2/9/2015. The high prevalence of breast disease and breast cancer (i.e. the problem is in every OB/GYN office, every day)

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1 Breast Cancer: What is the Gynecologist s Role in Detection, Management, and Surveillance? James W. Orr, Jr. M.D. FACOG, FACS Chair, Florida Board of Medicine Medical Director: Regional Cancer Center & Florida Gynecologic Oncology Fort Myers, Florida Fort Myers It is Important that we Understand Breast Disease? Women comprise ~100% of our practice. The high prevalence of breast disease and breast cancer (i.e. the problem is in every OB/GYN office, every day) 2 nd most common cause of fdeath thin US women leading cause of premature mortality from cancer in women as measured by total years of life lost It s important to be an advocate and provide the best level of care for your patients. Medical-legal legal aspects abound! Failure to diagnose History of Gynecologists and Cancer In 1913, a group of gynecologic surgeons formed the American Society for the Control of Cancer. Aims Educate Physicians Educate the public Ladies Home Journal - with Samuel Hopkins Adams - May 1913 What Can We Do About Cancer? Lee Cancer Care 1

2 History of Gynecologists and Cancer Forerunner of the American Cancer Society 2 OB/GYNs are recent Past Presidents of the American Cancer Society. The concept of a new American society dedicated to a multidisciplinary approach to breast health management was first discussed at an informal gathering of members of the Annual Meeting of ACOG in The 1 st formal meeting was The first issue of Breast Disease was published in 1987 and continued publication until Currently the official journal is The Breast Journal. 2

3 >60,000 DCIS Estim mated New Cases Es stimated Deaths 2015 ACS 635/day Alabama: 3,680/year 118/100,000 Alabama Uterine 660 Ovary 315 Cervix

4 Incidence Increased use of mammography Incidence %/year Mortality 1.9%/year Declined 34% between (33 to 22 per 100,000 women) Probability (%) of Developing Invasive Cancer Age Intervals Birth to 49 Age Age Age >70 Ever 1 in % 1 in % 1in29 3.5% 35% 1 in15 6.7% 1 in % 13.1% Lee Cancer Care ACS 2015 Number 122, August 2011 (Reaffirmed 2014) If Current Age Is The Probability of Developing Breast Cancer in the Next 10 Years Or 1 in: % 1, % % % % % 27 Lifetime risk 12.08% 8 4

5 Role of the Obstetrician Gynecologist in the Screening and Diagnosis of Breast Masses Number 122, April 2011; Reaffirmed 2014 Breast Cancer Screening Number 103, April 2009 Hereditary Breast and Ovarian Cancer Syndrome Number 126, March 2012 Management of Gynecologic Issues in Women with Breast Cancer. Role of the Obstetrician Gynecologist in the Screening and Diagnosis of Breast Masses 1. Should elicit risk factors during the medical and family history 2. Clinical breast examination 3. Instructions for periodic breast self-examination 4. Encourage screening mammography 5. Perform diagnostic procedures or referral to those who specialize in breast disease 6. Evaluate all palpable masses 7. Referral Who is at Risk? 5

6 Breast Cancer Risk Factors That Can Be Controlled Exercise Obesity Breastfeeding Alcohol All women are at at risk Hormone Hormone Replacement Therapy Not Not having children hld Birth Birth Control Pills Breast Cancer Risk Factors That Cannot Be Changed Age FH/Personal Hx Race Treatment with DES GENDER All women are at risk Radiation Reproductive History Genetic Factors Menstrual History Risk Assessment Models Why are breast cancer risk assessment models important? To offer patients accurate cancer risk assessment To identify appropriate referrals for genetic counseling To determine eligibility for chemoprevention To determine screening initiation and frequency Fewer than 1 in 10 high risk women have discussed risks with their physician 6

7 NCI/NSABP 1. Personal history of breast 7. Ever breast biopsy cancer/dcis/lcis/chest RT a. # biopsy 2. BRCA or other genetic risk b. + atypical factor hyperplasia 3. Current age 8. Race/ethnicty 4. Age at menarche a. Sub ethnicity 5. Age at 1 st birth 6. # 1 st degree relatives with breast cancer 5 year risk and lifetime risk BRCAPRO Probability of an inherited a deleterious change in BRCA1/BRCA2 Any size pedigree includes family history of breast and ovarian cancer, history of male breast cancer, oophorectomies, and bilateral synchronous and asynchronous diagnoses Provides updated age-dependent penetrance and prevalence estimates for both breast and ovarian cancer. Can We Rely on These Risk Models Alone? There are limitations to all these models: The Gail Model is not valid for families with BRCA1-2 mutations. The Gail Model does not predict the increased risk of hereditary ovarian cancer. The Clause model does not take personal risk factors into consideration. 7

