Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

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• Recognizing family history patterns associated with specific gene mutations is important:
  • A family history of invasive lobular cancer and gastric cancer:
    • May be associated with CDH1 mutations
      • These mutations confer a 6.6 times greater risk of breast cancer than the general population:
        • And are associated with a high risk of hereditary diffuse gastric cancer (55% to 80%)
  • Patients with CDH1 mutations:
    • Should be offered prophylactic gastrectomy
    • Consideration of bilateral prophylactic mastectomy:
      • Based on family history
    • If surgery is not pursued, guidelines for screening for gastric cancer include:
      • Yearly endoscopic surveillance with random mucosal biopsies;
    • Breast screening consists of:
      • Annual mammogram and breast MRI

• References:
  • Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H, et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol. 2015;1(1):23-32.
  • Weiss A, Garber JE, King T. Breast cancer surgical risk reduction for patients with inherited mutations in moderate penetrance genes. JAMA Surg. 2018;153(12):1145-1146
  • van der Post RS, Vogelaar IP, Carneiro F, Guilford P, Huntsman D, Hoogerbrugge N, et al . Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet. 2015;52(6):361-374.
  • National Comprehensive Cancer Network Guidelines. Genetic/familial high-risk assessment: breast and ovarian, Version 1/2018. https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed November 9, 2019.

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• Truncating CHEK2 mutations (such as the c.1100delC mutation):
  • Are considered rare:
    • Moderate penetrance mutations
• The lifetime risk of developing breast cancer with these mutations:
  • Is three times higher than the general population:
    • This means that the majority of patients with these mutations will not develop breast cancer:
      • Many of the cancers that do develop may be:
        • Sporadic and not related to the mutation
• Patients with these mutations should be counseled about their risk and the available risk management strategies:
  • Those with a significant family history of breast cancer should be counseled regarding high risk breast cancer screening:
    • Annual mammogram with consideration of annual MRI starting at age 40 or modified to an earlier age based on family history) 
  • Counseled regarding high risk breast cancer prevention strategies, including:
    • Chemoprevention and prophylactic surgery:
      • It should be emphasized that there is less absolute risk-reduction benefit with:
        • Prophylactic surgery compared to high-penetrance mutations like BRCA mutations
      • Recommendations should be based on:
        • Patient’s family history
    • National Comprehensive Cancer Network guidelines should be followed with recommendation for high-risk screening, including:
      • Colon cancer screening recommendations:
        • Among individuals with a CHEK2 mutation
• References:
• Stratton MR, Rahman N. The emerging landscape of breast cancer susceptibility. Nat Genet. 2008;40(1):17-22.
• Desmond A, Kurian AW, Gabree M, Mills MA, Anderson MJ, Kobayashi Y, et al. Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment. JAMA Oncol. 2015;1(7):943-951.
• Weiss A, Garber JE, King T. Breast cancer surgical risk reduction for patients with inherited mutations in moderate penetrance genes. JAMA Surg. 2018;153(12):1145-1146.
• Tung N, Domchek SM, Stadler Z, Nathanson KL, Couch F, Garber JE, et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol. 2016;13(9):581-588.

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• The Gail model:
  • Which is based on:
    • Age
    • Race/ethnicity
    • Age at menarche
    • Age at first live birth
    • Number of prior breast biopsies
    • Personal history of atypical hyperplasia
    • Family history of breast cancer in first-degree relatives
  • The Gail model does not address and is not appropriate:
    • For patients with LCIS
• The Tyrer-Cuzick model:
  • Incorporates:
    • Age
    • Nulliparity
    • Family history
    • LCIS
    • BMI
    • Age at menarche
    • Age at menopause
    • Hormone replacement therapy use
    • Prior breast biopsies
  • However, while the Tyrer-Cuzick model does incorporate personal history of atypical ductal hyperplasia and LCIS:
    • Data has emerged showing that this model:
      • Appears to overestimate risk
      • Has poor concordance among populations of women with high-risk breast lesions
  • This model does not accurately predict invasive breast cancer risk:
    • Should be avoided even it may be the most accurate in assessing risk secondary to family history:
      • Among women with LCIS
  • Breast cancer risk among women with LCIS:
    • Has been shown to be approximately 2% per year and modified by volume of LCIS
• 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
  • The BOADICEA model incorporates 3rd-degree relatives
  • Whereas the BRCAPRO only incorporates 1st- and 2nd-degree relatives
  • Neither of these models incorporate nulliparity or LCIS into the calculation

