Does genetic testing have any role for elderly breast cancer patients? A narrative review

Introduction

Identifying breast cancer patients with hereditary genetic mutations, particularly in BRCA1 and BRCA2 genes which are renowned to impose substantial life-time risks for cancers, has significant impact not only in the proband patients, affecting their cancer management and prevention, but also in cancer-free family members through family testing. Conventionally, genetic testing is offered to breast cancer patients who had hereditary risk factors including young age of disease onset, personal cancer history such as bilateral and multiple cancers, and strong family cancer history particularly those involving first-degree relatives and multiple generations. However, the prevalence of genetic mutations in relatively older breast cancer patients might have been underestimated over the years. Given that nearly half of the women diagnosed with breast cancer are age 65 and above, and the breast cancer incidence is increasing (1), the role of genetic testing and management of hereditary breast cancer in older women warrant attention. Therefore, this literature review aimed to highlight the controversies of genetic testing for elderly breast cancer patients, the breast cancer incidence of elderly BRCA mutation carriers, and to summarize the management considerations. We present the following article in accordance with the Narrative Review reporting checklist (available at https://abs.amegroups.com/article/view/10.21037/abs-21-122/rc).

Methods

Literature search was performed targeting published English literature from year 2000 onwards in PubMed. Search terms included “BRCA mutations”, “genetic mutations”, “hereditary breast and ovarian cancer syndrome”, “elderly”, “post-menopausal”, “genetic testing”, “cancer incidence”, “cancer detection rate”, “contralateral breast cancer”, “risk-reducing mastectomy”, “prophylactic mastectomy”, “chemoprevention”, “tamoxifen”, “bilateral salpingo-oophorectomy”. The search strategy is summarized in Table 1.

Prevalence of genetic mutations in elderly breast cancer patients

The prevalence of BRCA1/2 mutation-associated breast cancer among all breast cancer has been reported to be 5–15% (2). It is well-known that breast cancer patients with BRCA1/2 mutation have a young age of disease onset, with more than half being diagnosed at an age of less than or equal to 40 (3,4). However, the prevalence of pathogenic variants in older breast cancer patients is not well studied. Until recently, Kurian et al. reported a study with data from a Women’s Health Initiative which compared 2,195 female breast cancer patients who were diagnosed at a median age of 73 years old to 2,322 breast-cancer free women. The prevalence of mutations in 10 hereditary breast cancer associated genes, including BRCA1 and BRCA2, were 3.5% (95% CI: 2.82–4.42) of the unselected postmenopausal breast cancer patients, compared with 1.3% (95% CI: 0.87–1.84) of cancer-free women. In particular, 1.2% (95% CI: 0.78–1.73) were detected to have BRCA1/2 mutation; the percentage was even higher at 2.2% in postmenopausal women who were diagnosed before age 65. While for those aged 65 or above, 1.0–1.3% were found to have BRCA1/2 mutations and 1.3–3.2% had mutations in other breast-cancer associated genes. These percentages were higher when compared to only 0.22% BRCA1/2 mutation positive rate in control group (5). Thus, the mutation detection rate was lower in older breast cancer women when compared to their younger counterparts, but was higher when compared to cancer-free women.

One point to note was that in this study, this group of postmenopausal primary breast cancer patients were unselected. When considering their hereditary risks such as family history, personal cancer history, biology of cancer etc, 30.8% (8 out of 26) of the BRCA1/2 mutation positive and 32.1% (25 out of 78) of any other breast-cancer associated genes mutation positive breast cancer patients were fulfilling the conventional genetic testing guidelines (5). In other words, without genetic testing of all breast cancer patients, 0.8% (18 out of 2,195 patients) of BRCA mutations and 2.4% (53 out of 2,195 patients) of any other breast-cancer associated genes mutations in postmenopausal breast cancer patients would be underdiagnosed. These underdiagnosis rates may not seem to be over alarming. Nevertheless, this study by Kurian et al. has demonstrated that the prevalence of pathogenic variants in postmenopausal breast cancer patients was similar to that of Ashkenazi Jewish population, whose prevalence of BRCA mutation was 2.3% due to three founder mutations, and the percentage was higher in women and younger patients (6). Therefore, the U.S. Preventive Service suggested genetic counselling and testing in all patients with Ashkenazi Jewish ancestry (7). Similarly, could the prevalence of mutations in older breast cancer patients be high enough to justify universal genetic testing?