8 Guideline for High Risk (>20%) Screening* Yearly MRI and Mammogram Based on nonrandomized screening trials and observational studies Known BRCA1 or BRCA2 gene mutation Have a first-degree relative (mother, father, brother, sister, or child) with a BRCA1 or BRCA2 gene mutation, and have not had genetic testing themselves Have a lifetime risk of breast cancer of 20%-25% or greater, according to risk assessment tools that are based mainly on family history Based on Expert Opinion Had radiation therapy to the chest when they were between the ages of 10 and 30 years Have a genetic disease such as Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome, or have one of these syndromes in firstdegree relatives * Begin at age 30 Facility to do MRI guided biopsy Guideline for Moderate Risk (< 20%) Screening Insufficient Evidence for Yearly MRI Have a lifetime risk of breast cancer of 15%-20%, according to risk assessment tools that are based mainly on family history Have a personal history of breast cancer, ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), atypical ductal hyperplasia (ADH), or atypical lobular hyperplasia (ALH) Have extremely dense breasts or unevenly dense breasts when viewed by mammograms Family history: Still Relevant in the Genomics Era ARE PATIENTS REPORTS RELIABLE? Reported negative FH in 1 st or 2 nd degree relative was accurate: Over-reporting = 2.4% Reported + FH (Breast) in 1 st degree relative > 90% accurate Reported + FH (Breast) in 2 nd degree relative > 80% accurate DOES TAKING A FH REDUCE COSTS? Testing and preventive treatment for high risk could save up to $800 million of the more than $8 billion spent each year on breast cancer diagnosis, prevention, and treatment. CCJM

9 Minimum adequate family history for patients with cancer: Family history of cancer in 1 st degree relatives (parents, children, and full siblings) and 2 nd degree relatives (grandparents, aunts/ uncles, nieces/nephews, grandchildren, and half siblings). The following should be recorded d for each relative with cancer, Type of primary cancer(s) Age at diagnosis of each primary cancer Lineage (maternal and/or paternal) Patients should be asked; - A known hereditary cancer predisposition syndrome, - Prior genetic testing, - Any relevant information regarding ethnicity - Periodic updating Cancers for Which Genetic Counseling and Testing Should Be Considered, Even in Absence of Family History Triple negative Breast Cancer Epithelial Ovarian, Fallopian Tube or Peritoneal Cancer Colon Cancer demonstrating mismatch repair deficiency Endometrial Cancer demonstrating mismatch repair deficiency Importance of Breast Self-Awareness Women themselves detect ~ 50% of all breast cancers 70% of those cancers diagnosed < 50 years old Cancer

10 Periodic Breast Self- Examination Two large population-based studies (388,535 women). No statistically significant difference in breast cancer mortality, relative risk % confidence interval (CI) 0.90 to 1.24) Almost twice as many biopsies (3406) with benign results were performed in the screening group compared to the control group (1856), relative risk % CI 1.77 to 1.99 Regular self-examination or clinical examination for early detection of breast cancer. Cochrane Database of Systematic Reviews Canadian National Breast Screening Study (NBSS) CBE: (5 to 10 minutes per breast) CBE alone vs CBE + Mammography Breast cancer mortality (mean 13 years) not different CBE alone J Natl Cancer Inst # Patients 25,620 19,965 Sensitivity ~70% ~77% Specificity 84% 90% PPV 1.5% <5% Clinical Breast Examination: Preliminary Results from a Cluster Randomized Controlled Trial in India CBE Control No. No. P value Breast cancers Tumor, 2 cm No pathological node Early-stage Advanced disease Lee Cancer Care J Natl Cancer Inst