• References:
  • 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.
  • 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;24:1610-1612; erratum appears in Stat Med. 2005;24:156].
  • Valero M, Zabor E, Park A, Gilbert E, Newman A, King TA, et al. The Tyrer-Cuzick Model inaccurately predicts invasive breast cancer risk in women with LCIS. Ann Surg Oncol. 2020;27(3):736-740.
  • Boughey JC, Hartmann LC, Anderson SS, Degnim AC, Vierkant RA, Reynolds CA, et al. Evaluation of the Tyrer-Cuzick (International Breast Cancer Intervention Study) model for breast cancer risk prediction in women with atypical hyperplasia. J Clin Oncol. 2010;28(22):3591-3596.
  • 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.
  • Berry DA, Parmigiani G, Sanchez J, Schildkraut J, Winer E. Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. J Natl Cancer Inst. 1997;89(3):227-238.
  • Antoniou AC, Pharoah PP, Smith P, Easton DF. The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer. 2004;91(8):1580-1590.

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• In 2018, an estimated 6.8 million women worldwide survived breast cancer:
  • After being diagnosed within the previous 5 years
• Unfortunately, and because most cancer registries only record the incidence and mortality but not the date of relapse:
  • It is unknown how many of these 6.8 million women are:
    • Living with metastatic disease and how many are cancer-free survivors
• Meeting the long-term medical and psychosocial needs of survivors in low- and middle-income countries is particularly difficult due to limited resources:
  • These issues are attracting global attention
  • The emergent issues include but are not limited to:
    • Common adverse effects over long periods after cancer treatment
    • Loss of strength
    • Sexual dysfunction
    • Bone health
    • Physical health concerns
    • Mental health concerns

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• The risk of developing breast or ovarian cancer:
  • Is directly related to a woman’s age
  • An unaffected 30-year-old BRCA carrier:
    • Has a 66% and 12.2%:
      • Cumulative risk of developing breast cancer and ovarian cancer by age 80, respectively
  • By contrast, an unaffected 60-year-old BRCA carrier has a:
    • 48% and 3.8% cumulative risk of developing breast and ovarian cancer by age 80
  • When counseling women on the optimal timing of prophylactic surgeries:
    • It is important to consider the woman’s age:
      • As the cumulative risk decreases with each decade of life
    • Whereas risk-reduction surgery is a reasonable choice for a 40-year-old:
      • It is equally reasonable to pursue high-risk surveillance alone for a 60-year-old woman, if she so desires
  • The benefit of breast cancer risk-reduction associated with TAH-BSO:
    • Especially in postmenopausal women, has been questioned
    • Some studies report reduction in breast cancer risk associated with BSO:
      • But a recent study by Kotsopoulos found:
        • Only a reduction in breast cancer risk following BSO among premenopausal BRCA2 mutation carriers
      • The risk reduction seen in postmenopausal women is debated
• References:
  • Hartmann LC, Lindor NM. The role of risk-reducing surgery in hereditary breast and ovarian cancer. N Engl J Med. 2016;374(5):454-468.
  • Chen S, Iversen ES, Friebel T, Finkelstein D, Weber BL, Eisen A, et al. Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol. 2006;24(6):863-871.
  • Harris JR, Lippman ME, Morrow M, Osborne CK. Diseases of the Breast, Fifth Edition. Philadelphia, PA: Wolters Kluwer Health, 2014.
  • 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).

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👉Studies have shown that your risk for breast cancer is due to a combination of factors. The main factors that influence your risk include being a woman and getting older. Most breast cancers are found in women who are 50 years old or older.

👉Some women will get breast cancer even without any other risk factors that they know of. Having a risk factor does not mean you will get the disease, and not all risk factors have the same effect. Most women have some risk factors, but most women do not get breast cancer. If you have breast cancer risk factors, talk with your doctor about ways you can lower your risk and about screening for breast cancer.