Controversy of extending genetic mutation testing

Genetic testing extending to all breast cancer patients regardless of clinical hereditary risk factors is controversial. It has been argued that the proportion of mutation carriers who didn’t fulfil conventional testing criteria was not negligible, due to small pedigrees and incomplete penetrance. In an earlier study in 2007, it was shown that more than 60% of the mutation carriers didn’t fulfil clinical criteria for genetic testing (8). This high percentage could be due to more stringent genetic testing criteria in the past. In a more recent cohort of 1,371 breast patients including 42 (3.1%) BRCA mutation carriers, using young onset age of below 40 years old or triple-negative breast cancer as criteria detected 32–34% of carriers; using positive family history identified 37%; while using age less than 60 years old identified 90% (9). The potentially undiagnosed mutation carriers could be missed from preventive measures and enhanced surveillance. Recently, the American Society of Breast Surgeons Consensus Guideline in 2019 stated that all breast cancer patients (newly diagnosed or with a personal history) should be offered with genetic testing (10), and explained genetic testing criteria was initially set high due to cost in the past. In the era of next generation sequencing, the cost of testing has dropped dramatically.

On the other hand, given the high prevalence of breast cancer and good survival, offering all breast cancer patients genetic counselling and testing could still pose a significant challenge in terms of cost. A systematic review of BRCA genetic testing programmes evaluation showed that family history-based screening was potentially very cost-effective, while there was currently no evidence for screening of all newly diagnosed breast or ovarian cancers (11). The National Comprehensive Cancer Network recommended testing for BRCA1 and BRCA2 only in women with a high risk of hereditary breast cancer syndrome based on conventional genetic test criteria, with the latest inclusion of breast cancer of particular biological subtypes for therapeutic use of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors, such as HER2 negative metastatic breast cancer (12,13). US Preventive Services Task Force also recommended against routine genetic testing for breast cancer patients without personal or family history/ancestry which suggested a potentially harmful BRCA1/BRCA2 gene mutation (7). Particularly for elderly patients, it is important to know if there would be any benefits or changes in management if genetic mutation is identified.

Breast, ovarian and pancreatic cancer risk of elderly patients with BRCA mutations

Limited data was available for elderly BRCA mutation carriers in the literature. Lifetime risks of breast cancer were 45–80% for BRCA1 and 30–60% for BRCA2, while ovarian cancer risks were 20–55% for BRCA1 and 5–20% for BRCA2 mutation carriers (14-16). However, studies usually stopped risk estimates at age 70 with only a few extended to age 80 (17). In a prospective study by Kuchenbaecker et al, the cumulative breast cancer risk to age 80 years was 72% for BRCA1 and 69% for BRCA2 mutation carriers. The age with the highest risk of breast cancer was 41–50 years old for BRCA1 and 51–60 years old for BRCA2 mutation carriers, while older women at age 71–80 also had an elevated incidence of breast cancer: 16.5 and 21.9 per 1,000 person-years for BRCA1 and BRCA2 mutation respectively. This showed that breast cancer incidences in BRCA mutation carriers increased sharply in early adulthood until 50 years old, then the incidence reduced to be at a rate of 16–22 per 1,000 person-years until age 80 years (Table 2) (17). Similarly, for ovarian cancer, mutation carriers were at highest risk from age 61–70 with an incidence of 10–29 per 1,000 person-years, while older women at age 71–80 had an incidence of ovarian cancer at 5.7 and 2.3 per 1,000 person-years respectively for BRCA1 and BRCA2 mutation (Table 2) (17). This suggests that the risk increase of breast and ovarian cancer does decrease with age, but older mutation carriers still have a higher cancer risk than normal individuals and can still develop new malignancies beyond age 70.