11 Patient Detected Breast Cancer Not Seen on Mammography Tumor Size in cm Categories by Mammography (n=1,131) Seen Not Seen Tumor Size N (column%) N (column%) Chi Square p Value <15cm (207%) (20.7%) 101 (35.8%) < cm 165 (19.4%) 42 (14.9%) cm 238 (28.0%) 62 (22.0%) cm 160 (18.8%) 30 (10.6%) > 5.0 cm 110 (13.0%) 47 (16.7%) Total 849 (75.1%) 282 (24.9%) San Antonio Breast Symposium San Antonio Breast Symposium % 37% Mammography.brief history 1913: Salomon "Roentgen photographs of excised breast specimens give a demonstrable overview of the form and spread of cancerous tumors." 1976: ACS recommends annual screening 1979: NIH recommends annual screening 1992: Mammography Quality Standards Act (MQSA) required FDA certification of mammography facilities (ensure standardized personnel training and technique utilizing a low radiation dose) 1998: MQSA Reauthorization Act require patients to receive a written lay-language summary of results Mammographic Views (Screening) MLO Correctness Criteria Nipple well aligned Pectoral muscle displayed until the level of the posterior nipple line Presence of submammary angle free Folds and the absence of artifacts CC Cranio-caudal view Correctness Criteria External lateral portion of the breast Retromammary fat tissue (Chassaignac's bag) Pectoral muscle on the posterior edge Nipple in profile 11

12 Mammographic Views (Diagnostic) True lateral view - 90º view mediolateral view - ML view lateromedial view - LM view Lateromedial oblique view - LMO view Late mediolateral view - late ML view Step oblique views Spot view - spot compression view Double spot compression view Magnification view(s) Exaggerated craniocaudal views - exaggerated CC views XCCL view XCCM view Axillary view - axillary tail view Cleavage view - valley view Others Mammography Average-size lump found by woman practicing occasional breast self-exam (BSE) Average-size lump found by woman practicing regular breast self-exam (BSE) Average-size lump found by first mammogram Average-size lump found by getting regular mammograms BI-RADS Breast Imaging Reporting and Data System Category 0: Need additional imaging evaluation!!!!! Category 1: Negative Category 2: Benign Category 3: Probably benign finding: short interval follow-up suggested (2% risk) Category 4: Suspicious abnormality: biopsy should be considered: (34% risk) Category 5: Highly suggestive of malignancy Category 6: Known biopsy proven malignancy, appropriate action is being taken (>81% risk) 12

13 Breast Composition Categories As of the BI-RADS 5th edition a. The breasts are almost entirely fatty (10% of women) b. There are scattered areas of fibro-glandular density (40% of women) c. The breasts are heterogeneously dense, which may obscure small masses (40% of women) d. The breasts are extremely dense, which lowers the sensitivity of mammography (10% of women) Increased Breast Density: 50% incidence y/o 40% incidence > 50 y/o Mammogram sensitivity: 88% to 62% Independent risk factor for cancer: 1.5X-4.6X Society of Breast Imaging 2011 Mammograms CBE BSE Self- Awareness ACOG > 40: annually (1-3 yrs) >40: annually Consider for high risk Recommended ACS > 40: annually (1-3 yrs) >40: annually Optional > 20 Recommended (1-3 yrs) NCCN > 40: annually >40: annually Recommended Recommended NCI > 40: 1-2 years Recommended Not Recommended USPTF (2009) biennially Insufficient evidence Not Recommended ACOG Practice Bulletin 2011 Survival of 2294 Invasive Breast Cancer Patients by size of tumor, Swedish Two-County Trial of Breast Cancer Screening Survival pro obability Time in years since diagnosis Nystrom L et al. Lancet. 2002;359: Duffy SW, Tabar L, Vitak B, Warwick J. Breast J. 2006;12 (1):S91-S mm mm mm mm mm 50+ mm 13

14 Breast Cancer Screening Mammography Meta-analysis of 8 randomized trials: Reduction of rate of death for women > 40 years old Reduction of mortality by 16 to 35% for ages 50 to 69 years old Reduction of mortality by 15 to 20% for ages 40 to 49 years old Mean diameter of breast cancer has been decreasing by 10% every 5 years since the advent of mammographic screening Humphrey LL, Ann Inter Med. 2002;137: Fletcher SW, N Eng J Med. 2003;348: Pooled Relative Risk of Breast Cancer Mortality Related to Mammography (age 39-49) Ann Internal Medicine, 2009 Pan-Canadian Study of Mammography Screening and Mortality from Breast Cancer 2,796,472 screened participants : 85% of the Canadian population Breast cancer mortality: 40% lower than expected (range across provinces of 27% to 59%). No effect of age at entry No evidence that self-selection biased the reported mortality results J Natl Cancer Inst

