Attending Physician, Hemoncology. Breast Cancer Dr. Padma Poddutoori, PG-Y3, I.M. Dr.Sohail Chaudhry, Attending Physician, Hemoncology.

Clinical case presentation CC: lump in the left breast HOPI: A 47 yr old premenopausal woman who was doing well until 8 months back when she first noticed a lump in the left breast at 2 ‘O’ clock position. A diagnostic mammogram showed 2 nodular densities in the left upper quadrant, close to the palpable abnormality. U/S showed a cluster of cysts in between the 12 and 1 ‘O’ clock position and a thick walled cyst, in between 11 and 12 ‘O’ clock position, 1.8 cm from which greenish black fluid was aspirated.

Clinical case presentation contd… An U/S which was done 3 wks later, which showed a suspicious solid mass. Core needle biopsy done showed grade 2 invasive ductal carcinoma in 4 of 4 cores, ER and PR positive, no over expression of HER2/neu. Menstrual and gynecologic history: She was nulliparous with menarche at 13, was exposed to DES, no h/o OCP use and had undergone routine gynecologic screening Vaginal biopsy 23 yrs back showed adenosis with no evidence of cancer

Clinical case presentation contd… Allergies: stinging insects PMH: no h/o DM, HTN or CAD Social history: lives with her husband, non smoker, drinks fewer than 5 alcoholic beverages a wk. Family history: no h/o breast or ovarian cancer Medications: none

Clinical case presentation contd… Vitals: normal On examination: Breast: breasts were symmetric, no skin changes, nipple discharge or erosions. A flat mass 5x 5 cms was palpated in the upper outer quadrant left breast, not mobile, not attached to overlying skin, no lymphadenopathy, no mass in the right breast. Rest of the examination was normal

Imaging Radionuclide bone scan showed a focus of increased uptake in the right aspect of the T6 vertebral body, which suggested the possibility of a metastasis. Mammography revealed an ill defined mass in the upper outer quadrant of the left breast. A targeted ultrasonography of the left breast revealed an ill-defined, hypoechoic, lobulated mass, 3.5 cm by 2.7 cm x 2.0 cm, at 2 o’clock position. MRI of the breasts revealed an ill-defined, lobulated, enhancing mass, 2.9 cm x 2.7 cm x 2.5 cm, in the upper outer quadrant of left breast, corresponding to the mammographic and ultrasonographic findings. CT of the thoracic spine, performed revealed a lytic destructive lesion, 1.8 cm x 1.6 cm x 1.5 cm, in the right side of T6 vertebral body. A small, soft-tissue component extended into the right anterior lateral epidural space, without central canal stenosis. Needle biopsy of the T6 vertebral lesion was performed under CT guidance, and pathological examination showed metastatic carcinoma.

Breast Imaging Studies Gradishar W et al. N Engl J Med 2008;359:1382-1391

Spine Lesion Imaging Study Gradishar W et al. N Engl J Med 2008;359:1382-1391

Pathology All four tissue cores had involvement by both infiltrating ductal Ca and ductal CIS, with focally abundant extracellular mucin. Immunohistochemical staining showed the expression of both ER and PR.

Breast cancer incidence It is the most common malignancy in women-31% of all female cancers, 15% of cancer deaths-no 2 cause of cancer deaths 178,480 new invasive breast cancer cases were diagnosed in women in U.S in 2007 Epidemiology: Gender: female:male =100:1; BRCA mutations are associated with increased risk for br.cancer in men Age: 0.8% in women <30 yrs old, 6.5% in women 30-40 yrs old Race: Caucasians > African Americans Geography: north america highest rate in the world SES: higher in higher SES Disease site: left >right and higher in the UOQ and in retroareolar area

Basic principles of treatment of breast cancer Local and Regional Treatment Early breast cancer: lumpectomy with RT. Axillary Lymph-Node Dissection: recurrence is higher in women with positive axillary LN. Sentinel LN mapping can be done, which has 100% PPV and 95% NPV Radiotherapy: RT is an integral part of breast-conserving treatment. Postmastectomy RT reduces the incidence of local and regional recurrences by 50 to 75%.

Basic principles of treatment of breast cancer Systemic Hormone Therapy or Chemotherapy: For adjuvant therapy, combination CT is more effective than single-drug therapy, reducing the annual risk of death by 20%. The benefit is greater when tamoxifen is given for 5 yrs, and with ER positive tumors. Preoperative Chemotherapy: 90% of primary operable tumors decrease in size by >50% after CT, thus making lumpectomy a possibility for women who would otherwise have required a mastectomy. No survival benefit of pre-op CT over post-op CT Duration of Chemotherapy: 4-6 M. The combinations used most often are fluorouracil, doxorubicin, and cyclophosphamide (FAC); fluorouracil, epirubicin, and cyclophosphamide (FEC); doxorubicin and cyclophosphamide (AC); and cyclophosphamide, methotrexate, and fluorouracil (CMF). These combinations are given at intervals of 3-4 wks. 6 cycles of FAC or FEC (18 to 24 wks), 6 cycles of CMF (18 to 24 wks), or 4 cycles of AC (12 to 16 wks) are considered standard therapy. In premenopausal women, ovarian ablation has a benefit, equal to that of combn CT or tamoxifen. Combination CT and Hormonal Therapy: more effective than either alone. Recommended for women with a high risk of recurrent disease. Metastatic Breast Cancer: optimal palliation and prolongation of life are the main goals of treatment.