Besides breast and ovarian cancer risk, risk of pancreatic cancer is of particular concern for elderly mutation carriers, especially for those who had family history of pancreatic cancer (18). The pancreatic cancer risk was approximately doubled in both female BRCA1 and BRCA2 mutation (19). In a retrospective study of 69 female BRCA mutation carriers who lived to age 75 or above, 72% had a prior history of breast cancer and 39% had a history of ovarian cancer. Three out of four new cancers developed after genetic testing in the cohort were pancreatic cancers; all diagnosed in BRCA2 mutation carriers (20). Inherited pancreatic cancer was reported to have a younger age of onset (58–68 years old) than sporadic pancreatic cancer (61–74 years old) (21), but the common age of onset was still older than BRCA-associated breast and ovarian cancer. However, as there were no known effective screening options for pancreatic cancer (22), this could be a major cause of cancer-related morbidity/mortality in elderly BRCA mutation carriers whose breast cancer or ovarian cancer were either being treated or prevented by risk-reducing operations.

Contralateral breast cancer risks of elderly BRCA mutation carriers

While substantially higher risk of contralateral breast cancer has been reported in BRCA mutation carriers who had young age of onset of first breast primary cancer, it is of a lesser extent for older mutation carriers who had a later onset of first breast malignancy. Table 3 summarized the reported risks for contralateral breast cancer in BRCA1/2 mutation carriers. A retrospective, multicentre cohort study comprising 2,020 women with unilateral breast cancer showed that after 25 years, the contralateral breast cancer rate was 62.9% for BRCA1 mutation patients who were diagnosed with first breast cancer at an age younger than 40 years old, compared to only 19.6% for those who were diagnosed after 50 years old. Similar trend was also seen in patients with BRCA2 mutation; however, the difference is not statistically significant (23).

The above results were confirmed with prospective studies. A prospective, multicentre cohort with 6,036 BRCA1 and 3,820 BRCA2 female carriers showed that the cumulative risk of contralateral breast cancer 20 years after the first breast cancer diagnosis was 40% for BRCA1 and 26% for BRCA2. The hazard ratio (HR) declined with increasing age at the first breast cancer diagnosis: for women with first breast cancer at age 40–50 years, HR was 0.81; compared to 0.71 in women with first breast cancer at age <40 years (17). One possible confounding factor of age difference for contralateral breast cancer risk would be the use of hormonal therapy after first breast cancer. Breast cancer patients who are post-menopausal are indicated for aromatase inhibitor which was known to have better secondary breast cancer risk reduction than tamoxifen, while younger and premenopausal patients have a higher percentage of oestrogen receptor (ER) negative cancers; and for those ER positive ones, tamoxifen would be used. A prospective study to look for predictors of contralateral breast cancer by Metcalfe et al. following 810 women with BRCA mutations showed that the 15-year actuarial risk of contralateral breast cancer was 36.1% and 28.5% for women with BRCA1 and BRCA2 mutations respectively. Again, women older than 50 years old at the time of first breast cancer diagnosis had significantly lower risk to develop a contralateral breast cancer at 15 years, compared to those younger than 50 years (16.8% vs. 37.6% P=0.003). Use of tamoxifen was not found to be an independent predictor for contralateral breast cancer in multivariate analysis, in view high percentage of BRCA mutation carriers in the cohort (60%) had received oophorectomy; and oophorectomy could significantly reduce risk of contralateral breast cancer (24).

