MEDICAL GRANDROUNDS

JYN A. CABAL M.D.March 15, 2007

OBJECTIVES:• To present a case of invasive ductal

carcinoma• To give new updates regarding breast

cancer diagnosis and management

General Data• L.H.• 54 year-old• Female• Single• Nulliparous

First Cycle of Chemotherapy

History of Present Illness8 weeks PTA (+) mass on right outer

upper quadrant R breast on routine x-ray mammographyConsult done, on P.E.: (+) 6.5 cm mass on right outer upper & lower quadrant in largest diameter, no skin lesions, dimpling, nipple discharge or inversion

6 weeks PTA

4 weeks PTA

MR mammography breast core needle biopsy: Invasive Ductal Ca Grade III

R modified radical mastectomy

MR MAMMOGRAPHY

Scanty fibroglandular tissue, both breasts 2.4 x 3.6 x 3.7 cm enhancing

lobulated mass on upper outer quadrant of R breast, highly suspicious of malignancy0.6cm x 0.6 cm enhancing nodule in 6 o’ clock position of L breast

CORE NEEDLE BIOPSY• INVASIVE DUCTAL CA, GRADE III

• IMMUNOHISTOCHEMISTRY (IHC)ER 1+, PR 2+, HER-2/neu 3+

Histopathology

Invasive Ductal CaNuclear Grade IIIHistologic Grade III

3.9 cm in widest diameter

Axillary LN Negative (19 LN)

Histopathology - Stanford

• Estrogen receptor 3+, 95%• Progesterone Receptor 3+, 30%• HER-2/neu (-) for FISH (Fluorescence In

Situ Hybridization)

ER Assay

PR Assay

IHC – Her-2

DIAGNOSTICS• CT Scan of whole abdomen – fatty

infiltrating changes in the liver

• Bone Scan – no evidence of metastatic disease to the bone

DIAGNOSTICS• CBC

Hgb – 12.8 Lymphocytes - 35

Hct – 37 PC – 297 TWBC – 5300Segmenters - 53

Past Medical History• (+) Hypertension for 4 years on

Irbesartan 150 mg OD• 1993 -- (+) L ovarian cyst excision

borderline serous papillary tumor -- (+) TAH-BSO given Premarin

as hormone replacement therapy x 2 years

Personal/Social History• Single• Nulliparous• Non-smoker• Non-alcoholic beverage drinker

Menstrual History

• Menarche at age 17• Surgical menopause at age 41

Family History• (+) Colon Cancer, RCC – mother, 90y/o• (+) Gastric Cancer – father, deceased• (-) Breast Cancer• (+) HPN – maternal side• (-) Diabetes Mellitus• (-) Asthma

Review Of Systems(-) weight loss

(-) anorexia

(-) headache

(-) fever

(-) dyspnea

(-) cough

(-) chest pain

(-) palpitations

(-) orthopnea

(-) dysphagia

(-) constipation

(-) diarrhea

(-) dysuria

Physical Examination• General awake, conscious, coherent,

not in cardiopulmonary distress• BP- 120/70 HR- 70 RR- 36.2 T-

36.5• Wt- 68 kilos Ht- 167 cms. BSA- 1.77• BMI- 24.4 (overweight)

Neck trachea midline, freely movable, thyroid not palpable; no lymphadenopathy

Breast (+) 15 cm incisional scar on R ant chest wall, no lymphadenopathy, no skin lesions; L breast: no mass, skin dimpling, nipple discharge

Chest and Lungs symmetric chest expansion, tactile fremitus symmetric, resonant percussion throughout, no crackles, no wheezes

HeartApex beat and PMI at 5th intercostal space, LMCL; S1 heard best at apex, S2 heard best at base, no murmurs; regular rhythm

Abdomen full, soft, nontender; liver, spleen, and kidney not palpable

Lymphatic no palpable lymph nodes in neck, supraclavicular, axillary, epitrochlear, or inguinal areas

Musculoskeletal muscles appear symmetric with appropriate and equal strength bilaterally, full range of active and passive motion

Salient Features• 54 year old• Female• Single• Nulliparous• History of HRT use• History of family cancer

Admitting Impression

Doxorubicin (Adriamycin) 60 mg/m IV

Cyclophosphamide 600 mg/m IV

INVASIVE DUCTAL CARCINOMA

RISK FACTORS • Age• Current or prior

hormone replacement therapy

• Ethnicity/race• Family history of

breast cancer• Early menarche• Late menopause• Older age at first live

childbirth

• Atypical Hyperplasia/LCIS

• Genetic mutations such as BRCA ½ genes

• Prior thoracic RT• BMI• Alcohol consumption

Risk Factor – HRT Use• Women 50-64 years of age showed an

association between current use of estrogen-only HRT and increased risk of breast cancer

