Katherine D. Crew Breast and Ovarian Cancers Learning Objectives • Epidemiology and Risk Factors • Cancer Screening Katherine D. Crew, MD MS Division of Hematology/Oncology Columbia University College of Physicians and Surgeons • Staging, Prognosis, and Treatment Epidemiology Cancer Trends Siegel et al. CA:Cancer J Clin 2012 Incidence Mortality Case #1 • A healthy 27-year-old white woman of Ashkenazi Jewish descent comes to establish care. Her age at first menstrual period was 13 and she has no children. She has been on birth control pills for several years. She notes a family history of a mother with ovarian cancer at age 40 and a maternal grandmother with breast cancer in her 40s. She has a normal clinical breast exam. • She undergoes genetic testing and is found to have a deleterious mutation in the BRCA2 gene. Siegel et al. CA:Cancer J Clin 2012 Incidence Mortality Question #1 • Which of the following are appropriate for screening and prevention? a) Annual mammography and breast MRI b) Risk-reducing surgeries (mastectomies, BSO) c) Tamoxifen for chemoprevention d) All of the above Katherine D. Crew Hereditary Syndromes • Breast-Ovarian Cancer Syndrome – DNA repair – BRCA1 (17q12) – BRCA2 (13q112) • Hereditary Non-polyposis Colorectal Cancer Syndrome (HNPCC, Lynch II) – DNA mismatch repair – MSH2, MLH1, MSH6 Indications for Genetic Testing USPSTF, Ann Intern Med 2005; Bellcross et al. CEBP 2013 • Non-Ashkenazi Jewish: – 2 first-degree relative with breast cancer, 1 diagnosed at age≤50 – 3 or more first/second-degree relatives with breast cancer – Both breast and ovarian cancer among first/second-degree relatives – First-degree relative with bilateral breast cancer – 2 or more first/second-degree relatives with ovarian cancer – First/second-degree relative with both breast and ovarian cancer – Male relative with breast cancer BRCA1/BRCA2 Genetic Testing Risch et al. JNCI 2006; Pal et al. Cancer 2005; Nelson et al. Ann Intern Med 2005; Chen et al. JCO 2007 • Account for 2-7% of breast cancers, 10-15% of ovarian cancers • Prevalence is 1:400 in the general population, 1:40 in Ashkenazi Jews • Lifetime risk of breast cancer 40-60%, ovarian cancer 20-40% Ovarian Cancer Screening • Serum tumor markers • Pelvic examination • Transvaginal ultrasound • Serum proteomics • Ashkenazi Jewish: any first/second-degree relatives with breast or ovarian cancer CA-125 Tumor Associated Antigen • Membrane glycoprotein • Elevated in 80% of epithelial ovarian tumors (primarily serous) • Reliable index of response to therapy or progression of disease • Threshold is 35 U/ml – Sensitivity 78% Specificity 77% – NPV 72-82% Elevated CA-125 Differential Diagnosis Gynecologic Tumors Epithelial ovarian cancer Sertoli-Leydig tumors Granulosa tumors Fallopian tube carcinomas Endometrial carcinomas Endocervical carcinomas Benign Gynecologic Conditions Endometriosis Adenomyosis Leiomyomas Pregnancy Ectopic pregnancy Pelvic inflammatory disease Nongynecologic Tumors Pancreatic carcinoma Lung carcinoma Breast carcinoma Colon carcinoma Lymphoma Nongynecologic Conditions Pancreatitis Cirrhosis Laparotomy Peritonitis Tuberculosis Congestive heart failure Katherine D. Crew Ovarian Cancer Screening Signs and Symptoms Jacobs et al. Lancet 1999 • Randomized controlled trial of sequential CA125/TVUS (n=10,958) vs no screening (n=10,977) • 468 elevated CA-125, 29 referred after TVUS (23 FP, 6 cancers) – PPV 21% • 20 cancers in control group vs 10 additional cancers in screened group • Survival higher in screened group (73 months vs 42 months) (p=0.01) • Number of deaths similar between groups (18 controls vs 9 screened) (RR 2, 0.78-5.1) • • • • • • Abdominal mass Pelvic mass Pleural effussion Ascites Ventral hernia Inguinal