15 Twenty Five year Follow-up for Breast Cancer Incidence and Mortality of the Canadian National Breast Screening Study Cancers in mammography arm Control arm (n=524) Detected (n=666) Palpable (n=454) Nonpalpable (n=212) Variables DOBD: No 353 (67.4) 486 (73.0) 316 (69.6) 170 (80.2) DOBD: Yes 171 (32.6) 180 (27.0) 138 (30.4) 42 (19.8) Tumor size (cm) 2.1 ( ) 1.9 ( ) 2.1 ( ) 1.4 ( ) Lymph node status: Negative 303 (57.8) 394 (59.2) 252 (55.5) 142 (67.0) Positive 170 (32.4) 204 (30.6) 169 (37.2) 35 (16.5) BMJ 2014 Twenty Five year Follow-up for Breast Cancer Incidence and Mortality of the Canadian National Breast Screening Study Fifteen years after enrolment, an excess Estimated of 106 that cancers 31% of occurred all breast in the cancers breast cancer were over screened group. diagnosed (i.e., tumors were detected Represents on screening 22% that would of all never screen have detected led t d invasive cancers to clinical symptoms) One over-diagnosed breast cancer for every 424 women who received mammography screening in the trial. BMJ 2014 Effect of Three Decades of Screening Mammography on Breast-Cancer Incidence Screening Advance the time of diagnosis of cancers that are destined to cause death. Allow early Breast treatment cancer to confer was some over advantage over treatment at clinical diagnosed presentation in 31% Screening mammography: doubling the # early-stage breast cancers (70,000) (112 to 234 of cases all breast per 100,000 women) absolute cancers increase of diagnosed 122 cases per 100,000 in women. Concomitantly, late-stage cancer has decreased by 8%, (102 to 94 cases per ,000 women) absolute decrease of 8 cases per 100,000 women. N Engl J Med

16 Personalizing Mammography by Breast Density and Other Risk Factors for Breast Cancer: Analysis of Health Benefits and Cost-Effectiveness Ann Intern Med For every 1000 women screened.. 80 to 100: recalled for additional evaluation (additional views and/or ultrasound) 45 to 65 recalled have a false positive 20 restudied in 6 months (<2% cancers) 15 biopsy recommended 2 to 5 have breast cancer (10 to 13 negative biopsy false positives ) 1 in 4 to 1 in 5 women biopsied for calcifications will have cancer. 1 in 3 biopsied for suspicious masses will have cancer. Age at Exposure (yrs) Lifetime Incidence of Excess Breast Cancers per 100,000 Excess Breast Cancer Mortality per 100, (>200 naturally) The radiation exposure 0.5 to the breasts from 0.2 annual natural background radiation is about 80 ¾ that of the exposure 0.2to the breasts from view bilateral mammography (4 milligray). ngton, DC: s, 2006 BEIR VII, Phase 2. Washin National Academies Press 16

17 Film vs Digital Analog Digital Digital vs. Analog Mammography 49,528 asymptomatic women Both digital and film screening mammogram Increased accuracy in women <50 Heterogeneously dense breast Premenopausal and perimenopausal Increased detection breast cancer by 15 to 20% Pisano ED,. N Engl J Med. 2005;353(17): Diagnostic Accuracy of Digital Mammography: DMIST 33 institutions (n = 49,528) Radiology, 2008: 246;

