Risk Of Contralateral Breast Cancer Research Articles

Abstract GS02-04: Surgical Treatment of Women with Breast Cancer and a BRCA1 Mutation: An International Analysis of the Impact of Bilateral Mastectomy on Survival

Abstract Background: Women with breast cancer and a BRCA1 mutation face a high risk of contralateral breast cancer. For this reason, many women with a unilateral breast cancer opt for bilateral mastectomies. Some will have a contralateral prophylactic mastectomy as a second surgery. However, it is not clear to what extent this operation impacts breast cancer mortality. The objective of the current study was to evaluate the differences in survival by surgical treatment in an international cohort of women with a BRCA1 mutation and unilateral breast cancer. Methods: Eligible participants were identified from a large international cohort of women with breast cancer and a BRCA1 mutation, from 26 collaborating centres. Patients with DCIS and stage IV breast cancer were excluded. Patients with synchronous bilateral cancer were excluded. Demographic data were patient reported and clinical and treatment data were collected from medical records. Women were followed from date of breast cancer diagnosis to either date of last follow-up or date of death. Results: There were 2482 eligible participants from 26 centres from 11 countries. The mean age of breast cancer diagnosis was 43.1 years (range 18-70 years). Among those who had a unilateral mastectomy or lumpectomy, the risk of contralateral breast cancer at 20 years was 27.5%. After experiencing a contralateral cancer the hazard ratio for breast cancer death was 2.14 (95%CI 1.43-3.18), P=0.0002. The fifteen-year breast cancer specific survival in the entire cohort was 82.9%. The survival was 78.7% for those who had a unilateral mastectomy, 86.2% for those who had a lumpectomy, and 88.7% for those who had bilateral mastectomies. 529 of the women who initially underwent a unilateral surgery subsequently had a contralateral or bilateral preventive mastectomy in the follow up period. 529 of the women with unilateral surgery had a contralateral or bilateral preventive mastectomy in the follow up period. After adjusting for age of diagnosis, tumor size, nodal status, chemotherapy (yes/no) and preventive mastectomy (time dependent) the hazard ratio for breast cancer mortality for bilateral surgery versus unilateral surgery was 0.78 (95% CI 0.55-1.13), p = 0.19. Discussion: Women with a BRCA1 mutation and breast cancer who develop a contralateral breast cancer have double the risk of mortality compared to women who do not develop contralateral breast cancer. We observed a small non-significant reduction in mortality for those who had bilateral mastectomies as initial treatment, but the cohort will require longer follow up for definitive results. Women with a BRCA1 mutation should be counselled on the risks of contralateral breast cancer and make surgical decisions with this knowledge. Citation Format: Kelly Metcalfe, Jan Lubinski, Jana Soukupová, Rinat Bernstein-Molho, Mina Lee, Evans Gareth, Arvids Irmejs, Robert Fruscio, Cynthia Villareal Garza, Joanne Ngeow, Jennifer Plichta, Rinat Yerushalmi, Steven Narod. Surgical Treatment of Women with Breast Cancer and a BRCA1 Mutation: An International Analysis of the Impact of Bilateral Mastectomy on Survival [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS02-04.

TP53-associated early breast cancer: new observations from a large cohort.

A large well-annotated recent international cohort of Li-Fraumeni (LFS) patients with early-stage breast cancer (BC) was examined for shared features. This multicentre cohort study included females with a germline TP53 pathogenic or likely pathogenic variant and nonmetastatic BC diagnosed between 2002-2022. Clinical and genetic data were obtained from institutional registries and clinical charts. Descriptive statistics were utilized to summarize proportions and differences were assessed by Chi square or Wilcoxon rank sum tests. Metachronous contralateral breast cancer (CBC) risk, radiation-induced sarcoma risk, and recurrence-free survival (RFS) were analyzed by Kaplan-Meier methodology. Among 227 females who met study criteria, the median age of first BC diagnosis was 37 years (range 21-71), 11.9% presented with bilateral synchronous BC and 18.1% had ductal carcinoma in situ (DCIS) only. In total, 166 (73.1%) underwent mastectomies including 67 bilateral mastectomies as first BC surgery. Among those with retained breast tissue, CBC rate was 25.3% at 5-years. Among 186 invasive tumors, 72.1% were stages I-II, 48.9% node-negative, and the most common subtypes were HR+/HER2- (40.9%) and HR+/HER2 + (34.4%). At a median follow-up of 69.9 months (IQR 32.6-125.9), invasive HR+/HER2- disease had the highest recurrence risk among the subtypes (5-year RFS 61.1%, p = .0012). Among those who received radiation therapy (n = 79), the 5-year radiation-induced sarcoma rate was 4.8%. We observed high rates of DCIS, HR+ and HER2+ breast cancers, with a worse outcome in the HR+/HER2- luminal tumors despite appropriate treatment. Confirmation of these findings in further studies could have implications for BC care in LFS.

