Cesar Rodriguez Valdes, M.D. James Graham Brown Cancer Center Department of Medical Oncology

1. Male breast cancer: our experience and a topic review Cesar Rodriguez Valdes, M.D. James Graham Brown Cancer Center Department of Medical Oncology

2. Learning objectives • Overview general principles of breast cancer in men. • Identify differences between male and female breast cancer: • Discuss resultsof latest publications on the topic. • Present our experience treating male breast cancer. • Review current guidelines for treatment.

3. Epidemiology • Less than 1% of breast cancer cases. • 2,450 men will be diagnosed this year. -- (288,130) • 470 patients will die. -- (39,520) • Detection in late 60’s. • 45-74 years of age • More advanced stage. • More deaths. • Higher incidence in Europe and North America. • Africa with rates up to 15%

4. Epidemiology

5. Epidemiology Incidence . • In situ: 7.1% (15%) • Stage I: 36.9% (23%) • Stage II: 41.9% (31%) • Stage III: 9.6% (15%) • Stage IV: 4.5% (15%)

6. Clinical features • Most tumors are detected after a lump or discharge is noticed. • less than 2 cm. • Approximately 6 months prior to seeking tx. • Location: retro- and peri-areolar. • 53% of cases • Stage: more lymph node involvement at diagnosis. • 39-55% (31%)

7. Risk factors genetic epidemiologic

8. Epidemiologic risk factors • Estrogen-testosterone imbalance • Liver disease. • Testicular problems. • Orchiectomy, undescended testes, trauma, orchitis. • Klinefelter’s syndrome. • 50 times increased risk • Exogenous administration of estrogen. • Gender reasignment. • Anti-androgen therapy. • Prostate cancer patients. Korde L et al. J Clin Oncol 2010

9. Epidemiologic risk factors • Obesity • Increased conversion of testosterone to estrogen. • Doubles risk of breast cancer. • Gynecomastia • Seen in 38% of male breast cancer patients. • History • Prior history of breast cancer • 30 fold increased risk of contralateral cancer. • First-degree relatives • Seen in 20% of cases. Korde L et al. J Clin Oncol 2010

10. Epidemiologic risk factors • Environmental and occupational. • Ionizing radiation exposure. • Longer latent period than women by 20-30 years. • Increased heat exposure • Ovens, furnaces, truck drivers. • Electromagnetic radiation ??????? Korde L et al. J Clin Oncol 2010

11. Genetic risk factors • BRCA 2 gene mutation. • Most predominant. • 10% lifetime risk of developing breast cancer. • Variability among ethnicities. • Iceland: 40% • Italy: 7% • U.S.: 27% (data not available) • BRCA 1 gene mutation. • 1-5% of male breast cancer patients. Note: higher association with patients having positive family history. • Testing on all men recommended despite of history.

12. Genetic risk factors • CHEK2 gene mutation • DNA repair • 10 fold increase in MBC • Associated to patients with family history. • CYP17 gene mutation • Encodes for cytochrome P450c17 involved in synthesis of estrogens and androgens. • AR gene mutation • Encodes for androgen receptor.

13. Genetic risk factors • Cowden syndrome • PTEN mutation described in two male cases. • Mutation in gene suppresion gene leading to development of hamartomas and increased risk of cancer. (thyroid, breast, kidney, colon) • Klinefelter syndrome • XXY makeup seen in 1 of 650 males. • Tommasi et al. • Comparative genomic hybridization assay

14. Histopathology • Type of histology. • 90% invasive ductal carcinoma. (85%) • 5-10% ductal carcinomas in situ. (15%) • 4% papillary carcinomas. • Tumor grade. • Grade I: 11% (7%) -- (24.5%) • Grade II: 50% (61%) -- (45.3%) • Grade III: 29% (30%) -- (27.5%)

15. Histopathology • Hormone receptors. • ER: 92% • PR: 84% • Her2: -

16. Management

17. Management

18. Management • Surgical approach • Breast • Modified radical mastectomy. • Radical mastectomy. • Significant chest wall defects. • Transverse thoracoepigastric flap or TRAM • Lumpectomy with radiation. • Difficult due to location and breast volume

19. Surgical management (cont’d) • Lymph nodes • Sentinel lymph node. • Tumor size < 2.5 cm with no clinical signs of lymph node involvement. • Axilary lymph node dissection.

20. Adjuvant radiation • Retrospective studies are not reliable due to time span interval, changes in radiation, and type or surgeries performed. • Cutuli et al. 496 patients from 20 French institutions. • Ribeiro et al. Historical cohort of 428 patients from Manchester, UK. • Adjuvant radiation should be mandatory in: • Breast conserving surgery. • Tumors larger than 1cm with areola, skin or muscle involvement. • High grade, lympho-vascular invasion, high proliferation rate. • Nodes: 3 axillary lymph nodes or supraclavicular node involvement.

21. Neoadjuvant chemotherapy • Indications for treatment: • Ulcerated neoplasia. • Fixation to the surrounding tissues. • Advanced lymph node involvement. • Surgically difficult procedures.

22. Adjuvant chemotherapy • Few prospective studies exist. • Bagley et al. 1987. • 24 men with stage II treated with CMF. • 80% 5-year survival. • Yildirim and Berberoglu 1998. • 121 men treated over 22 years in Ankara, Turkey. • Relative risk of death if no chemotherapy was 1.4. • Recommendation to follow guidelines for female breast cancer.

23. Adjuvant chemotherapy • Patient co-morbidities should be taken into consideration. . • Use of chemotherapy if hormone negative tumors. • Use of taxanes if positive lymph nodes. • There is no data in the use of trastuzumab. • Suggested if Her2 positive.

24. Hormonal therapy • 39 patients with stage II and stage III where given adjuvant tamoxifen for 1-2 years. • 66% 5-year survival in patients with tamoxifen compared to historical control of 44% (p=0.006)

25. Hormonal therapy • Tolerance has not been studied well in prospective studies. • Reduced libido, DVT, impotence, mood changes, hot flushes. • It is believed the actual efficacy is higher if studies showed response rates over 5 years.

26. Hormonal therapy • Aromatase inhibitors: • No good studies are available. • Healthy men have shown a 50% reduction in estradiol. • Cutuli et al. Used AI in 38 patients with mutiple co-morbidities reporting similar response to tamoxifen, but results are still being evaluated. • Letrozole: • Two case reports have shown good response.

27. Metastatic setting Ann Int Med 2002(137) 678-687 • Retrospective series studies from 1942-2000. • 50% of patients have a response to tamoxifen. • Hormonal therapy has been considered the first line therapy due to lower toxicities and good response.

28. Our experience • Out of 13 patients (9 with local involvement and4 with positive lymph node): • 38% underwent modified radical mastectomy with lymph node resection. • 53% underwent simple mastectomy with sentinel lymph node resection. • One patient undewent lumpectomy and SLND. • Adjuvant treatment: • 31% received adjuvant radiation. • 61% received tamoxifen (23% as first line) • 30% received chemotherapy • One patient relapsed (triple negative, refused chemo).

29. Conclusions and recommendations • Male breast cancer even though very similar to female breast cancer: < • Is more advanced at time of detection. • Has distinct histopathology. • Has higher response to hormone therapy. • Has more complications in treatment due to age and co-morbidities. • Lacks awareness amongst the population.

30. Conclusions and recommendations • Male breast cancer patients must be referred for genetic counseling. • More prospective studies are required to help understand etiology and determine differences in treatment should be made.

31. Thank you. Trivia question: what is the ribbon for male breast cancer?