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• Two randomized clinical trials:
  • Were initiated and terminated early due to an increase in breast cancer events in patients in the hormone replacement therapy (HRT) arm with a personal history of breast cancer
    • The HABITS (Hormonal Replacement Therapy after Breast Cancer- Is It Safe?) trial:
      • Randomized 442 patients with a personal history of breast cancer to:
        • HRT with estradiol with or without progesterone (based on the presence of a uterus) vs. nonhormonal symptom management
      • More women in the HRT arm than the non-HRT arm had hormone receptor-positive breast cancer (62.3% vs 54.5%), and approximately half of patients in each group had taken HRT before their diagnosis of breast cancer
      • At median follow-up of 4 years, new breast cancer events occurred twice as frequently in the HRT group (hazard ratio [HR] 2.4) compared to the nonhormonal symptom management group
  • A similar trial in Stockholm found no difference in breast cancer recurrence in patients randomized to HRT vs. no HRT at 11 years of follow-up:
    • But reported an increased risk of contralateral breast cancer in those receiving HRT (HR 3.6, p=0.013)
• Estrogen alone:
  • Can be used to reduce symptoms for postmenopausal women without a personal history of breast cancer who have had a hysterectomy, and was associated with a nonsignificant lower risk of breast cancer in the Women’s Health Initiative trial at 13 years of follow-up (HR 0.79)
  • However, the WHI cohort did not include women with a personal history of breast cancer, and therefore these data cannot be extrapolated to this population
• Expert guidelines:
  • Recommend the use of topical low-dose vaginal estrogen therapy for women with bothersome genitourinary symptoms and contraindications to the use of systemic HRT:
    • This is a reasonable strategy in breast cancer survivors due to the local nature of vaginal estrogen and its low systemic absorption
• References
  • Holmberg L, Iversen OE, Rudenstam CM, Hammar M, Kumpulainen E, Jaskiewicz J, et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst. 2008;100(7):475-482.
  • Fahlén M, Fornander T, Johansson H, Johansson U, Rutqvist LE, Wilking N, et al. Hormone replacement therapy after breast cancer: 10 year follow up of the Stockholm randomised trial. Eur J Cancer. 2013;49(1):52-59.
  • Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, et al. Menopausal hormone therapy and health outcomes during the intervention and extended post-stopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.
  • The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24(7):728-753.

• The Tyrer-Cuzick model:
  • Estimates breast cancer risk based largely on family history, and it includes breast density as part of the risk caclulation
• The Gail model:
  • Which calculates breast cancer risk based on age, race/ethnicity, age at menarche, age at first live birth, number of prior breast biopsies, personal history of atypical hyperplasia, and family history of breast cancer in first-degree relatives, does not include breast density or genetic testing results
• BRCAPRO and BOADICEA:
  • Are both Mendelian models that estimate breast cancer risk based on the probability that the individual carries a mutation in a major breast cancer susceptibility gene, such as BRCA1 or BRCA2
  • These models do not incorporate nulliparity or breast density into the calculation
• The Claus model:
  • Is based only on family history of breast cancer in first- and second-degree relatives, is not thoroughly validated in independent cohorts, and does not include factors such as nulliparity
• References
  • Amir E, Freedman OC, Seruga B, Evans DG. Assessing women at high risk of breast cancer: a review of risk assessment models. J Natl Cancer Inst. 2010;102(10):680-691.
  • Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med. 2004;23(7):1111-1130. [See comment in Stat Med. 2005;24:1610-161; erratum appears in Stat Med. 2005;24:156].
  • Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81(24):1879-1886.
  • Claus EB, Risch N, Thompson WD. Autosomal dominant inheritance of early-onset breast cancer implications for risk prediction. Cancer. 1994;73(3):643-651.