Risk Factors You Cannot Change

• Getting older. The risk for breast cancer increases with age; most breast cancers are diagnosed after age 50.
• Genetic mutations. Inherited changes (mutations) to certain genes, such as BRCA1 and BRCA2. Women who have inherited these genetic changes are at higher risk of breast and ovarian cancer.
• Reproductive history. Early menstrual periods before age 12 and starting menopause after age 55 expose women to hormones longer, raising their risk of getting breast cancer.
• Having dense breasts. Dense breasts have more connective tissue than fatty tissue, which can sometimes make it hard to see tumors on a mammogram. Women with dense breasts are more likely to get breast cancer.
• Personal history of breast cancer or certain non-cancerous breast diseases. Women who have had breast cancer are more likely to get breast cancer a second time. Some non-cancerous breast diseases such as atypical hyperplasia or lobular carcinoma in situ are associated with a higher risk of getting breast cancer.
• Family history of breast or ovarian cancer. A woman’s risk for breast cancer is higher if she has a mother, sister, or daughter (first-degree relative) or multiple family members on either her mother’s or father’s side of the family who have had breast or ovarian cancer. Having a first-degree male relative with breast cancer also raises a woman’s risk.
• Previous treatment using radiation therapy. Women who had radiation therapy to the chest or breasts (like for treatment of Hodgkin’s lymphoma) before age 30 have a higher risk of getting breast cancer later in life.
• Women who took the drug diethylstilbestrol (DES), which was given to some pregnant women in the United States between 1940 and 1971 to prevent miscarriage, have a higher risk. Women whose mothers took DES while pregnant with them are also at risk.

Risk Factors You Can Change

• Not being physically active.Women who are not physically active have a higher risk of getting breast cancer.
• Being overweight or obese after menopause. Older women who are overweight or obese have a higher risk of getting breast cancer than those at a normal weight.
• Taking hormones. Some forms of hormone replacement therapy (those that include both estrogen and progesterone) taken during menopause can raise risk for breast cancer when taken for more than five years. Certain oral contraceptives (birth control pills) also have been found to raise breast cancer risk.
• Reproductive history. Having the first pregnancy after age 30, not breastfeeding, and never having a full-term pregnancy can raise breast cancer risk.
• Drinking alcohol. Studies show that a woman’s risk for breast cancer increases with the more alcohol she drinks.

Research suggests that other factors such as smoking, being exposed to chemicals that can cause cancer, and changes in other hormones due to night shift working also may increase breast cancer risk.

Who Is at High Risk for Breast Cancer?

If you have a strong family history of breast cancer or inherited changes in your BRCA1 and BRCA2 genes, you may have a high risk of getting breast cancer. You may also have a high risk for ovarian cancer.

👉Talk Rodrigo Arrangoiz breast surgeon about ways to reduce your risk, such as medicines that block or decrease estrogen in your body, or surgery.external icon

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👉The initial treatment for thyroid cancer is surgery.

👉Many patients are treated with a total thyroidectomy and these patients are followed for cancer recurrence by measuring levels of the thyroid protein thyroglobulin as a cancer marker.

👉More recently, patients who are low risk and with the cancer confined to one lobe are offered to be treated a lobectomy. Indeed, the number of lobectomies done for thyroid cancer has been increasing recently. However, in patients with a normal lobe after a lobectomy, the thyroglobulin level is much less reliable as a cancer marker.

👉In this study, the authors report on their experience from a single institution on measuring thyroglobulin levels after a lobectomy for thyroid cancer.

👉THE FULL ARTICLE TITLE
Ritter A et al 2020 Detecting recurrence following lobectomy for thyroid cancer: Role of thyroglobulin and thyroglobulin antibodies. J Clin Endocrinol Metab 105:1–7. PMID: 32219303.

👉The authors looked at all their adult patients over a 15 years period that had a thyroid lobectomy for thyroid cancer and were monitored by serial serum thyroglobulin and thyroglobulin antibody for cancer recurrence.

👉Most of the 167 patients were female and all were disease stage I (low risk for cancer recurrence). The average cancer size was 9.5 mm and only a small percentage had some aggressive features.

👉Overall, the blood thyroglobulin levels did not correlate with cancer size or more aggressive cancer features and there was fairly equal distribution in patients whose thyroglobulin levels declined, increased, or remained stable over time.

👉Of the group, 10% of patients had a completion thyroidectomy during the study period, and 12 of them had cancer and 6 had benign nodules.

👉The trend in serum thyroglobulin was the same for those patients with cancer in the other thyroid lobe compared to those that had benign disease.

👉The authors conclude that serum thyroglobulin and thyroglobulin antibody levels after thyroid lobectomy are not sensitive to detect cancer recurrence. They therefore recommend ultrasound surveillance as well as more research to determine if there is a certain thyroglobulin level that would prompt suspicion for recurrence.

