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Lucy K Helyer MD CCFP FRCS(C)

“I never want to be in this situation again”: Prevention of the contralateral breast cancer: What is the risk and what can we do?. Lucy K Helyer MD CCFP FRCS(C). Objectives. Contra lateral breast cancer (CBC) Incidence and prevalence Risk factors Risk reduction strategies

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Lucy K Helyer MD CCFP FRCS(C)

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  1. “I never want to be in this situation again”:Prevention of the contralateral breast cancer:What is the risk and what can we do? Lucy K Helyer MD CCFP FRCS(C)

  2. Objectives • Contra lateral breast cancer (CBC) • Incidence and prevalence • Risk factors • Risk reduction strategies • Contra lateral prophylactic mastectomy (CPM) • Chemoprevention • Surveillance and screening • Lifestyle modifications

  3. Breast Cancer • #1 diagnosed cancer in Canadian women • 1/9 will be diagnosed in their life time • 1/27 will die of breast cancer • Nova Scotia • 740 new diagnosis in 2010 • 180 deaths due to breast cancer Canadian Cancer Statistics 2010

  4. Age specific survival ratio 6%-10% increase in survival Canadian Cancer Statistics 2003

  5. Survival of women with breast cancer in Ontario The risk of recurrent disease never approaches 0 Distant disease the cause of mortality Canadian Cancer Statistics 2003

  6. Incidence of CBC • Average risk woman • 5.3%- 9% risk of developing breast cancer over 30yrs • Breast cancer survivors • 0.5%-1.0% per year • SEER Data • 134,501 women 1973-1996 DCIS, stage 1 or 2 • 10yr actuarial rate of 6.1%, 20 yr of 12% • High risk women • <45yr 6.2% 10 yr actuarial • ILC 11.7% 20 yr risk compared to 12.1% for IDC

  7. Contra lateral breast cancers • Synchronous – simultaneous presentation with primary • Detected within 6-12 months of primary diagnosis • Clinically/mammographically detectable breast cancer • Rare 0.4%-3% • 3-10% invasive disease and 21-68% in situ disease retrospective studies (autopsy) • CPM- 1960-1970’s 50% of speceimens • DCIS, LCIS or atypia

  8. Contra lateral synchronous breast cancer • Incidence of invasive cancer • Occult invasive cancer in mastectomy specimens • 5% (1960-1970) • MRI used for pre-op • Evaluation of early stage • 3% ACRIN (1999-2005)

  9. Prognosis of synchronous BC Worse overall survival than unilateral disease Quan et al 2008 Am J Surg 10% worse survival for pt with synchronous tumors compared with unilateral BC Significantly worse survival than metachronous Multifactorial reasons Young age and Triple negative disease P < 0.001

  10. Metachronous breast cancer MBC • Definition • Detection > 12months after primary diagnosis • Breast cancer survivors an  risk of a subsequent CBC • 1.5 - 5 fold higher risk of BC over general pop • Cumulative risk • Overall risk is 0.5% - 0.75%/yr • Majority diagnosed are stage 1 with 5 yr OS of 90% • Risk is modified by “risk factors”

  11. Survival and CBC Quan et al Am J Surg 2008 • OS predicted by initial stage for those presenting with Stage II/ III disease • Early (<36months) metachronous tumors were hypothesized to be • synchronous tumors • resistant to adjuvant treatment and thus bad actors

  12. Risk factors for CBC • Multifactorial • Personal history of breast cancer • Genetic mutation • Chest irradiation • Hodgkin’s lymphoma or mediastinal sarcoma • Histopathology of primary tumor • Adjuvant treatment • Reproductive and lifestyle factors

  13. Risk factors in Br Ca survivors Risk is cumulative and is dependent on • Breast Cancer specific survival • Prognosis of primary tumor • Risk of distant disease • Age at diagnosis/ presence of co-morbidities • Genetic risk • Type of adjuvant treatment • Preventative strategy and lifestyle

  14. Age at diagnosis

  15. CBC risk factors • Yi et al MD Anderson Case series • 542 women undergoing CPM • A CBC was associated with • Genetic risk • Gail risk >1.67% at five years (reproductive/lifestyle factors) • Ipsilateral moderate-high risk pathology • Ipsilateral multicentric disease • Invasive lobular histology Yi et al Cancer 2009