INDICATIONS FOR ADJUVANT SYSTEMIC THERAPY AFTER SURGERY IN WOMEN WITH OPERABLE BREAST CANCER. TYPE OF DISEASE ADJUVANT THERAPY INDICATED Breast cancer without evidence of invasion Noninvasive breast cancer (ductal or lobular carcinoma in situ) Breast cancer with evidence of invasion, but -ve axillary LN Microinvasive breast cancer (<1 mm in largest diameter) Invasive ductal or lobular carcinoma <1 cm in largest diameter Invasive carcinoma <3 cm in largest diameter with favorable histologic findings (pure tubular, mucinous, or papillary) Invasive ductal or lobular carcinoma »1 cm in largest diameter Invasive carcinoma »3 cm in largest diameter with favorable Invasive breast cancer with positive axillary lymph nodes All tumors, regardless of size or histologic findings None Chemotherapy, hormonal therapy, or both

SELECTION OF ADJUVANT SYSTEMIC THERAPY FOR WOMEN WITH OPERABLE PRIMARY BREAST CANCER AND INDICATIONS FOR ADJUVANT TREATMENT. CHARACTERISTICS OF PATIENT AND TUMOR LEVEL OF RISK ADJUVANT SYSTEMIC THERAPY* AGE ESTROGEN-RECEPTOR STATUS LEVEL OF RISK ADJUVANT SYSTEMIC THERAPY <50 yr Negative Positive Unknown »50 yr Any Low Moderate or high Chemotherapy Hormonal therapy Or Chemotherapy or Chemotherapy and hormonal therapy Chemotherapy and hormonal therapy or Investigational therapies Chemotherapy and hormonal therapy Tamoxifen Or Chemotherapy and hormonal therapy Chemotherapy and hormonal therapy or Investigational therapies

TEN-YEAR CANCER-FREE SURVIVAL AND OVERALL SURVIVAL AMONG WOMEN TREATED WITH CHEMOTHERAPY WITH OR WITHOUT RADIOTHERAPY AFTER MASTECTOMY. STUDYAND OUTCOME NO. OF SUBJECTS PERCENT SURVIVING CHEMOTHERAPY CHEMOTHERAPY AND RADIOTHERAPY P VALUE British Columbia Cancer-free survival Overall survival Danish Breast Cancer Cooperative Group 318 1708 41 56 54 64 34 48 45 54 0.007 0.07 <0.001

Optimal Palliative Therapy for Women with Metastatic Breast Cancer Hortobagyi G. N Engl J Med 1998;339:974-984

Hormonal therapy Pre-menopausal women: Tamoxifen x 5 yrs AI[Arimidex or Famara] with LHRH agonist +/- zometa ? A study was conducted in premenopausal women- 2 groups enrolled: Tamoxifen +LHRH agonist +/- Zometa vs AI + LHRH agonist +/- Zometa Post menopausal women: AI[Arimidex or Famara] x 5 yrs Tamoxifen x 5 yrs Famara x 5 yrs Tamoxifen x 2.5 yrs Aromasin [Exemestane]

HORMONAL THERAPIES FOR WOMEN WITH METASTATIC BREAST CANCER ORDER OF THERAPY PREMENOPAUSAL WOMEN POSTMENOPAUSAL WOMEN First line Antiestrogens or ovarian ablation (chemical, surgical, or postradiation) Antiestrogens Second line Ovarian ablation after antiestrogens; antiestrogens after ovarian ablation Aromatase inhibitors Third line Progestins Fourth line Androgens Androgens or estrogens

Newer modalities of treatment Bevacizumab (Avastin, Genentech) is a humanized monoclonal antibody directed against all isoforms of VEGF-A. Trastuzumab, a monoclonal antibody targeting the extracellular domain of the HER2 protein, was approved in 1998 as a first-line treatment in combination with paclitaxel for HER2-positive metastatic breast cancer. Exemestane[Aromasin] inhibits aromatization in vivo by about 98 %. Exemestane therapy after 2-3 yrs of tamoxifen therapy significantly improved disease-free survival as compared with the standard 5 yrs of tamoxifen treatment.

Analyses of Toxic Effects and Efficacy

Demographic and Disease Characteristics of Eligible Patients Table 1. Demographic and Disease Characteristics of Eligible Patients. Miller K et al. N Engl J Med 2007;357:2666-2676

Survival Analyses Miller K et al. N Engl J Med 2007;357:2666-2676

Enrollment, Patients, and the Timing of Chemotherapy and Trastuzumab in Trial B-31 and Trial N9831 Romond E et al. N Engl J Med 2005;353:1673-1684

Kaplan-Meier Estimates of Disease-free Survival (Panel A) and Overall Survival (Panel B) Romond E et al. N Engl J Med 2005;353:1673-1684

What can be done in this patient?

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