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• Receipt of mantle field radiation before the age of 30:
  • Is associated with a significantly increased risk of breast cancer compared to the general population
• Patients with a history of Hodgkin’s lymphoma treated with mantle field radiation therapy:
  • Are more likely to be diagnosed with:
    • Breast cancer at a younger age
    • Have hormone receptor negative breast cancer
    • And have a second breast cancer
• Because the increased risk of breast cancer has been seen as early as 8 years following receipt of radiation therapy:
  • High risk screening after mantle field radiation therapy:
    • Should begin at the age of 25 or
    • 8 years after radiation therapy
      • Whichever occurs later
• The estimated cumulative incidence of breast cancer by the age of 50 among patients with a history of Hodgkin’s lymphoma treated with mantle field radiation therapy is:
  • 35%
• Among all women at high risk for breast cancer (lifetime risk greater than 20%):
  • Annual screening MRI:
    • Has been associated with 77% to 100% sensitivity for detecting a new cancer
    • While mammography is associated with 16% to 40% sensitivity
• In 2007, the American Cancer Society convened an expert panel to review the evidence on MRI screening as an adjunct to annual mammography for women at high risk of developing breast cancer:
  • Annual screening MRI is recommended for patients with:
    • A clinical history of chest radiation between the ages of 10 and 30 years
  • As well as women with a known BRCA mutation
  • Untested first-degree relatives of BRCA mutation carriers
  • Those with other genetic mutations increasing breast cancer risk
  • Women with a greater than 20% lifetime risk secondary to family history
• The addition of bilateral breast ultrasound to a screening regimen of mammography and MRI:
  • Is associated with a substantial increase in false positives:
    • Leading to additional biopsies with no incremental benefit over mammography and MRI alone
• There is insufficient evidence to recommend for or against:
  • Annual screening breast MRI:
    • In women who have a history of:
      • Lobular carcinoma in situ
      • Atypical lobular hyperplasia
      • Atypical ductal hyperplasia
• There is no evidence to support MRI:
  • In women with a less than 15% lifetime risk of breast cancer
  • In women with dense breast tissue
  • In women with a personal history of breast cancer
• References:
  • Veit-Rubin N, Rapiti E, Massimo U, Benhamou S, Vinh-Hung V, Vlastos G, et al. Risk, characteristics, and prognosis of breast cancer after Hodgkin’s lymphoma. Oncologist. 2012;17(6):783-791.
  • Henderson TO, Amsterdam A, Bhatia S, Hudson MM, Meadows AT, Neglia JP, et al. Systematic review: surveillance for breast cancer in women treated with chest radiation for childhood, adolescent, or young adult cancer. Ann Intern Med. 2010;152(7):444-455; w144-454.
  • Moskowitz CS, Chou JF, Wolden SL, Bernstein JL, Malhotra J, Novetsky Friedman D, et al. Breast cancer after chest radiation therapy for childhood cancer. J Clin Oncol. 2014; 32(21):2217-2223.
  • Saslow D, Boetes C, Burke W, Harms S, Leach MO, Lehman CD, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57(2):75-89.
  • National Comprehensive Cancer Network. Breast Cancer Screening and Diagnosis, Version 1.2019. https://www.nccn.org/professionals/physician_gls/pdf/breast-screening.pdf. Accessed February 23, 2020.
  • Riedl CC, Luft N, Bernhart C, Weber M, Bernathova M, Tea MK, et al. Triple-modality screening trial for familial breast cancer underlines the importance of magnetic resonance imaging and questions the role of mammography and ultrasound regardless of patient mutation status, age, and breast density. J Clin Oncol. 2015;33(10):1128-1135.
  • van Zelst JCM, Mus RDM, Woldringh G, et al. Surveillance of Women with the BRCA1 or BRCA2 Mutation by Using Biannual Automated Breast US, MR Imaging, and Mammography. Radiology. 2017;285(2):376-388.

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👉For women diagnosed with ductal carcinoma in situ (DCIS), the risk of dying of breast cancer was three times higher than among women in the general population, according to findings from a large epidemiologic study.

👉Within a cohort of nearly 145,000 women who were treated for DCIS, 1540 died from invasive breast cancer, which was higher than the 458 expected breast cancer deaths in an equivalent number of cancer-free women from the general population.

👉The standardized mortality ratio (SMR) for death from breast cancer among women with DCIS was 3.36. The higher risk for death persisted more than 15 years after diagnosis.

👉Notably, the risk for death was higher in certain groups. Among Black women and those younger than 40, mortality rates approached 10%.

👉It’s hard to study the death rate for DCIS, as the numbers are rather low, and you have to go to a large database in order to obtain adequate numbers to show a difference. These results are not going to change clinical practice.