  16. Hereditary Breast Cancer • Genetic mutation-5-10% of cases • confers the largest risk of CBC • BRCA 1 or 2 • Estimated 3% annual risk • Risk may approach 50% lifetime • 3-5 life years gained seen with prophylactic mastectomy • Dependent on age of first diagnosis • Stage at diagnosis

  17. Hereditary breast cancer and CBC • Graeser et al JCO 2009 German pop study • 2020 women with documented mutation BRCA1/2 • Cumulative risk of CBC 25yrs 47% • BRCA1 • Trend of younger presentation with both primary and CBC • 62.9% of those dx <40 represented with a CBC • 19.6% if >50 presented with CBC • BRCA1 1.6 > risk of CBC than BRCA2 • Life time  risk of breast cancer

  18. Hereditary breast cancer and CBC • ATM ( ataxia-telangiectasia gene) • P53 - Li Fraumeni syndrome • PTEN/MMAC1 • Cowden’s syndrome bilateral risk Risk between gen population (0.5-1.0%/yr) and BRCA (1.0-3.0%/yr)

  19. CBC risk and familial BC • Familial designation- 15-20% of cases • Non genetic, no mutation able to be isolated….yet • Likely conferred by large number of low penetrence genes • One + 1st degree relative without the meeting the criteria for hereditary cancers • 2-10 fold increase in bilateral breast cancer risk • Risk is modified by age of patient at diagnosis as well as: • 0 first or second degree relatives -----RR 1 • 1 first degree relative --------------------RR1.9 • Relative >45 at age of diagnosis -----RR 1.5 • Relative <46 at age of diagnosis ------RR 2.7 • Sister < 46 ------------------------------RR 3.4 • Mother <46 -------------------------------2.4

  20. CBC risk and Histopathology • Lobular invasive • Classically described with bilateral risk • Likely due to inclusion of LCIS (3x risk of CBC) • Arpino et al using pre-op MRI • CBC in 20.9% of ILC cases versus IDC 11.9%* • Bedrosian et al • Compared survival of 18369 pt with ILC no CPM to 2332 ILC with CPM • No association between survival and CPM

  21. Risk of developing a CBC Life Expectancy Protective Effect Individualize RISK before making any recommendations

  22. CBC risk reduction options : • Surgery • CPM • Plus or minus reconstruction • Effect of chemotherapy/hormonal therapy • Screening • Lifestyle modifications

  23. Prophylactic mastectomy • In women with no cancer, prophylactic mastectomy reduces the incidence of breast cancer by 90% • If a CPM reduces breast cancer mortality • 1. contralateral breast cancer would have to be diagnosed • A more advanced stage, worse pathologic grade • Fewer available treatment options • 2.It adds an additive disease burden effect of a lower or equal stage cancer • First concern • Unsubstantiated- most women have surveillance mammography • Second concern • Unsupported in more recent studies when patients are stratified by age, receptor status and treatment

  24. Cochrane review of CPM in breast cancer survivors….. • ↓ in the incidence of Br Cancer specific mortality • No change in the over all survival •  cancer anxiety • Studies methodological limitations • Women should be aware of their true risk of developing breast cancer and the limitations of current evidence when considering prophylactic mastectomy”

  25. Impact on overall survival of ALL BC patients • Unknown but likely small • Prophylactic mastectomy • CON • “Systemic risk of the initial breast cancer far outweighs that of the CBC which is being prevented” • Complication rate 15-20% • 50% women require>2 surgeries • Should be timed to not delay adjuvant treatment • Pro • Risk of CBC will approach 0 • Surveillance is minimized

  26. Depends on the penetrance of the mutation • Most to gain if the risk of CBC 65% and least to gain if risk 25% • Most to gain if young age • Average 30yr BRCA1 patient • Compared with surveillance with annual mammography • Tamoxifen will gain 0.4-1.3 life years • Prophylactic oophorectomy 0.2-1.8 life years • Contralateral prophylactic mastectomy 0.6-2.1 years • Both surgeries and tamoxifen benefit for • node positive patients 3.3 life years • Node negative patients 4.4 life years • >50yrs only those patients with high penetrance genes benefit from all interventions • CPM should be discussed

  27. Risk of Contra-lateral breast cancer Expert Rev. Anticancer Ther 11(8), 2011

  28. Contralateral mastectomy • Reasonable indications • Previous radiation for Hodgkin's lymphoma • Known BRCA mutation • Difficulty in surveillance • Dense breast tissue on mammography • Diffuse calcifications • Strong family history but not gene positive • Therapeutic mastectomy with • Large breast creates symmetry and balance issues AGE