• The rate of cancer development in setting of LCIS:
  • Has been reported to be approximately 2% per year:
    • Translating into a cumulative long-term rate of 26% at 15 years
• While a minority of patients elect to proceed with bilateral prophylactic mastectomy for LCIS:
  • The estimated breast cancer incidence is generally not considered high enough to justify such extensive surgery
  • Furthermore, women with a history of LCIS:
    • Typically develop low- or intermediate-grade malignancies clinically detected at an early stage
• Multiple studies support a low upgrade rate on excision (1% to 5% for patients diagnosed with LCIS on core biopsy and rad-path concordant) with a 1% upgrade rate reported in a prospective study with central pathology review:
  • Therefore surgical excision is not routinely indicated
• The risk conferred by LCIS:
  • Is independent of family history
• Chemoprevention:
  • Reduces breast cancer risk by 40% to 65% in women at elevated risk:
    • Data from the NSABP P-1 trial suggest that women with LCIS derive even greater benefit than this estimate
• References:
  • King TA, Pilewskie M, Muhsen S, Patil S, Mautner SK, Park A, et al. Lobular carcinoma in situ: a 29-year longitudinal experience evaluating clinicopathologic features and breast cancer risk. J Clin Oncol. 2015;33(33):3945–3952.
  • Wong SM, King T, Boileau JF, Barry WT, Golshan M. Population-based analysis of breast cancer incidence and survival outcomes in women diagnosed with lobular carcinoma in situ. Ann Surg Oncol. 2017;24(9):2509-2517.
  • Nakhlis F, Gilmore L, Gelman R, et al. Incidence of Adjacent Synchronous Invasive Carcinoma and/or Ductal Carcinoma In-situ in Patients with Lobular Neoplasia on Core Biopsy: Results from a Prospective Multi-Institutional Registry (TBCRC 020). Ann Surg Oncol. 2016;23(3):722-728.
  • King MC, Wieand S, Hale K, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001;286(18):2251-2256.

• The rate of cancer development in setting of LCIS:
  • Has been reported to be approximately 2% per year:
    • Translating into a cumulative long-term rate of 26% at 15 years
• While a minority of patients elect to proceed with bilateral prophylactic mastectomy for LCIS:
  • The estimated breast cancer incidence is generally not considered high enough to justify such extensive surgery
  • Furthermore, women with a history of LCIS:
    • Typically develop low- or intermediate-grade malignancies clinically detected at an early stage
• Multiple studies support a low upgrade rate on excision (1% to 5% for patients diagnosed with LCIS on core biopsy and rad-path concordant) with a 1% upgrade rate reported in a prospective study with central pathology review:
  • Therefore surgical excision is not routinely indicated
• The risk conferred by LCIS:
  • Is independent of family history
• Chemoprevention:
  • Reduces breast cancer risk by 40% to 65% in women at elevated risk:
    • Data from the NSABP P-1 trial suggest that women with LCIS derive even greater benefit than this estimate
• References:
  • King TA, Pilewskie M, Muhsen S, Patil S, Mautner SK, Park A, et al. Lobular carcinoma in situ: a 29-year longitudinal experience evaluating clinicopathologic features and breast cancer risk. J Clin Oncol. 2015;33(33):3945–3952.
  • Wong SM, King T, Boileau JF, Barry WT, Golshan M. Population-based analysis of breast cancer incidence and survival outcomes in women diagnosed with lobular carcinoma in situ. Ann Surg Oncol. 2017;24(9):2509-2517.
  • Nakhlis F, Gilmore L, Gelman R, et al. Incidence of Adjacent Synchronous Invasive Carcinoma and/or Ductal Carcinoma In-situ in Patients with Lobular Neoplasia on Core Biopsy: Results from a Prospective Multi-Institutional Registry (TBCRC 020). Ann Surg Oncol. 2016;23(3):722-728.
  • King MC, Wieand S, Hale K, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001;286(18):2251-2256.

• BRCA1 and BRCA2:
  • Are genes that produce tumor suppressor proteins:
    • Which help repair damaged DNA
  • They are the most common gene alterations seen in the hereditary breast cancer population
    • They are associated with an increased risk of breast cancer:
      • Estimated to be 55% to 70% for BRCA 1 carriers and 45% to 70% in BRCA2 carriers by age 70
  • While both BRCA1 and BRCA2 mutations are associated with an increased risk of breast cancer:
    • BRCA1 breast cancers more commonly occur in younger, premenopausal women and are more likely to be triple negative
  • BRCA1 is associated with a higher risk of ovarian cancer compared to BRCA2:
    • With a lifetime risk of 40% to 45% in BRCA1 carriers compared to 15% to 20% in BRCA2 carriers
  • BRCA2 breast cancers:
    • More closely resemble the sporadic breast cancer pattern, with a predominance of hormone receptor positive cancers in women greater than 50 years
• CHEK2 and PALB2:
  • Are moderate penetrance genes that are less common than BRCA mutations
  • Similar to BRCA 2 deleterious mutations:
    • CHEK2 and PALB2 mutations are associated with hormone receptor positive postmenopausal breast cancer
• References
  • Loi M, Desideri I, Olmetto E, Francolini G, Greto D, Bonomo P, et al. BRCA mutation in breast cancer patients: Prognostic impact and implications on clinical management. Breast J. 2018;24(6):1019-1023.
  • Peshkin BN, Isaacs, C et al. Overview of hereditary breast and ovarian cancer syndromes. UpToDate website. Updated February 10, 2020. https://www.uptodate.com/contents/genetic-testing-and-management-of-individuals-at-risk-of-hereditary-breast-and-ovarian-cancer-syndromes. Accessed February 15, 2020.
  • Economopoulou P, Dimitriadis G, Psyrri A. Beyond BRCA: new hereditary breast cancer susceptibility genes. Cancer Treat Rev. 2015;41(1):1-8.