👉When DCIS is diagnosed, patients should know how its treated, what are the different options, and what is the chance that it will recur. More aggressive surgery provides peace of mind for the patient, but it doesn’t change survival.

👉The study was published online September 16 in JAMA Network Open.

👉An earlier study by Narod and colleagues yielded similar findings. That study found that about 3.3% of women with DCIS die of breast cancer within 20 years; the risk was higher among young women and Black women. However, the authors point out that the risk of dying of breast cancer after a diagnosis of DCIS had not been compared with women in the general population

👉We are well aware that if someone has a diagnosis of DCIS, they are at a higher risk of breast cancer going forward compared to someone without risk, and this is not a new fact.

👉Looking at the SEER [Surveillance, Epidemiology and End Results] database, no information on genetic status, family history, and other risk factors, and many of the women with DCIS that had excision excluded radiation therapy, which would have reduced their risk of recurrence.

👉These findings raises the awareness that DCIS is a difficult clinical problem that is multifaceted and often more confusing clinically than invasive cancers. There has been a push recently to decrease treatment for DCIS, but this study might require taking a second look at less aggressive management.

👉In this study, the investigators estimated the risk of dying of breast cancer following a DCIS diagnosis and compared that with the risk among cancer-free women. They used the SEER registries database to identify 144,524 women who were diagnosed with first primary DCIS from 1995 to 2014. The primary outcome was breast cancer death.

👉The mean follow-up time was 9.2 years. There were 4502 (3.1%) cases of ipsilateral invasive recurrence during that period, resulting in a 20-year actuarial risk of 13.9%. During that same period, there were 5527 (3.8%) contralateral invasive breast cancer events, for a 20-year actuarial risk of 11.3%. Overall, the 20-year actuarial risk for breast cancer death in this population was 3.3%.

👉Overall, the SMR for death from breast cancer among women with DCIS was 3.36, but it varied in accordance with age and race. For women younger than 40 years, the SMR was much higher, at 11.95; for women aged 40 to 49 years, it was 4.15.

👉The SMR for White women was 3.03; for Black women, it was 7.56. It was lower for East Asian women (1.89) and Southeast Asian women (2.40).

👉Black women do worse than White women, and we need to look at the disparities in treatment and care, as well as income.

👉Income had an effect on survival. For example, for patients earning >$40,000, the SMR was 4.11, compared to 2.73 for those with an income of >$50,000. “Income most likely doesn’t affect treatment of DCIS and the treatment of the cancer when it comes back,” he said, “but there may have been differences in treatment for distant metastasis.

👉All women in the cohort were treated surgically, and roughly half (n = 68,118 women; 47.1%) also received radiotherapy. Among women who underwent lumpectomy, the SMR was 2.81 (95% CI, 2.55 – 3.04) for women treated with radiotherapy and 3.42 (95% CI, 3.07 – 3.80) for those who underwent surgery alone. Among patients who did not receive radiotherapy, the SMR was 4.12 among those who underwent a single mastectomy (95% CI, 3.59 – 4.67) and 4.14 for those who underwent a double mastectomy (95% CI, 2.83 – 5.59).

👉The SMR was 4.12 for those who did not receive radiotherapy. For patients who underwent a lumpectomy, the SMR was 3.42 for those who did not receive radiotherapy and 2.81 for those who did. Among patients who did not receive any radiotherapy, the SMR was 4.12 for patients who underwent a unilateral mastectomy and 4.14 for those who underwent a bilateral mastectomy.

👉During the entire follow-up period, the annual mortality rate from breast cancer was 0.12% per year. It increased during the first 10 years and remained constant through years 15 through 20. The cumulative 20-year risk for breast cancer–specific mortality following DCIS was 3.3% overall, but for Black women who were diagnosed before age 50 years, the 20-year risk was much higher, at 8.1%.

👉Mount Sinai’s Bernik said that one interesting point of this article is that the highest risk for recurrence was among women who underwent mastectomy. However, these women may have been at a higher risk for death as a result of having more extensive disease with close margins or of having genetic mutations that increase the likelihood of recurrence. “These women were also younger and could have had longer follow-up and therefore were more likely to have a recurrence picked up in the database,” Bernik said. “Mastectomy patients generally also don’t use an antiestrogen after bilateral mastectomies.

👉The study’s bottom line, is that women with DCIS are at a higher risk for invasive cancer in the future.

JAMA Netw Open. Published online September 16. 2020. Full text

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