BREAST CANCER Anterpreet Neki, MD , MS

MORTALITY RATES OF CANCER IN WOMEN - 2008

Estimated reduction in US overall breast cancer mortality is 28-65% IMPACT OF RESEARCH ON BREAST CANCER SCREENING AND RISK-REDUCTION Estimated reduction in US overall breast cancer mortality is 28-65% (Breast cancer mortality RR >50 y- 0.78 and 40-49 y- 0.85) The identification of DCIS has increased 7-fold since 1980 Berry et al NEJM 2005

WHY HOPE ?

269,800 Cancer Deaths (all sites) SCA-14 SABCS V6 02-13-07.pptSCA-10 breast cancer slides_8-21-06.ppt 12/19/2017 3:01 AM Breast Cancer Is a Significant Public Health Concern for Women – Cancer Deaths 26% Lung and bronchus 15% Breast 9% Colon and rectum 6% Pancreas 5% Ovary 4% Non-Hodgkin lymphoma 3% Leukemia 3% Uterine corpus 2% Liver & intrahepatic bile duct 2% Brain & other nervous system 25% All other sites 40,170 Deaths 192,370 New BC Cases 269,800 Cancer Deaths (all sites) Adapted from American Cancer Society. Cancer Facts and Figures 2009. 5

BREAST CANCER EPIDEMIOLOGY -Most common cancer in women in the world -commoner in developed nations (obesity,inactivity) -14% of cancer deaths (second after lung CA) -mortality decreased by 34% in last 2 decades -black women have a lower rate of Breast CA, but relatively higher mortality

RISK FACTORS -1:8 -Exogenous hormones,obesity,exercise,alcohol,diet,breast density -Older age, female -Earlier menarche, late menopause,late first birth,nulliparity -Benign breast disease -Family history (5-10%): 1 deg relative,BRCA1/2 mutations,p53 -Ashkenezi jews -Radiation exposure

SCREENING -Mammographic screening : 23% reduction in breast CA relted mortality in F 50-70 yrs, and 15% decrease in mortality in 40-50 yrs -Annual mammograms and MRI in BRCA mutants starting at age 25 -Core biopsy of suspicious tissue for pathology, ER, PR, HER2 -H/o mantle radiation: annual mammogram and MRI

Breast Cancer: Then and Now SCA-14 SABCS V6 02-13-07.pptSCA-10 breast cancer slides_8-21-06.ppt 12/19/2017 3:01 AM Breast Cancer: Then and Now Then ~75% of women survived ≥5 years Mastectomy was the only surgical option Single-agent chemotherapy was standard of care Hormonal therapy with tamoxifen was under investigation only Genes involved in breast cancer development have not yet been identified Now ~90% of women survive ≥5 years Lumpectomy is available Combination chemotherapy is the standard of care Hormonal therapy is widely used Receptor-based therapy is widely used Understanding of genetic components have expanded National Cancer Institute. Available at: http://www.cancer.gov/cancertopics/cancer-advances-in-focus/breast. 10

DIAGNOSIS Ultrasound guided core needle biopsy ER/PR/HER2 PROGNOSIS Size, multiple, histology, grade, lymph nodes, proliferative rate, ER/PR, Her2,Intrinsic molecular subtypes (luminalA/B, basal/triple negative) OncotypeDx (node-,ER+)= Recurrance score (low= do not benefit from chemo in addition to hormonal therapy)

STAGING T tumors size T0-4 N Number/nature of nodes N0-3 M Metastasis M0-1 Stage 1-4 TNM

TREATMENT LOCAL Surgery : Mastectomy Lumpectomy+Radiation Radiation Hormonal therapy Her2based (Herceptin, Pertuzumab), Chemotherapy (>0.5 cm, LN+) (doxorubicin,cyclophosphamide,taxol,etc) METASTATIC Palliative chemo, radiation, bone support (Zometa,Xgeva)

BREAST CONSERVING SURGERY Radical Mastectomy Modified Radical Mastectomy Lumpectomy

ONCOTYPE Dx ASSAY Distant Recurrence at 10 Years Benefit from chemo Tam Tam + Chemo 0.4 0.3 Intergroup Trial For Randomization Distant Recurrence at 10 Years Benefit from chemo 0.2 0.1 0.0 Minimal, if any, Chemo Benefit Clear Chemo Benefit 10 20 30 40 50 Recurrence Score Recurrence Score Sparano, TBCI San Antonio, 2005

Paik S et al. NEJM 2004

OLD PARADIGM: “pre-genomic era” Breast cancer is divided into ER+, ER- Chemotherapy: NIH consensus conference Nov 2000: “It is accepted practice to offer cytotoxic chemotherapy to most women … primary breast cancers larger than 1 cm (both node negative and positive, ER positive or negative)” Hormone Therapy: For ER + HER 2 neu status

Most Important Paradigm Shift: Breast Cancer is not one disease 65-75% “A” Breast Cancer Breast Cancer ER + ER- “B” HER2+ 15-20% Basaloid 15% “Triple Negative” BRCA 1 P53 STAGE SIZE

HORMONE THERAPY SERMs Tamoxifen Fulvestrant Aromatase inhibitors Steroidal Exemestane Non-steroidal Anastrazole Letrozole

ENDOCRINE RESISTANCE

ONCOTYPE DX ASSAY

Survival Improvement in Metastatic Breast Cancer Patients SCA-14 SABCS V6 02-13-07.pptSCA-10 breast cancer slides_8-21-06.ppt 12/19/2017 3:01 AM Survival Improvement in Metastatic Breast Cancer Patients 100 Period 1987-1993 Period 1994-2000 75 Censored events P<0.001 Survival, % 50 25 12 24 36 48 60 Months Survival of breast cancer patients presenting with metastases at diagnosis has improved over time, strongly suggesting that improvement is related to treatment Need to switch curve key/references Andre F, et al. J Clin Oncol. 2004; 22(16):3302-3308. 27

SURVELLENCE -H&P 3m for 3 yr, then 6m for 4,5 yr, then annually -report new lumps,pain, SOB,bone pain, headaches -genetic counselling (h/o ovarian CA, 1deg relative with Br CA<50,>/=2 first deg or sec deg relatives,bilateral,male relative with Br CA -monthly self-exam -annual mammogram -pelvic exam if vaginal bleeding on Tamoxifen

SUMMARY -Early diagnosis /mammogram , improved survival -lumpectomy+radiation results in breast conservation -prognostic new tests (OncoType Dx)call help select cases for chemotherapy -Improved oral Hormonal agents +/-Herceptin in patients with appropriate receptors , help consolidate treatment and imrove survival -multiple new chemo/targeted /hormonal therapy combinations to slow metastatic disease -bone support agents available -continued close followup ,annual mammograms