  29. Over 50% of women quote psychological fear as the reason for the CPM NA phenomenon  in mastectomy rates for both invasive and insitu ? Pre-op MRI use <10% in Europe Contrary to the shift to minimal surgery with the lumpectomy and local radiation

  30. Decision to have a CPM is complex • Frank and open discussion between the patient, oncologist, surgeon and plastic surgeon. • Weigh the risks of CBC taking into consideration • Age at diagnosis • Stage • Adjuvant treatment • Pros • No screening, decrease risk of Br C • Cons • Not minimal surgery, change is body image/sexuality

  31. Plastic surgery for reconstruction; the optimal plan • Simultaneous reconstruction • Pt less happy with results, rushed decision • Radiation to implant/flap compromises cosmesis • Complications will delay adjuvant treatment • Skin sparring will have fewer scars, possibly sensation and better look…nipple sparring!! • Delayed • More time for decision, but have to have mastectomy scars • ALL DEPENDS ON THE PLASTIC SURGEON

  32. Risk of CBC: Chemoprevention • Persistent and constant risk of contra lateral breast cancer….. • High prevalence of high risk pathology in contra lateral breast • Prevention trials • P1 for those with Gail risk >1.67 • STAR • IBIS 2  Invasive and in situ ER + disease by 50%

  33. Chemoprevention for CBC-Tamoxifen • EBCTCG • Adjuvant tamoxifen meta-analysis • CBC 2.0% to 1.3% (39% risk reduction) • Stronger association for postmenopausal ♀ • More protection the longer therapy lasted • NSABP- B14 • 53 months follow-up • ~50% CBC---all ages • Subset analysis premenopausal • 6 CBC in the TX group vs. 23CBC in No Tx group Suggests Tamoxifen is protective over the contralateral breast

  34. Swedish Trial Alkner 2009 • 564 ♀ randomized 2 yrs of tam median f/u 14yrs • ↓ of CBC HR 0.5 • < 40 yrs HR 0.09

  35. 4% • EBCTCG 2009 JCO • Meta-analysis of AI vs. Tam • No change in survival between treatment arms • Decrease in recurrences • Distant • Locoregional • Contra lateral No difference with 5 years of AI and the switch to AI after 2-3 yrs of Tamoxifen

  36. Chemoprevention- cytotoxic drugs • Adjuvant Polychemotherapy • EBCTCG 1992 • Metanalysis of 31 randomized trials • CBC 1.8% vs.. 1.7% P=NS • Herring et al 1986 MD Anderson • 797 operable breast cancer • FAC vs.. nothing • Comparable groups age, XRT and stage • Second malignancy rates • 1.9% vs.. 5.0% • Increase latency 17.5mo vs. 13mo Treats or slows the growth of the occult CBC 2005 Lancet over view suggests a 20% ↓CBC

  37. Chemotherapy/hormonal therapy • Treats the contralateral breast • Delays presentation of CBC • May not be an issue if have distant disease • Prevents the malignant transformation of high risk histology present in the CBC • Delays presentation or treats only receptor positive disease • Longer prospective studies needed

  38. Other medicationsbisphosphonates • Monsees et al J Natl Cancer Inst 2011 • Nested Case control study • 351 CBC compared to 662 control pt • Nitrogenous bisphosphonates associated with OR of 0.41 with CBC • Aldendronate OR 0.39 95% CI (0.18-0.88)

  39. Risk of CBC by Surveillance/ early detection • Intensive surveillance • P/E, mammography annually • +/- blood and x-rays • No difference in OS or time to recurrence with increased surveillance • Increase in number of investigations • ASCO recommendations • Monthly self breast exams ( no evidence) • Annual mammography and P/E 3-6 months

  40. Mammography-evidence • Retrospective analyses (1960,70,80’s) • No survival difference between those CBC detected via exam and mammogram • Screening mammogram tumors were smaller and an earlier stage very hard to show any benefit • Overall survival dependent on primary tumor • Mammograms for <40yr • Maybe effective in detecting CBC • The age group at most risk and most to gain in life years • OTHER MODALITIES???