Impact of genetic mutation on management for elderly patients

Identifying patients with mutations in cancer-associated genes can affect patient management regarding high-risk surveillance, risk-reduction strategies and therapeutic options related to surgery, systemic therapies and radiation (25-27). For instance, BRCA mutation carriers with breast cancer fulfilling certain criteria are indicated for PARP inhibitors, and patients may consider risk-reducing operations. Additionally, cancer-free mutation carriers could be identified through genetic counselling and testing for proband family members; and this could potentially prevent cancer occurrence or detect cancer early. The difference between elderly and younger BRCA mutation carriers may warrant specific recommendations due to the difference in cancer risk, comorbidities and survival.

Risk-reducing operations

After a positive test, most international guidelines such as the National Comprehensive Cancer Network would recommend starting regular imaging surveillance from age 25–30 or 10 years before the age of the first cancer in the family, and would discuss risk-reducing surgery such as risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) (7,13). Women might consider RRM at any age. For RRSO, it was usually recommended to mutation carriers at 35–40 years old for BRCA1 and age 40–45 for BRCA2 (7,13,28), taking into account the median onset age of ovarian cancer and adverse effects from surgical menopause. However, all the guidelines do not specify how the surveillance programme should be catered to patients with increasing age, or risk-reducing surgery should no longer be advised.

Benefits of risk-reducing mastectomy for primary breast cancer could be smaller in older patients due to competing causes of mortality. In a simulation model, the actuarial risk of developing breast cancer until age 80 years was estimated to be 70.8%. The actual risk after incorporating competing risks including ovarian cancer was 64.0%. The probability of being alive at age 80 increased from 42.7% to 51.3% by having bilateral risk-reducing mastectomy at age 25 years. However, if the risk-reducing mastectomy was performed at 50 years old, the survival gain was only 2.8%, from 42.7% to 45.5%. This showed that the survival benefit of risk-reducing mastectomy declined with increasing age at mastectomy (29).

Similarly, a long period was required to demonstrate a reduction in mortality for contralateral mastectomy. In another simulation model, among women who retained the contralateral breast, 0.4% of women were expected to die of a contralateral breast cancer within 5 years; the percentage increased to 6.8% at 20 years after diagnosis (30). In addition, as discussed above, patients with a later age of onset of first breast cancer had a comparatively lower risk of contralateral breast cancer. In other words, elderly breast cancer patients with BRCA mutations might not have apparent benefits even if they opt for a preventive contralateral mastectomy.

On the other hand, risk-reducing salpingo-oophorectomy (RRSO) was consistently shown to have protective effect on ovarian cancer, primary and secondary breast cancer. In a cohort of 551 BRCA mutation female carriers, 259 had RRSO and 292 did not. RRSO reduced the risk of ovarian cancer by 95% in BRCA1/2 mutation carriers. In addition, in a subgroup analysis of 241 women without history of breast cancer, RRSO also decreased the risk of primary breast cancer with a risk ratio of 0.47 (95% CI: 0.29–0.77) (31-33). Particularly for women younger than age 35, RRSO had a 61% decrease in the risk of breast cancer. For women older or equal to 50 years old, the risk reduction was 48% (31). However, most of the studies did not include subgroup analysis for patients who were older in age. Nonetheless, there was no data to completely exclude elderly genetic mutation carriers from preventive RRSO. Given that diagnosis of ovarian cancer in elderly women were correlated with worse outcomes, it might still be beneficial to consider RRSO in patients with a good performance status (34-36). Since there are no definite guidelines to aid clinicians to counsel older genetic mutation carriers, recommendation for screening and preventive surgery should be considered individually based on cancer risk, comorbidities and personal preferences.

Chemoprevention

Studies have addressed the protective effect of endocrine manipulation in BRCA mutation carriers. Special attention is required before these could apply to relatively older patients, especially for the implications of ER status and age of breast cancer onset.

