and Outcomes between Patients with Initially Metastatic Breast Carcinomaand Patients with Recurrent Breast Carcinoma

Variable

No. of patients (%)

PAll patients (n � 370) IMBC group (n � 119) RBC group (n � 251)

Age at diagnosis (yrs)Mean � SD 59.8 � 14.1 61.7 � 12.8 58.1 � 14.3 � 0.001

Menopausal statusPremenopausal 101 (27.3) 27 (22.7) 74 (29.4) 0.02Postmenopausal 269 (72.7) 92 (77.3) 177 (70.5)

BMI (kg/m2)Mean � SD 27.5 � 5.2 27.8 � 5.4 27.4 � 4.6 0.57

T status at diagnosisT1–2 217 (58.6) 49 (41.2) 181 (72.1) � 0.001T3–4 153 (41.3) 70 (58.8) 70 (27.9)

Lymph node statusKnown 318 (86.0) 70 (58.8) 248 (98.8) � 0.001Unknown 52 (14.0) 49 (41.2) 3 (1.2)

No. of positive lymph nodes0 83 (22.4) 8 (11.4) 75 (30.2) 0.0021–3 88 (23.8) 18 (25.7) 70 (28.2) 0.684–10 71 (19.2) 20 (28.6) 51 (20.6) 0.16� 10 76 (20.5) 24 (34.3) 52 (21.0) 0.02

Histologic typeDuctal 322 (87.0) 95 (79.8) 227 (90.4)Lobular 37 (10.0) 18 (15.1) 19 (7.6) 0.018Other 11 (3.0) 6 (5.0) 5 (2.0)

Grade of differentiationWell or moderately differentiated 181 (48.8) 63 (52.9) 118 (47.0) 0.20Poorly differentiated 189 (51.2) 56 (47.1) 133 (53.0)

Estrogen receptor statusPositive 209 (56.5) 71 (60.3) 138 (55.0) 0.34Negative 161 (43.5) 48 (39.7) 113 (45.0)

Progesterone receptor statusPositive 146 (39.4) 45 (38.1) 101 (40.4) 0.67Negative 224 (60.5) 74 (61.9) 150 (59.6)

DFI (mos)� 24 229 (61.9) 119 (100.0) 110 (43.8) � 0.001� 24 141 (38.1) 0 (0.0) 141 (56.2)

No. of sites of metastatic disease1 214 (57.8) 63 (52.9) 151 (60.1) 0.21� 2 156 (42.2) 56 (47.1) 100 (39.9)

Dominant site of metastatic diseaseSkin or soft tissue 79 (21.4) 12 (10.1) 67 (26.7) � 0.001Bone 103 (27.8) 49 (41.2) 54 (21.5) � 0.001Viscera 188 (50.8) 58 (48.7) 130 (51.8) 0.78

Metastatic sitea

Skin 95 (25.6) 12 (10.1) 83 (33.1) � 0.001Lymph nodes 75 (20.2) 25 (21.0) 50 (19.9) 0.89Bone 179 (48.3) 83 (69.7) 96 (38.2) � 0.001Pleura 47 (12.7) 18 (15.1) 29 (11.6) 0.40Lung 108 (29.2) 30 (25.2) 78 (31.1) 0.39Liver 69 (18.6) 21 (17.6) 48 (19.1) 0.77CNS 15 (4.1) 5 (4.2) 10 (4.0) 0.92

First-line therapy for metastatic diseasea

CT 210 (56.7) 76 (63.9) 134 (54.9) 0.044ET 218 (58.9) 78 (65.5) 140 (57.4) 0.041CT alone 145 (39.2) 41 (34.5) 104 (42.6) 0.61ET alone 153 (41.3) 43 (36.1) 110 (45.1) 0.54CT � ET 65 (17.6) 35 (29.4) 30 (12.3) � 0.001None 7 (1.9) 0 (0.0) 7 (2.8) 0.102

(continued)

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16.7%, respectively (P � 0.43); this difference may beattributable to the classification of surgically resectedlocal recurrences (n � 16) as complete responses. Amarginally significant difference in partial responserate in favor of patients with IMBC (28.0% vs. 18.4%; P� 0.05) also was noted, as was a significantly higherrate of disease progression as the best response totherapy among patients with RBC (17.8% vs. 27.8%; P� 0.048). Comparison of overall response rates forpatients who received chemotherapy alone (41.5%[IMBC] vs. 31.7% [RBC]; P � 0.13), patients who re-ceived endocrine therapy alone (30.2% [IMBC] vs.32.7% [RBC]; P � 0.35), and patients who receivedcombined treatment (51.4% [IMBC] vs. 56.7% [RBC]; P� 0.54) revealed no significant differences betweenthe two study groups.