• Women with a pathogenic variant in BRCA1:
  • Have a lifetime cumulative ovarian cancer risk of 44% (95% CI 36% to 53%)
• The NCCN guidelines recommend:
  • Risk-reducing bilateral salpingectomy-oophorectomy (BSO), for women who have completed childbearing:
    • Be performed by age 35 to 40 in BRCA1 patients
  • Of note, hysterectomy at the time of BSO is not routinely recommended
• There is a lack of data to support survival benefit to ovarian cancer screening
• Pelvic MRI serves no role in screening for ovarian cancers
• For high-risk patients who decline or defer BSO:
  • Screening is typically offered and includes transvaginal ultrasound and cancer antigen (CA) 125 every six months beginning at age 30 or 5 to 10 years before the earliest age of first diagnosis of ovarian cancer in the family:
    • This screening strategy appears most effective with use of longitudinal algorithms as opposed to a single cutoff for CA 125
• There is no current effective chemoprevention option for risk-reduction in ovarian cancer, though research is underway
• References
  • Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402-2416.
  • National Comprehensive Cancer Network. Genetic/familial high risk assessment: breast and ovarian, Version 1.2020 https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf Accessed February 23, 2020.
  • Menon U, Karpinskyj C, Gentry-Maharaj A. Ovarian cancer prevention and screening. Obstet Gynecol. 2018;131(5):909-927.
  • Kathawala RJ, Kudelka A, Rigas B. The chemoprevention of ovarian cancer: the need and the options. Curr Pharmacol Rep. 2018;4(3):250-260.

• Although BRCA1 associated breast cancers tend to be triple negative and not influenced by estrogen:
  • A 37% reduction in breast cancer risk is seen after BSO
• In BRCA2 mutation carriers:
  • BSO confers a 64% breast cancer risk reduction
• Eisen et al:
  • Showed that BSO before the age of 50 led to a greater reduction in breast cancer risk compared to patients who underwent BSO after the age of 50
• Given that chemotherapy-induced cessation of menses:
  • Reduces estrogen exposure:
    • The added reduction from BSO in patients with chemotherapy-induced menopause is not as significant as in patients with intact ovarian function
• In a study by Domchek et al:
  • BSO reduced breast cancer specific mortality, ovarian cancer specific mortality and overall mortality by 90%, 95%, and 76%, respectively in BRCA mutation carriers
• A prospective study by Kostopoulos:
  • Examined the effect of BSO on breast cancer risk and found the largest risk reduction provided by BSO among premenopausal BRCA2 mutation carriers
• References
  • Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010;304(9):967-975.
  • Eisen A, Lubinski J, Klijn J, Moller P, Lynch HT, Offit K, et al. Breast cancer risk following bilateral oophorectomy in BRCA1 and BRCA2 mutation carriers: an international case-control study. J Clin Oncol. 2005;23(30):7491-7496.
  • Kotsopoulos J, Huzarski T, Gronwald J, Singer CF, Moller P, Lynch HT, et al. Bilateral oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2017;109(1).

• The Women’s Health Initiative (WHI):
  • Studied the effects of estrogen alone in postmenopausal women with hysterectomy and found a possible reduction in breast cancer risk:
    • Therefore, for this population, particularly younger newly postmenopausal women:
      • This regimen is a good choice for management of menopausal symptoms in the short term
• On the other hand:
  • The WHI showed a significant increased risk of breast cancer in women:
    • Taking combined hormone replacement therapy with estrogen and progestin
• There are no data to support claims that bioidentical hormones are safer than other hormones, and they must be assumed to have the same risks as commercial hormone preparations
• The risk of breast cancer associated with transdermal estrogens and progestins:
  • Does not differ from oral preparations
• The Nurses’ Health Study:
  • Found significantly increased risk of breast cancer in women who used estrogen and testosterone therapies
• References
  • Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-1712.
  • Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.
  • Boothby LA, Doering PL, Kipersztok S. Bioidentical hormone therapy: a review. Menopause. 2004;11(3):356-367.
  • Burry KA, Patton PE, Hermsmeyer K. Percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen. Am J Obstet Gynecol.1999;180(6 Pt 1):1504-1511.
  • Tamimi RM, Hankinson SE, Chen WY, Rosner B, Colditz GA. Combined estrogen and testosterone use and risk of breast cancer in postmenopausal women. Arch Intern Med. 2006;166(14):1483-1489.