It has been reported that 70–80% of BRCA1-associated breast cancers are ER negative (37), compared to 30% of sporadic tumours (38) and BRCA2-associated tumours (39). However, in a small study comparing 31 BRCA1 mutation positive to 81 age-matched unselected breast cancer patients, women over age 50 were equally likely to be ER positive, which means older BRCA1 mutation carriers have a higher proportion to be ER positive than younger carriers (40). For prevention of disease-recurrence or contralateral breast cancer, after primary breast cancer, these patients would likely be benefited from adjuvant aromatase inhibitors, which was consistently shown to be more superior than tamoxifen in reducing recurrences and breast cancer risks by multiple trials. A meta-analysis showed that aromatase inhibitors when compared to adjuvant tamoxifen in 5-year treatment could reduce recurrence rate by 30% while treatment differs, and reduce 10-year breast cancer mortality rate by 15% (41). For those patients whose primary breast cancers are ER negative, or breast cancer-free patients, opinion for tamoxifen as chemoprevention rather than adjuvant treatment for high-risk patients was inconclusive. It was generally assumed that women with BRCA1 mutations, since majority are ER negative breast cancer, are not impacted by hormonal therapy. However, studies suggested otherwise. In a recent meta-analysis including mainly retrospective analysis with BRCA1/2 carriers, tamoxifen started after treatment of the first breast cancer resulted in a significant breast cancer risk reduction for both BRCA1/2 mutation carriers: in BRCA1 mutation carriers, summary risk ratio was 0.47(95% CI: 0.37–0.60) and in BRCA2 mutation carriers, summary risk ratio was 0.39 (95% CI: 0.28–0.54) (42). There were not any primary prevention trials of tamoxifen or raloxifene conducted with BRCA mutation carriers specifically; only a subgroup analysis of the NSABP trial showed a potential breast cancer risk reduction in BRCA2 (risk ratio =0.38; 95% CI: 0.06–1.56) but not in BRCA1 (risk ratio =1.67; 95% CI: 0.32–10.7) mutation carriers (43). Results of this trial should be interpreted with caution since the numbers of patients in each group were very small: 8 patients with BRCA1 mutations (5 with tamoxifen, 3 did not) and 11 patients with BRCA2 mutations (3 received tamoxifen, 8 did not). Therefore, it may not have the statistical power to confirm a genuine benefit. To conclude, elderly breast cancer patients who are ER positive should utilize aromatase inhibitor as adjuvant hormonal therapy for risk reduction, while those who are breast-cancer free, prospective data supporting the use of tamoxifen for primary prevention was lacking but retrospective data suggested a potential benefit.

Conclusions

Hereditary breast cancer is usually associated with young age of onset. Nevertheless, recent studies have shown that the prevalence of breast cancer-associated mutations could have been underestimated in older women with breast cancer: BRCA1/2 mutation detection rates were 2% in postmenopausal patients to age 64, and 1% in those who were 65 years or older. Whether we should extend the genetic testing criteria to include older breast cancer patients who do not have any other particular hereditary risk factors such as family history is controversial. This will need to take into account the balance between the under-diagnosis of pathogenic variants and increased medical cost. Before considering genetic testing for all breast cancer patients regardless of age, broadening the genetic testing criteria such as identifying additional risk factors and testing patients until an older age such as 60–65 years old besides the conventional ones could serve as a middle ground to increase detection of mutations while avoiding over testing in extreme elderly patients who has a lower prevalence of mutations. Genetic test should only be offered to older patients if a positive test would potentially alter management which benefits the patients. Current management guidelines for BRCA mutations are designed based on evidence targeting the younger population. Given a comparatively lower risk of breast cancer and contralateral breast cancer than younger mutation carriers, and less benefit of risk-reducing mastectomy at an older age, individual factors such as comorbidity, competing causes of mortality, cancer risks, personal preference and beliefs should all be taken into account when formulating management plans for elderly breast cancer patients with genetic mutation.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Kwok-Leung Cheung) for the series “Diagnosis and Treatment on Primary Breast Cancer in Older Women” published in Annals of Breast Surgery. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://abs.amegroups.com/article/view/10.21037/abs-21-122/rc