With regard to survival, the primary endpoint ofthe current study, there was no difference between theIMBC group and the RBC group (Fig. 1). The medianOS after the diagnosis of metastatic disease was 25.1months (95% CI, 20.6 –29.4 months) for patients withIMBC and 23.3 months (95% CI, 18.5–27.2 months; P� 0.81) for patients with RBC. In addition, patients inthe IMBC group had a median PFS of 10.2 months

(95% CI, 8.6 –11.5 months), similar to the median PFSof 9 months (95% CI, 7.5–10.5 months) that was ob-served in the RBC group (P � 0.58).

Analysis of Prognostic Factors in Metastatic BreastCarcinomaAll prognostic analyses were performed consideringthe entire series of 370 patients as a whole. Histologicfactors associated with poor outcome included T3– 4tumor size classification (P � 0.001), � 4 positiveaxillary lymph nodes (P � 0.018), poor tumor differ-entiation (P � 0.0025), negative ER status (P � 0.001),and negative PgR status (P � 0.001). Clinical charac-teristics associated with poor outcome included vis-ceral involvement (P � 0.001), multiple metastaticsites (P � 0.001), the absence of a complete responseto first-line therapy (P � 0.001), and DFI � 24 months(P � 0.0012). ER-positive patients had significantlyhigher rates of response to treatment compared withER-negative patients (45.2% vs. 27.1%; P � 0.001);likewise, the response rate for PgR-positive patientswas significantly higher than the response rate forPgR-negative patients (46.6% vs. 31.4%; P � 0.006).Nonetheless, ER status was not predictive of a com-

TABLE 1(continued)

Variable

No. of patients (%)

PAll patients (n � 370) IMBC group (n � 119) RBC group (n � 251)

Chemotherapy for metastatic diseaseAnthracycline-based 90 (42.8) 57 (75.0) 33 (24.6) � 0.001CMF 17 (8.1) 10 (13.1) 7 (5.2) 0.003Taxanes 57 (27.1) 1 (1.3) 56 (41.8) � 0.001HDCT 19 (9.0) 5 (6.6) 14 (10.4) 0.57Vinca alkaloid–based 27 (12.8) 3 (4.0) 24 (18.0) 0.015

Endocrine therapy for metastatic diseaseTamoxifen 125 (57.3) 76 (97.4) 49 (35.0) � 0.001Aromatase inhibitors 60 (27.5) 0 (0.0) 60 (42.9) � 0.001Other 33 (15.1) 2 (2.6) 31 (22.1) 0.001

Response to first-line treatmentComplete response 56 (15.5) 15 (12.7) 41 (16.7) 0.43Partial response 78 (21.6) 33 (28.0) 45 (18.4) 0.05Stable disease 140 (38.5) 49 (41.5) 91 (37.1) 0.41Progressive disease 89 (24.4) 21 (17.8) 68 (27.8) 0.05

Global response to first-line treatmenta

Any therapy (%) 36.9 40.3 35.2 0.35CT alone (%) 34.5 41.5 31.7 0.13ET alone (%) 32.0 30.2 32.7 0.89CT � ET (%) 53.8 51.4 56.7 0.54

Survival rate (95% CI)Overall 24.0 (20.7–27.3) 25.1 (20.6–29.4) 23.3 (18.5–27.2) 0.81Progression-free 9.6 (8.1–11.1) 10.2 (8.6–11.5) 9.0 (7.5–10.5) 0.58

IMBC: initially metastatic breast carcinoma; RBC: recurrent breast carcinoma; SD: standard deviation; BMI: body mass index; DFI: disease-free interval; CNS: central nervous system; ET: endocrine therapy; CMF:

cyclophosphamide, metothrexate, 5-fluoruracil; HDCT: high-dose chemotherapy.a Sum of percentages may exceed 100%.