(Beral V. Lancet. 2003;362:419-427)

• Nurses’ Health Study demonstrated a significantly increased breast cancer risk after long term use (20 years or longer) of estrogen alone

(Chen WY, Manson JE, Hankinson SE, et al. Arch Intern Med. 2006;166:1027-1032)

Breast Cancer Work UpHistory and P.E.Breast Imaging:

Mammogram Breast ultrasoundMagnetic Resonance Imaging

Breast Cancer Work UpBreast BiopsyTumor tests: Estrogen receptors

Progesterone receptorsHER-2/neu/cerb-b2

Other tests: CBC, platelet count, CXR, liver function tests, CT Scan, PET Scan

MRI in Patients with Breast Cancer: Current Applications• Detects cancer that is occult on

conventional imaging such as mammography and sonography

• In preoperative evaluation, it can detect multifocal and multicentric disease that was previously unsuspected which facilitates accurate staging

• For patients who have undergone lumpectomy, it can be helpful in assessment of residual tumor load

• Can be helpful to diagnose recurrence when conventional imaging and P.E. are non-confirmatory

• Can assess response to neoadjuvant chemotherapy for locally advanced breast ca

• Patient selection for preoperative breast MRI:

•Young patient•Patient with dense or moderately dense breasts

•Patients with difficult tumor histologic findings such as infiltrating lobular carcinoma and tumors with extensive intraductal component in which tumor size assessment is difficult

Tumor Tests• ESTROGEN and PROGESTERONE RECEPTORS

- are parts of cells that attach to hormones estrogen and progesterone; serve as “welcome mats”

- Hormone Receptor Assay: ER (+) and PR (+) – response rate of 70% ER (+) and PR (-) – response rate of 30% ER (-) and PR (-) – response rate of 10%- tumors that lack either or both of these

receptors are more likely to recur than tumors that have them

Tumor Tests

• HER-2/neu/cerb-B2 oncogene- codes for a surface membrane

receptor that interacts with an unidentified growth factor and is frequently amplified in human breast carcinoma

- mapped to chromosome 17

TESTS for HER-2/neu • IMMUNOHISTOCHEMISTRY

- test that detects HER-2/neu protein on the surface of the cell by staining the cell with antibodies

- can be 0, 1+ (negative), 2+ (borderline),

3+ (positive)- if IHC 2+, have the tissue tested

with FISH test

Tests for HER-2/neu• FLOURESCENCE IN SITU HYBRIDIZATION

(FISH)- gold standard for confirmatory testing- measures HER-2 gene abnormality - “paints” the HER-2 genes inside the

cell so they may be accurately counted- may be (+) or (-)

** All in all, IHC has been shown to miss 15-20% of positive specimens compared with less than 5% with FISH

• Only tests IHC 3+ or FISH (+) respond well to therapy that work against HER-2

Risk Categories for Node Negative Breast Cancer (Alberta Breast Cancer Program 2006)

Risk Category Risk Factors

Low - < 1 cm, no negative risk factors- 1 - 2 cm, grade 1, no negative risk factors 

High - 1 - 2 cm with any 2 or more negative risk factors,- 2 - 3 cm with any one negative risk factor,- any > 3 cm (regardless of other risk factors)

Intermediate all other combinations of factors that do not fit into either the low or high risk criteria above

NEGATIVE RISK FACTORS

- histologic grade 3- estrogen receptor negative- cerbB2 overexpression- presence of lymph/vascular invasion- age < 35 years  

Surgical Procedures of Breast Ca• Lumpectomy/Breast Conservation Therapy

• Simple Mastectomy

• Modified Radical Mastectomy

• Radical Mastectomy

Surgical Procedures of Breast Ca

Lumpectomy vs Mastectomy• Mastectomy with axillary LN

dissection or breast-conserving therapy with lumpectomy, axillary dissection, & whole breast irradiation are medically equivalent primary treatment options in the majority of women with Stage I and Stage II breast cancers.(Fisher B, et al.. N Engl J Med October 17, 2002;347:1233-41. )

• Survival outcomes for young women with breast cancer receiving either breast-conserving therapy or mastectomy are similar

(Kroman N, Holtveg H, Wohlhart J, et al. Effect of breast conserving therapy vs redical mastectomy on prognosis for young women with breast ca. Cancer 2004; 100:688-693)

Lumpectomy or breast conservation therapy is usually not recommended for:

• women who have already had radiation therapy to the affected breast

• women with 2 or more areas of cancer in the same breast that are too far apart to be removed through 1 surgical incision, while keeping the appearance of the breast satisfactory