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://abs.amegroups.com/article/view/10.21037/abs-21-122/coif). The series “Diagnosis and Treatment on Primary Breast Cancer in Older Women” was commissioned by the editorial office without any funding or sponsorship. AK serves as an unpaid editorial board member of Annals of Breast Surgery from September 2021 to August 2023. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Youn HJ, Han W. A Review of the Epidemiology of Breast Cancer in Asia: Focus on Risk Factors. Asian Pac J Cancer Prev 2020;21:867-80. [Crossref] [PubMed]
2. Armstrong N, Ryder S, Forbes C, et al. A systematic review of the international prevalence of BRCA mutation in breast cancer. Clin Epidemiol 2019;11:543-61. [Crossref] [PubMed]
3. Kwong A, Wong LP, Wong HN, et al. Clinical and pathological characteristics of Chinese patients with BRCA related breast cancer. Hugo J 2009;3:63-76. [Crossref] [PubMed]
4. Atchley DP, Albarracin CT, Lopez A, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 2008;26:4282-8. [Crossref] [PubMed]
5. Kurian AW, Bernhisel R, Larson K, et al. Prevalence of Pathogenic Variants in Cancer Susceptibility Genes Among Women With Postmenopausal Breast Cancer. JAMA 2020;323:995-7. [Crossref] [PubMed]
6. Hartge P, Struewing JP, Wacholder S, et al. The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J Hum Genet 1999;64:963-70. [Crossref] [PubMed]
7. US Preventive Services Task Force. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 2019;322:652-65. [Crossref] [PubMed]
8. Møller P, Hagen AI, Apold J, et al. Genetic epidemiology of BRCA mutations--family history detects less than 50% of the mutation carriers. Eur J Cancer 2007;43:1713-7. [Crossref] [PubMed]
9. Grindedal EM, Heramb C, Karsrud I, et al. Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers. BMC Cancer 2017;17:438. [Crossref] [PubMed]
10. Manahan ER, Kuerer HM, Sebastian M, et al. Consensus Guidelines on Genetic` Testing for Hereditary Breast Cancer from the American Society of Breast Surgeons. Ann Surg Oncol 2019;26:3025-31. [Crossref] [PubMed]
11. D'Andrea E, Marzuillo C, De Vito C, et al. Which BRCA genetic testing programs are ready for implementation in health care? A systematic review of economic evaluations. Genet Med 2016;18:1171-80. [Crossref] [PubMed]
12. Forbes C, Fayter D, de Kock S, et al. A systematic review of international guidelines and recommendations for the genetic screening, diagnosis, genetic counseling, and treatment of BRCA-mutated breast cancer. Cancer Manag Res 2019;11:2321-37. [Crossref] [PubMed]
13. Daly MB, Pilarski R, Yurgelun MB, et al. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2020. J Natl Compr Canc Netw 2020;18:380-91. [Crossref] [PubMed]
14. King MC, Marks JH, Mandell JB, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 2003;302:643-6. [Crossref] [PubMed]
15. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003;72:1117-30. [Crossref] [PubMed]
16. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007;25:1329-33. [Crossref] [PubMed]
17. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA 2017;317:2402-16. [Crossref] [PubMed]
18. Pereira SP, Oldfield L, Ney A, et al. Early detection of pancreatic cancer. Lancet Gastroenterol Hepatol 2020;5:698-710. [Crossref] [PubMed]
19. Iqbal J, Ragone A, Lubinski J, et al. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer 2012;107:2005-9. [Crossref] [PubMed]