MBC Prognosis Is Unrelated to Presentation/Jimeno et al. 1837

plete response to treatment; complete response rateswere 16.3% for ER-positive patients and 12.3% forER-negative patients (P � 0.29). In contrast, PgR-pos-itive patients had a significantly higher complete re-sponse rate compared with PgR-negative patients(20.3% vs. 10.9%; P � 0.02). Year of diagnosis (1992–1995 vs. 1994 –1998) was not associated with outcomein the current study cohort. Results of the univariateanalysis of potential prognostic factors are summa-rized in Table 2. Cox regression analysis was used toevaluate the independent prognostic impact of eachvariable (Table 3). On multivariate analysis, larger tu-mor size (T3– 4; P � 0.025), negative PgR status (P� 0.007), multiple metastatic sites (P � 0.014), visceralinvolvement (P � 0.014), and the absence of a com-plete response to first-line therapy (P � 0.001) werefound to be independently associated with a shorterOS from the time of diagnosis of metastatic disease.Figure 2 presents OS results in association with eachof these independent variables.

DISCUSSIONIn the current series, the incidence of IMBC wasslightly greater than the reported incidence figure (de-rived from cancer registry data) for Stage IV breastcarcinoma in the European Union.4 Our hospital-based study may have overestimated the incidence ofIMBC, particularly because all cases in which metas-tases were detected within the first 3 months aftersurgery were classified as IMBC.

Comparison of the clinical characteristics of pa-tients with IMBC and patients with RBC revealed cer-tain marked differences between the two groups. Pa-tients with IMBC tended to be older and to present

FIGURE 1. Overall survival of patients with initially metastatic breast carci-

noma (IMBC) and patients with recurrent breast carcinoma (RBC).

TABLE 2Median Overall Survival According to Potential Prognostic Variables:Univariate Analysis

VariablemOS in mos(95% CI) P

All patients 24.0 (20.7–27.3)Age at diagnosis (yrs)

� 50 23.3 (19.5–27.7)� 50 24.9 (20.6–29.3) 0.76

Menopausal statusPremenopausal 24.9 (20.6–29.2)Postmenopausal 23.0 (18.3–27.7) 0.81

BMI (kg/m2)Greater than median 37.0 (22.6–51.4)Less than median 22.2 (18.5–25.8) 0.11

Yr of diagnosis1992–1995 26.0 (21.7–30.3)1996–1998 19.9 (15.6–24.2) 0.07

T classification at diagnosisT1–2 28.6 (23.5–33.7)T3–4 18.0 (13.9–22.0) � 0.001

No. of positive lymph nodes0 29.5 (17.8–41.3)1–3 31.9 (23.5–40.4)4–10 24.8 (18.3–31.5)� 10 18.9 (15.5–22.3) 0.018

Histologic typeDuctal 25.1 (21.1–28.9)Lobular 17.0 (7.9–26.3) 0.16

Grade of differentiationWell or moderately differentiated 37.1 (29.1–45.0)Poorly differentiated 20.7 (16.4–25.0) 0.0025

Estrogen receptor statusPositive 29.0 (22.2–35.8)Negative 16.1 (13.1–18.9) � 0.001

Progesterone receptor statusPositive 50.4 (36.7–64.1)Negative 17.0 (14.5–19.7) � 0.001

Adjuvant treatmentYes 21.4 (17.3–25.5)No 26.0 (19.0–33.0) 0.18

DFI (mos)� 24 20.1 (17.0–23.0)� 24 33.2 (27.8–38.2) 0.0012

No. of metastatic sites1 29.0 (22.6–35.5)� 2 15.0 (11.1–18.9) � 0.001

Dominant site of metastaticdisease

Skin or soft tissue 38.0 (14.6–61.4)Bone 37.0 (19.9–54.0)Viscera 15.0 (12.7–17.3) � 0.001

Response to treatmentComplete response 65.1 (45.6–84.6)Partial response 27.7 (20.8–34.6) � 0.001Stable disease 24.0 (19.8–28.2)Progressive disease 6.4 (4.3–8.5)

mOS: median overall survival; CI: confidence interval; BMI: body mass index; DFI: disease-free interval.

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with larger tumors and more advanced lymph nodestatus; this difference in lymph node status was biasedby the fact that lymph node staging was not performedfor a large proportion of patients with IMBC. Someinvestigators have reported that older patients tend topresent with more advanced disease,17,18 and our datasupport this assertion. Nonetheless, this finding mayindicate that larger tumor size is not a distinctiveattribute of IMBC but rather a consequence of delayeddiagnosis.