  41. Lifestyle Changes:Obesity B-14 node negative ER- breast cancer • Looked at adjuvant therapy • Late analysis • Obesity and CBC relationship in >50yrs • BMI>30 HR 2.05 95%CI (1.13-3.73) • BMI >35 HR 2.13 95% CI ( 1.06-4.28) • Li et al 2009 • Nested case control trial • 329 patients with CBC compared to 729 controls • All ER + • Obese > 30BMI all ages • CBC OR 1.5 (95% CI 1.0-2.11)

  42. Population registry in Wisconsin Population registry from Wisconsin • BMI • 25.1-28.8 HR 1.57 (1.15-2.16) • >28.9 HR 1.56 (1.13-2.16) • Weight gain post diagnosis • <16.79 KG no increase risk • 16.79-36.28 HR 1.71 (1.17-2.49) • >36.29 HR 1.63 ( 1.03-2.60) Trentham-diatz 2007

  43. Life Style:Alcohol and smoking • Alcohol • > 7 drinks a week at primary diagnosis • Odds ratio 1.4, 95%CI 1.0-2.1 of CBC • >7 drinks between diagnosis • Odd ratio 1.7, 95%CI 1.0-2.91 of CBC • Smoking • Current smoker at first diagnosis • CBC OR 1.8 95%CI (1.1-3.21) • Still smoking OR 2.2 95% CI (1.2-4.01) • Smoker + >7 drinks a week • At primary dx OR 3.7 (1.4-9.81) • At CBC dx OR 7.2 (1.9-25.51) Li, c et al JCO 2009

  44. Life style:Physical activity • 73 studies show a reduction in breast cancer in women who are physically active • 25% risk reduction • Activities range from recreational to household with moderate intensity and sustained over a lifetime

  45. Conclusions • Is everyone who has BC at risk for a CBC? YES……….. But to varying degrees • Age is Very important (<50yrs) • Less risk of dying of something else ie comorbidity • Longer life to live with breast cancer • Genetic profile • Confirmed by genetic analysis or family history • Those who are young with hereditary cancer benefit the most from CPM

  46. Conclusions: Everyone else has a lesser degree of risk Individual decision if it is high enough for CPM

  47. Surveillance is important for everyone • Mammogram • Lifestyle need to change the little things • Obesity, Smoking, amount of Alcohol and physical activity • Adjuvant hormonal therapy • Treatment and prevention! • Bottom line is • A CPM is not the wrong thing to do • There are lots of other ways to reduce the risk.

  48. References • Dowsett M, Cuzick J, Ingle J, Coates A, Forbes J, Bliss J, Buyse M, Baum M, Buzdar A, Colleoni M, Coombes C, Snowdon C, Gnant M, Jakesz R, Kaufmann M, Boccardo F, Godwin J, Davies C, Peto R. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol. 2010 Jan 20;28(3):509-18. • Meakin JW, Hayward JL, Panzarella T, Allt WE, Beale FA, Bulbrook RD, Bush RS, Clark RM, Fitzpatrick PJ, Hawkins NV, Jenkin RD, Pringle JF, Rider WD. Ovarian irradiation and prednisone following surgery and radiotherapy for carcinoma of the breast.Breast Cancer Res Treat. 1996;37(1):11-9. • Alkner S, Bendahl PO, Fernö M, Nordenskjöld B, Rydén LTamoxifen reduces the risk of contralateral breast cancer in premenopausal women: Results from a controlled randomised trial. Eur J Cancer. 2009 Sep;45(14):2496-502. Epub 2009 Jun 15. • Trentham-Dietz A, Newcomb PA, Nichols HB, Hampton JM. Breast cancer risk factors and second primary malignancies among women with breast cancer.Breast Cancer Res Treat. 2007 Oct;105(2):195-207. Epub 2006 Dec 21. • Li CI, Daling JR, Porter PL, Tang MT, Malone KE. Relationship between potentially modifiable lifestyle factors and risk of second primary contralateral breast cancer among women diagnosed with estrogen receptor-positive invasive breast cancer.J Clin Oncol. 2009 Nov 10;27(32):5312-8. Epub 2009 Sep 8. • Dignam JJ, Wieand K, Johnson KA, Fisher B, Xu L, Mamounas EP. Obesity, tamoxifen use, and outcomes in women with estrogen receptor-positive early-stage breast cancer.J Natl Cancer Inst. 2003 Oct 1;95(19):1467-76.

  49. Thanks

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