Top 10 Risk factors for MALE Breast Cancer

1. Aging

Risk increases with age. On average, men with breast cancer are about 72 years old when they are diagnosed.

2. Family history of breast cancer

About 1 out of 5 men with breast cancer have a close relative, male or female, with the disease.

3. Inherited gene mutations

Men with a BRCA2 gene mutation have an increased risk of breast cancer, with a lifetime risk of about 6 in 100. BRCA1 mutations can also cause breast cancer in men, but the risk is lower, about 1 in 100 ( in women BRCA1 has higher risk). Mutations in CHEK2, PTEN and PALB2 genes might also be responsible for some breast cancers in men.

4. Klinefelter syndrome

XXY : Men with Klinefelter syndrome (1 in 1000) have lower levels of androgens and more estrogens, have gynecomastia.
Increases breast cancer risk 20 – 60 times the risk of a man in the general population.

5. Radiation exposure

Prior chest radiation treatment for lymphoma has an increased risk of developing breast cancer.

6. Alcohol

Heavy drinking ⬆️ risk likely due to its effects on the liver.

7. Liver disease

Cirrhosis lower levels of androgens and higher levels of estrogen. Also higher chance of developing gynecomastia.

8. Estrogen treatment

Estrogen-related drugs were once used in hormonal therapy for men with prostate cancer. Transgender/transsexual individuals who take high doses of estrogens as part of sex reassignment could also have a higher breast cancer risk. Not much published data yet.

9. Obesity

Fat cells in the body convert androgens to estrogens. Obese men have ⬆️ levels of estrogens in their body.

10. Testicular conditions

Certain conditions, such as having an undescended testicle, mumps as an adult, or history of orchiectomy may increase male breast cancer risk.

https://amp.cancer.org/cancer/breast-cancer-in-men/about/key-statistics.html

• Nipple-sparing mastectomy (NSM):
  • Has increasingly become an acceptable choice for risk reduction in the BRCA1 and BRCA2 mutation carrier population due to a potential superior cosmetic outcome compared to skin-sparing mastectomy
• Macromastia (C cup breast or higher):
  • Can result in malposition of the nipple and may require alternative incisions or a standard skin-sparing mastectomy approach for optimal cosmetic results
• Grade I ptosis is not a contraindication to NSM:
  • However, ptosis of grade 2 or higher:
    • Can also result in malposition of the nipple-areolar complex (NAC)
• Regarding future cancer risk:
  • There may be a small risk associated with leaving the NAC in situ
  • The greater risk appears to be within the at-risk breast tissue left on thicker mastectomy skin flaps rather than within the NAC itself:
    • As studies have shown the majority of cancer recurrences occur outside of the NAC:
      • Therefore, optimizing dissection technique and choosing appropriate incisions are essential to obtaining optimal oncologic outcomes with this procedure
• A previous benign biopsy of calcifications is not a contraindication to NSM:
  • However, extensive malignant calcifications, tumors less than to 2 cm from the nipple, nipple discharge, or a rash on the nipple are contraindications to NSM
• References:
  • Tousimis E, Haslinger M. Overview of indications for nipple sparing mastectomy. Gland Surg. 2018;7(3):288-300.
  • Manning AT, Wood C, Eaton A, Stempel M, Capko D, Pusic A, et al. Nipple-sparing mastectomy in patients with BRCA1/2 mutations and variants of uncertain significance. Br J Surg. 2015;102(11):1354-1359.
  • Yao K, Liederbach E, Tang R, Lei L, Czechura T, Sisco M, et al. Nipple-sparing mastectomy in BRCA1/2 mutation carriers: an interim analysis and review of the literature. Ann Surg Oncol. 2015;22(2):370-376.
  • Moo TA, Pinchinat T, Mays S, Landers A, Christos P, Alabdulkareem H, et al. Oncologic outcomes after nipple-sparing mastectomy. Ann Surg Oncol. 2016;23(10):3221-3225
  • Jakub JW, Peled AW, Gray RJ Greenup RA, Kiluk JV, Sacchini V, et al. Oncologic safety of prophylactic nipple sparing mastectomy in a population with BRCA mutations: A multi-institutional study. JAMA Surg. 2018;153(2):123-129.