The incidence of lobular carcinoma was found tobe greater in the IMBC group than in the RBC group.Differences in the pattern of metastatic spread be-tween invasive ductal carcinoma and lobular carci-noma are well known, with lobular carcinoma beingmore prone to bone and serosal spread19,20; however,to date, no such differences in terms of initial meta-static spread have been reported.21

There were noteworthy differences between thetwo groups in terms of the pattern of metastatic dis-semination. These dissimilarities may be indicative ofdifferences in tumor biology,19,20 or they may simplybe a consequence of delayed diagnosis in the IMBCgroup; the predominance of a clinically silent diseasetype (e.g., osseous malignancy) may account for suchdelays. Although the association between hormonereceptor status and bone metastases is widely ac-cepted,7,22 this association was not observed in thecurrent study.

Treatment was more homogeneous in the IMBCgroup than in the RBC group, with combined che-moendocrine therapy being more common for pa-tients with IMBC. This finding suggests that in themetastatic setting, treatment generally is influencedby prior therapy; the fact that most patients with RBChad previously received adjuvant therapy may havediscouraged clinicians from using combined ap-proaches.

Although they must be interpreted with caution,the clinical response data that were obtained mayreflect a trend toward decreased therapeutic efficacy

among patients with recurrent disease. It is not yetknown whether this trend is a consequence of the useof less intensive first-line therapy for patients withmetastatic disease, resistance resulting from priortherapy, or a more aggressive pattern of disease. Al-though the current study was not designed to addressthis issue, it is noteworthy that a higher response ratewas observed among patients who received combinedchemoendocrine therapy. It has been suggested thatcompared with chemonaive patients, patients whohave received adjuvant chemotherapy (and especiallyanthracycline-based adjuvant chemotherapy) are lesslikely to respond to subsequent treatment for meta-static disease.16,23–26

It is noteworthy that with respect to OS, the pri-mary outcome endpoint in the current study, therewas no difference between the IMBC group and theRBC group; to our knowledge, the current study rep-resents the first time that this comparison has beenperformed. This equivalence in OS results may beattributable to the observed balance between theIMBC group and the RBC group with respect to inde-pendent prognostic factors; similar distributions werenoted in both groups with respect to three of the fiveprognostic factors that were identified (PgR status,number of metastatic sites, and visceral dominance),the IMBC group exhibited marginally more favorablecharacteristics with respect to one prognostic factor(response to treatment), and the RBC group exhibitedmore favorable characteristics with respect to the re-maining prognostic factor (tumor size).

Clark et al.7 found that tumor size was associatedwith OS on univariate analysis but not on multivariateanalysis; this conclusion also has been reported byother investigators.9,27 For the current study cohort,only PgR status maintained its prognostic significancefollowing Cox regression analysis. Hormone receptorstatus has been reported to be a prognostic factor forpatients with MBC in a number of studies8,10 –12,27,28;however, in the majority of these studies, only ERstatus was assessed. Recent reports have concludedthat PgR status may be a more accurate predictor ofsurvival6 and a better indicator of response to endo-crine therapy following disease recurrence.29 With re-spect to visceral involvement, number of metastaticsites, and response to first-line therapy, the results ofthe current study are consistent with previous re-ports.6,8 –12,30 –34 It is noteworthy that the median OSduration was equivalent for patients who had partialresponses and patients who had stable disease; thisfinding has been noted by others as well.35 Axillarylymph node status at diagnosis did not predict out-come in the metastatic setting; this result was consis-

TABLE 3Factors Independently Associated with Overall Survival: MultivariateAnalysis

Variable HR (95% CI) P

T3–4 disease 1.22 (1.02–1.44) 0.025Positive PgR status 0.52 (0.32–0.83) 0.007� 2 metastatic sites 1.45 (1.04–2.02) 0.025Soft tissue or bone as dominant site 0.29 (0.10–0.78) 0.014Absence of complete response to therapy 1.83 (1.49–2.25) � 0.001

HR: hazard ratio; CI: confidence interval; PgR: progesterone receptor.

MBC Prognosis Is Unrelated to Presentation/Jimeno et al. 1839

FIGURE 2. Independent prognostic factors for overall survival. (A) Tumor size. (B) Progesterone receptor (PgR) status. (C) Number of metastatic sites. (D)

Nonvisceral/visceral dominance. (E) Response type.

1840 CANCER May 1, 2004 / Volume 100 / Number 9

tent with the findings of some studies6,27,36,37 but in-consistent with the findings of others.7–9,38

In conclusion, although the IMBC group and theRBC group differed in terms of clinical and histologiccharacteristics, survival outcomes were similar in bothgroups. In addition, the prognostic factors identifiedin the current series were consistent with those pre-viously reported in the literature.

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