adenopathy Germ cell tumors Sex cord stromal tumors Metastatic Serous Mucinous Endometrioid Clear cell Transitional cell Undifferentiated Dysgerminoma Yolk sac tumor (EST) Immature teratoma Mature teratoma Embryonal carcinoma Choriocarcinoma Gonadoblastoma Granulosa cell tumor Sertoli-stromal cell tumors Steroid cell tumors Gynandroblastoma Numerous Abdominal pain Early satiety Nausea and vomiting Abdominal distension Constipation Vaginal bleeding Dyspnea FIGO Staging Classification Epithelial tumors • • • • • • • Stage I IA Growth limited to the ovaries One ovary, no ascites, no tumor on the surface with capsule intact IB Both ovary, no ascites, no tumor on the surface with capsule intact IC Stage IA or IB with tumor on the ovarian surface, capsule ruptured or ascites with malignant cells Stage II IIA Growth involving one or both ovaries with pelvic extension Extension to the uterus and/or tubes IIB Extension to other pelvic tissues IIC Stage IIA or IIB with tumor on the ovarian surface, capsule ruptured or ascites with malignant cells Stage III IIIA Peritoneal implants outside the pelvis, positive retroperitoneal or inguinal nodes, superficial liver metastases Microscopic seeding of abdominal peritoneum IIIB Abdominal implants < 2 cm in diameter, nodes negative IIIC Abdominal implants > 2 cm in diameter, positive retroperitoneal or inguinal nodes Stage IV Distant metastasis, parenchymal liver disease, cytologically pleural effusion Stage Distribution Survival by Stage Siegel et al. CA:Cancer J Clin 2012 Siegel et al. CA:Cancer J Clin 2012 Katherine D. Crew Current Standard of Care • Early stage disease – Surgery – Potentially chemotherapy • Advanced stage disease – Surgery – Chemotherapy Early Stage Ovarian Cancer • Surgery – Diagnosis and staging – TAH/BSO, lymphadenectomy, omentectomy, peritoneal biopsies • Adjuvant treatment – Stage IA, IB (grade 1 and 2)-observation – Stage IC, any grade 3-chemotherapy Surgical Cytoreduction Advanced Stage Disease • Surgery – Surgical cytoreduction • Adjuvant chemotherapy – Platinum based therapy – Intraperitoneal chemotherapy • Possible consolidation therapy Based on GOG 52 and 97 • • Optimal-residual disease < 1 cm Suboptimal-residual disease > 1 cm Adjuvant Chemotherapy Adjuvant Chemotherapy McGuire et al. N Engl J Med 1996 Ozols et al. J Clin Oncol 2003 • Cyclophosphamide/cisplatin vs cisplatin/paclitaxel • Cisplatin/paclitaxel vs carboplatin/paclitaxel Katherine D. Crew Intraperitoneal Chemotherapy Trial Agents Recurrent Ovarian Cancer Outcome SWOG 8501 Cis/Cyclophosphamide (IV) vs Cis (IP)/Cyclophosphamide Improved survival with IP (41 vs 49 months) GOG 114 Cis/taxol (IV) vs Carbo (AUC 9)/taxol/cis (IP) Improved PFS and borderline OS with IP (63 vs 52 months) Severe toxicity GOG 172 Cis/taxol vs Cis/taxol (IP) Improved OS with IP (66 vs 50 months) • 70-80% of patients respond to primary therapy • 80% of patients with stage III/IV tumors ultimately relapse Recurrent Ovarian Cancer Treatment of Recurrence • Cytotoxic agents – Carboplatin, cisplatin, topotecn, liposomal doxorubicin, gemcitabine, etoposide, vinorelbine, docetaxel, cyclophosphamide, doxorubicin, trabectadin, pemetrexed • Hormonal agents – Progestins, GnRH agonists, SERMs • Targeted therapy – Bevacizumab, PARP inhibitors, HER2/neu inhibitors, EGFR inhibitors, mTOR inhibitors, other VEGF inhibitors Control Disease: SD, TTP GOALS Maintain Quality of Life Extend Survival Selection of Treatment • • • • • • • Type and number of prior regimens Prior toxicity Current symptoms and disease volume Performance status/co-morbidities Treatment free interval Social/quality of life Schedule Platinum Free Interval P R E V I O U S T R E A T M E N T Time to recurrence, months 0 3 6 12 18 