• women whose initial lumpectomy along with (one or more) re-excision has not completely removed the cancer

• women with certain serious connective tissue diseases such as scleroderma, which make them especially sensitive to the side effects of radiation therapy

• pregnant women who would require radiation while still pregnant (risking harm to the fetus)

• women with a tumor larger than 5 cm (2 inches) that doesn't shrink very much with neoadjuvant chemotherapy

• women with a cancer that is large relative to her breast size

Neodjuvant Therapy

• Chemotherapy given before surgery• Can shrink large cancers so that they

are small enough to be removed by lumpectomy instead of mastectomy

• Not indicated unless invasive breast cancer is confirmed

• Indication:

women with large clinical stage IIA, stage IIB, and T3N1M0 tumors who meet the criteria for breast conserving therapy except for tumor size and who wish to undergo breast conservation therapy

• Several randomized trials have assessed the value of neodjuvant chemotherapy in postmenopausal women with estrogen receptor positive breast cancer.

• Neodjuvant therapy with an aromatase inhibitor is an option in the treatment of postmenopausal women with hormone receptor-positive disease

• The use of either Anastrozole or Letrozole provides superior rates of breast conserving surgery and usually objective response.

(Smith IE. Dowsett M, Ebbs SR, et al. J Clin Oncol. 2005; 23:5108-5116)

Adjuvant Therapy• A form of therapy added to the

primary treatment to keep cancer from returning

Radiation Chemotherapy Hormone Therapy Biologic Therapy

Hormonal Therapy• Indication:

Patients with invasive breast cancers that are estrogen and progesterone receptor positiveException: LN (-) cancer < 0.5cm or 0.6cm to 1cm with favorable prognostic factors

TAMOXIFEN – selective estrogen receptor modulator - 1986: received FDA approval as adjuvant therapy in node-positive postmenopausal women with breast cancer - 1990: tamoxifen was approved for women of any age with node-negative disease, as long as hormone receptors were positive or unknown

AROMATASE INHIBITOR (AI) - suppresses estrogen production indirectly via inhibition of the aromatase enzyme

AnastrozoleLetrozole

• Switching to Anastrozole after the first 2 to 3 years of Tamoxifen is well tolerated and significantly improves event-free and recurrence-free survival in postmenopausal patients with early breast cancer

J Clin Oncol. 2005 Aug 1;23(22):5138-47.

• Risk of breast cancer recurrence was lower in women in the letrozole arm relative to the tamoxifen arm.

(Thurlimann B, et al .N Engl J Med. 2005;353:2747-2757.)

Chemotherapy• Recommended based on:

tumor size (> 1cm) tumor grade presence or absence of LN involvement

tumor hormone receptor status

• NCCN Recommendation < 70 y/o AC x 4

(doxorubicin/cyclophosphamide) + sequential paclitaxel x 4, every 2 weekly regimen

Doxorubicin, followed by CMF Cyclophosphamide/epirubicin, and

fluorouracil with or without docetaxel

Cyclophosphamide, methotrexate and fluorouracil [CMF]

Doxorubicin and cyclophosphamide [AC]

Doxorubicin and cyclophosphamide followed by paclitaxel or docetaxel [AC -->T] or docetaxel concurrent with AC [TAC]

Cyclophosphamide/Docetaxel (TC) Gemcitabine/paclitaxel (GT) Epirubicin/cyclophosphamide (EC) Cyclophosphamide, doxorubicin,

and fluorouracil [CAF]

Biologic Therapy• TRASTUZUMAB (Herceptin)

- is a monoclonal antibody with specificity for the extracellular domain of HER-2/neu receptor, preventing breast cancer cells to grow

- can shrink some breast cancer metastases that return after chemotherapy or continue to grow during chemotherapy

• Adverse Effects: Fever and chills Weakness Nausea/Vomiting Cough Diarrhea Headache Heart problems

• HERA Trial

The use of trastuzumab resulted in a 46% reduction in the risk of recurrence in patients following all local therapy & a variety of standard chemotherapy regimens.

( Piccart-Gebhart MJ Procter M, Leyland-Jones B, et al. N Engl J Med.2005; 353: 1659-1672)

• There is a 52 % reduction in risk of recurrence and a 33% reduction in the risk of death in patients with HER-2 (+),node (+) breast cancer & node (-) with primary tumors >1cm if ER/PR (-) or >2cm if ER/PR (+).

(Joint Analysis of NSABP B-31 & NCCTG N9831 Trial, 2005)

Key Points• The accuracy of HER-2 assays used in

clinical practice is a major concern since this could affect patient’s treatment.

• Breast MRI is an adjunct to other breast imaging and should not be used in lieu of standard breast imaging.

THANK YOU !