18 Computer-aided Detection Mammography for Breast Cancer Screening: Systematic Review and Meta-analysis. analysis. Pooled sensitivity was 86.0% (95% CI %) and specificity was 88.2% (95% CI %). Of the 100,000 women screened, CAD yielded an additional 50 (95% CI 30-80) correct breast cancer diagnoses, 1,190 (95% CI 1,090-1,290), recalls of healthy women, and 80 (95% CI ) biopsies of healthy women. A total of 96% (95% CI %) of women recalled based upon CAD and 65.1% (95% CI %) of women biopsied based upon CAD were healthy. No studies reported patient-oriented clinical outcomes (n = 347,324) Noble, Arch Gynecol Obstet. 2009;279: Breast Cancer Screening Role of Ultrasound US acknowledged to be a highly operator dependent with interobserver and intra-observer variability, unknown sensitivity, and low specificity. Detection of Breast Cancer With Addition of Annual Screening Ultrasound or a Single Screening MRI to Mammography in Women With Elevated Breast Cancer Risk Conclusion The addition of screening ultrasound or MRI to mammography in women at increased risk of breast cancer resulted in not only a higher cancer detection yield but also an increase in false-positive findings 2012: FDA approved the first ultrasound system, the somo-v Automated Breast Ultrasound System (ABUS), for breast cancer screening in combination with standard mammography specifically for women with dense breast tissue JAMA

19 Breast Cancer Screening Role of Ultrasound Typically used to distinguish a cyst from a solid lesion or to guide biopsy! 3 features of a lesion are evaluated: Boundaries and shape Internal architecture (echoes) Its posterior shadowing Supplemental Screening with Ultrasound in Women with Dense Mammograms? No RCT showing survival benefit of screening women with dense breasts with supplemental whole breast ultrasound screening + mammography DMIST: DM (digital mammography) was significantly more sensitive than film (.59 vs.27 p <.0013) in women < 50 or with dense breasts. DM should be used for women with dense breasts regardless of any decision regarding g ultrasound. WB-US requires long scanning time (median 19 mins in ACRIN666), expertise, training, and incremental breast imaging radiologist time. Mammography and MR have consistently outperformed mammography and WB-US for very high-risk women independent of breast density Society of Breast Imaging 2011 Breast Cancer Screening Solid masses typically require pathologic evaluation! Lee Cancer Care 19

20 Breast Cancer Screening MRI Pro s Nearly 100% negative predictive value for invasive carcinoma 3-4% of cancers only detected by MRI Noninvasive No radiation Con s EXPENSIVE Time consuming Inconsistent between centers Reserved for high-risk women Lee Cancer Care Comparative Sensitivity Histology Mammo US MRI DCIS 55% 47% 89% IDC 81% 94% 95% ILC 34% 86% 96% Lee Cancer Care Clinical Indications for Breast MRI Implant evaluation Axillary carcinoma of unknown primary Screening women at high risk Breast cancer patients?? - Extent of disease - Contralateral screening for occult disease - Positive or close margins - Prior to surgery response to neoadjuvant chemotherapy Lee Cancer Care 20

21 Breast Tomosynthesis: 3D Digital Mammography FDA approval 2011 Clinical Trials Increased lesion visibility Facilitation of margin analysis Reduction in call-back rate from screening Lesion location Jong RAl. Radiology. 2003;228(3): Emerging Technology Breast Tomosynthesis Tomosynthesis is a 3-dimensional digital mammographic technique Detector remains stationary while the tube moves Acquires data through a series of 11 positions through a 50 degree arch Detector reads out the captured information to create an image Screening Digital Breast Tomosynthesis: Effect Recall Type and Patient Treatment Screening digital mammography (DM) + tomosynthesis Recall rate: DM= 9.3% DBT= 6.4% Overall reduction of 31% (P <.00001). Limitations of DBT: Recall rate: Masses: Longer interpretation DM = 8.9% times, DBT = 26.8% Distortions Higher costs, DM = 0.6% DBT = 53% 5.3% Calcifications DM = 13.4% DBT 20.3% Increased radiation dose. Asymmetries DM = 32.2% DBT = 13.3% Focal asymmetries DM = 32.2% DBT= 18.2% Ultrasonography: DM= 2.6% DBT =28.3% No significant difference in biopsy PPV (30% vs 23%) No significant difference in cancer detection rate per 1000 patients (prior studies suggest a benefit) Radiology