24 Refractory Resistant Sensitive Very sensitive Katherine D. Crew Ovarian Cancer: Summary Case #2: Breast Cancer • Surgical therapy should consist of complete staging and cytoreduction • Standard front line therapy should contain platinum and taxane • Treatment of relapsed ovarian cancer is based on patient specific variables with the goal of extending survival and maximizing quality of life • 49-year-old African American woman with suspicious calcifications on a screening mammogram. • Breast biopsy revealed invasive ductal carcinoma. She is s/p lumpectomy → poorly differentiated, 1.8 cm, negative lymph nodes, ER/PR+, HER2-. Risk Factors for Breast Cancer Singletary, Ann Surg 2003 Question #2: Breast Cancer • Which of the following factors does NOT affect breast cancer prognosis? a) b) c) d) Age Family history Tumor hormone receptor status Tumor molecular profiling Breast Cancer Screening • Self Breast Examination • Clinical Breast Examination Risk Factor Relative Risk Alcohol intake (>2 drinks/day) Body mass index HRT use (>5 years) 1.2 1.2 1.3 Early age of first menstrual period (<12 years) Late menopause (>55 years) Age at first birth (>30 years or no children) Current age (≥ 65 years) 1.3 1.2-1.5 1.7-1.9 5.8 Benign breast disease Prior breast cancer 5-20 6.8 Family history 2nd degree relative with breast cancer 1st degree relative, age>50 1st degree relative, age<50 1.5 1.8 3.3 BRCA1/2 mutation carrier 15-200 Breast Cancer Staging • Stage 0: Non-invasive or ductal carcinoma in situ (DCIS) • Stage I: Tumor < 2 cm, negative lymph nodes • Mammogram • Breast Ultrasound • Breast MRI • Stage II: Tumor 2-5 cm or 1-3 positive lymph nodes • Stage III: Tumor > 5 cm or ≥ 4 positive lymph nodes • Stage IV: Distant metastases Katherine D. Crew Breast Cancer Treatment Local Therapy Systemic Therapy • Surgery • Radiation Therapy • Chemotherapy • Hormonal therapy • Biologic therapy Choice of Adjuvant Therapy EVALUATION OF RISK OF RECURRENCE CHOICE OF ADJUVANT THERAPY CONSIDERATION OF ACUTE AND LATE SIDE EFFECTS PATIENT'S PREFERENCE Prognostic Factors Patient-Related Factors Tumor-Related Factors • • • • • • • • • Adjuvant Systemic Therapy Age Race Obesity Lymph node status Tumor size Tumor grade Hormone receptor status HER2 expression Tumor molecular profiling (Oncotype DX, MammaPrint) NODE NEGATIVE NODE POSITIVE ESTROGEN RECEPTOR POSITIVE Hormonal Therapy +/Chemotherapy Chemotherapy + Hormonal Therapy ESTROGEN RECEPTOR NEGATIVE Chemotherapy Chemotherapy Oncotype DX Paik et al. NEJM 2004 Chemotherapy Chemotherapy Drugs Benefits Adriamycin (AC) 20-30% ↓ in recurrence risk Risks Cardiac toxicity Cyclophosphamide Acute leukemia, Ovarian failure Taxanes (T) Neuropathy Katherine D. Crew Trastuzumab Trastuzumab Romond et al. NEJM 2005; Piccart-Gebhart et al. NEJM 2005 • HER2/neu overexpression in 20-25% breast cancer • Benefits: ~50% ↓ in recurrence risk AC→TH AC→T • Humanized mAb directed against the extracellular domain of HER2 • Risks: Cardiac toxicity Recurrence Ratio=0.45 Hormonal Therapy Baum et al. Lancet 2002; Goss et al. NEJM 2003; Coombes et al. NEJM 2004 Hormonal Therapy Hormonal Agents Benefits Risks Tamoxifen (premenopausal) 50% ↓ in recurrence risk Uterine cancer Clot formation Aromatase inhibitor (postmenopausal) - anastrozole (Arimidex) - letrozole (Femara) - exemestane (Aromasin) 60-65% ↓ in recurrence risk Osteoporosis Joint symptoms ↑ Cholesterol Conclusions • Cancer screening has led to improvements in survival. • A proper staging work-up is essential for prognosis and treatment management. • Understanding of prognostic factors and long-term side effects of treatments to guide follow-up care in cancer survivors. Thank You!
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