20. Salyer C, Kobelka C, Barrie A, et al. Clinical characteristics and outcomes in elderly women with BRCA1 and BRCA2 mutations. Gynecol Oncol 2019;154:374-8. [Crossref] [PubMed]
21. Matsubayashi H, Takaori K, Morizane C, et al. Familial pancreatic cancer: Concept, management and issues. World J Gastroenterol 2017;23:935-48. [Crossref] [PubMed]
22. US Preventive Services Task Force. Screening for Pancreatic Cancer: US Preventive Services Task Force Reaffirmation Recommendation Statement. JAMA 2019;322:438-44. [Crossref] [PubMed]
23. Graeser MK, Engel C, Rhiem K, et al. Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2009;27:5887-92. [Crossref] [PubMed]
24. Metcalfe K, Gershman S, Lynch HT, et al. Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer 2011;104:1384-92. [Crossref] [PubMed]
25. Pierce LJ, Haffty BG. Radiotherapy in the treatment of hereditary breast cancer. Semin Radiat Oncol 2011;21:43-50. [Crossref] [PubMed]
26. Sikov WM. Assessing the role of platinum agents in aggressive breast cancers. Curr Oncol Rep 2015;17:3. [Crossref] [PubMed]
27. Livraghi L, Garber JE. PARP inhibitors in the management of breast cancer: current data and future prospects. BMC Med 2015;13:188. [Crossref] [PubMed]
28. Kauff ND, Barakat RR. Risk-reducing salpingo-oophorectomy in patients with germline mutations in BRCA1 or BRCA2. J Clin Oncol 2007;25:2921-7. [Crossref] [PubMed]
29. Giannakeas V, Narod SA. The expected benefit of preventive mastectomy on breast cancer incidence and mortality in BRCA mutation carriers, by age at mastectomy. Breast Cancer Res Treat 2018;167:263-7. [Crossref] [PubMed]
30. Narod SA. The impact of contralateral mastectomy on mortality in BRCA1 and BRCA2 mutation carriers with breast cancer. Breast Cancer Res Treat 2011;128:581-3. [Crossref] [PubMed]
31. Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002;346:1616-22. [Crossref] [PubMed]
32. Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst 2009;101:80-7. [Crossref] [PubMed]
33. Kauff ND, Satagopan JM, Robson ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002;346:1609-15. [Crossref] [PubMed]
34. Tew WP, Fleming GF. Treatment of ovarian cancer in the older woman. Gynecol Oncol 2015;136:136-42. [Crossref] [PubMed]
35. Tortorella L, Vizzielli G, Fusco D, et al. Ovarian Cancer Management in the Oldest Old: Improving Outcomes and Tailoring Treatments. Aging Dis 2017;8:677-84. [Crossref] [PubMed]
36. Rostoft S, Audisio RA. Recent advances in cancer surgery in older patients. F1000Res 2017;6:1242. [Crossref] [PubMed]
37. Verhoog LC, Brekelmans CT, Seynaeve C, et al. Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet 1998;351:316-21. [Crossref] [PubMed]
38. Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 1998;351:1451-67. [Crossref] [PubMed]
39. Agnarsson BA, Jonasson JG, Björnsdottir IB, et al. Inherited BRCA2 mutation associated with high grade breast cancer. Breast Cancer Res Treat 1998;47:121-7. [Crossref] [PubMed]
40. Vaziri SA, Krumroy LM, Elson P, et al. Breast tumor immunophenotype of BRCA1-mutation carriers is influenced by age at diagnosis. Clin Cancer Res 2001;7:1937-45. [PubMed]
41. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet 2015;386:1341-52. [Crossref] [PubMed]
42. Xu L, Zhao Y, Chen Z, et al. Tamoxifen and risk of contralateral breast cancer among women with inherited mutations in BRCA1 and BRCA2: a meta-analysis. Breast Cancer 2015;22:327-34. [Crossref] [PubMed]
43. Breast Cancer Association Consortium. Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. N Engl J Med 2021;384:428-39. [Crossref] [PubMed]