22 Breast PEM/PET Preoperative identification of non-invasive breast cancer (DCIS) which accounts for 30% of newly diagnosed patients and. PEM has a 91% sensitivity for DCIS which far exceeds all other imaging modalities. Lee Cancer Care Tissue Diagnosis: Ductal Carcinoma In Situ and Invasive Ductal Carcinoma X-Ray PEM Flex Whole Body PET X-Ray CT Scintimammography Breast-specific specific Gamma Imaging (BSGI), or Molecular Breast Imaging (MBI) 2010 practice guideline Society of Nuclear Medicine 1. Recently detected breast malignancy 2. Patients at high risk for malignancy 3. Patients with indeterminate breast abnormalities 4. Patients with technically difficult breast imaging 5. Patients for whom MRI is indicated but contraindicated 6. Patients undergoing preoperative chemotherapy Lee Cancer Care Tc-99m sestamibi Chemoprevention of Breast Cancer Women at increased BC risk: 5-year projected absolute risk of BC 1.66% based on BCRAT or with lobular carcinoma in situ. Age >35 years, tamoxifen (20 mg per day for 5 years) should be discussed as a risk reducing option. Postmenopausal women: raloxifene (60 mg per day for 5 years) or exemestane (25 mg per day for 5 years) should be discussed as a risk reducing option. J Clin Oncol

23 Chemoprevention: All Cancers Chemoprevention: ER + Cancers nst 2009;101: Cummings J Natl Cancer In RR 0.67 Pre-Postmenopausal RR 0.41 Post menopausal Atypical Hyperplasia of the Breast: Risk Assessment and Management Options Atypical hyperplasia: found in approximately 10% of the 1,000,000 benign breast biopsies Atypical ductal and atypical lobular hyperplasia: equal frequency. RR of Breast cancer 4 Cumulative risk 25 years No effect of a + Family History Hartman NEJM

24 Atypical Hyperplasia of the Breast: Risk Assessment and Management Options MANAGEMENT Chemoprevention: - 38% relative reduction in the risk of breast cancer (invasive and noninvasive) among all the study participants who were enrolled in the SERM randomized trials - Relative-risk reductions in women with atypical hyperplasia subgroup: 41 to 79% Hartman NEJM 2015 Atypical Hyperplasia of the Breast: Risk Assessment and Management Options Risk of subsequent cancer Hartman NEJM 2015 Atypical Hyperplasia of the Breast: Risk Assessment and Management Options MANAGEMENT Core Biopsy: Atypical ductal hyperplasia Upgrading 15 to 30% with surgical excision, despite the use of large-gauge (9- or 11-gauge) core-needle biopsy with vacuum assisted devices Atypical lobular hyperplasia Upgrading < 6% NCCN: Excision remains the current standard of atypical ductal hyperplasia on core biopsy Hartman NEJM

25 How Do We Know Where or Which Way to Go? Gonadotropin-Releasing Hormone Analogues for the Prevention of Chemotherapy-induced Premature Ovarian Failure in Cancer Women: Systematic review and Meta-Analysis of Randomized trials. Nine studies 225 events of POF occurring in 765 analyzed patients. Significant reduction in the risk of POF (OR=0.43; 95% CI: ; p=0.013) in patients receiving GnRHa. Similar in subgroups of patients defined by age and timing of POF assessment, Present in breast cancer but unclear in ovarian cancer and lymphoma. Cancer Treat Rev Concurrent treatment with gonadotropinreleasing hormone agonists for chemotherapy-induced ovarian damage in premenopausal women with breast cancer: a meta-analysis of randomized controlled trials 5 RCTs: 528 patients GnRH agonist protected against postchemotherapy POF, RR of 0.40 Both treatment groups experienced similar rates of - resumed menses - spontaneous pregnancy Breast

26 Clinical Utility of Gene-expression Profiling in Women with Early Breast Cancer: an Overview of Systematic Reviews Oncotype DX and MammaPrint: ability to predict treatment outcomes, change in treatment decisions, and cost-effectiveness, Five systematic reviews: No direct evidence of clinical utility for either test. Indirect evidence that Oncotype DX predicted treatment effects of adjuvant chemotherapy No indirect evidence of predictive value was found for MammaPrint. Genet Med Oncotype DX Breast Cancer Assay: intended to predict potential benefit of chemotherapy and likelihood of distant breast cancer recurrence Node negative or node positive, ER-positive, HER2-negative invasive breast cancer. Oncotype DX Breast Cancer Assay for DCIS patients quantifies the 10-year risk of local recurrence (DCIS or invasive carcinoma) in women with ductal carcinoma in situ treated by local excision, with or without tamoxifen. 26