95 (PB-095) Poster - The INFLUENCE 3.0 model: time-dependent risks of locoregional recurrence and contralateral breast cancer, now also including patients treated with neoadjuvant systemic therapy

95 (PB-095) Poster - The INFLUENCE 3.0 model: time-dependent risks of locoregional recurrence and contralateral breast cancer, now also including patients treated with neoadjuvant systemic therapy

Society of Surgical Oncology Breast Disease Site Working Group Statement on Contralateral Mastectomy: Indications, Outcomes, and Risks.

Rates of contralateral mastectomy (CM) among patients with unilateral breast cancer have been increasing in the United States. In this Society of Surgical Oncology position statement, we review the literature addressing the indications, risks, and benefits of CM since the society's 2017 statement. We held a virtual meeting to outline key topics and then conducted a literature search using PubMed to identify relevant articles. We reviewed the articles and made recommendations based on group consensus. Patients consider CM for many reasons, including concerns regarding the risk of contralateral breast cancer (CBC), desire for improved cosmesis and symmetry, and preferences to avoid ongoing screening, whereas surgeons primarily consider CBC risk when making a recommendation for CM. For patients with a high risk of CBC, CM reduces the risk of new breast cancer, however it is not known to convey an overall survival benefit. Studies evaluating patient satisfaction with CM and reconstruction have yielded mixed results. Imaging with mammography within 12 months before CM is recommended, but routine preoperative breast magnetic resonance imaging is not; there is also no evidence to support routine postmastectomy imaging surveillance. Because the likelihood of identifying an occult malignancy during CM is low, routine sentinel lymph node surgery is not recommended. Data on the rates of postoperative complications are conflicting, and such complications may not be directly related to CM. Adjuvant therapy delays due to complications have not been reported. Surgeons can reduce CM rates by encouraging shared decision making and informed discussions incorporating patient preferences.

Increased risk of contralateral breast cancer for BRCA1/2 wild-type, high-risk Korean breast cancer patients: a retrospective cohort study

BackgroundThis study aimed to investigate the contralateral breast cancer (CBC) recurrence rate in Korean breast cancer patients according to their BRCA1/2 germline mutation status, focusing particularly on the CBC recurrence risk in BRCA1/2 negative (BRCAx) patients.MethodsWe conducted a retrospective study on 13,107 primary breast cancer patients. The patients were divided into high-risk and low-risk groups for hereditary breast cancer based on the Korean National Health Insurance Service’s eligibility criteria for BRCA1/2 germline mutation testing. The high-risk group was further categorized into the BRCAmutation group, the BRCAxgroup, and the not tested group. We evaluated the overall survival and cumulative risk of developing CBC in these patients.ResultsAmong 4494 high-risk patients, 973 (21.7%) underwent genetic testing for BRCA1/2 germline mutation, revealing mutations in 158 patients (16.2%). We observed significant overall survival differences across all four groups, with the high-risk, not-tested group demonstrating notably worse overall survival (p < 0.001). However, when adjusted for other prognostic factors, there was no significant differences in hazard ratio of death between the four groups. The cumulative risk of CBC also varied among the groups. Patients with BRCA1/2 mutations showed a 7.3-fold increased risk of CBC compared to the low-risk group (95% CI 4.11–13.0, p < 0.001). Interestingly, BRCAx patients also demonstrated a significantly higher risk of CBC (HR 2.77, 95% CI 1.76–4.35, p < 0.001). The prognostic importance of the BRCAx for CBC recurrence persisted after adjusting for the age and subtype, but became insignificant when the family history of breast cancer was adjusted.ConclusionBreast cancer patients who are at high risk of hereditary breast cancer but with wild-type BRCA 1/2 genes (BRCAx) have increased risk of developing contralateral breast cancer when compared to the low-risk patients. More careful surveillance and follow-up can be offered to these patients especially when they have family history of breast cancer.

Postlumpectomy imaging: is there a role for the study of the contralateral breast?-a retrospective cohort.

Some patients with breast cancer submitted to breast-conserving surgery might benefit from a postlumpectomy imaging examination previously to radiation therapy. This aims to document the complete removal of cancer and might be accomplished using mammogram with breast and axillary ultrasonography. These modalities study not only the affected side but also the contralateral side. In fact, it is well-documented that women with breast cancer have an increased risk for contralateral breast cancer. Thus, we intended to evaluate the value of postlumpectomy imaging undertaken before adjuvant radiotherapy regarding the evaluation of the contralateral breast and axilla. In this retrospective study, medical records for patients with breast cancer submitted to breast-conserving surgery and referred to our radiotherapy unit between 2018 and 2019 were reviewed. All patients had to be submitted to bilateral mammogram with breast and axillary ultrasonography previously to radiotherapy. Patients with bilateral disease or with a history of breast cancer were excluded. One thousand two hundred forty patients were analyzed. 19 (1.5%) had suspicious findings for contralateral breast disease, and 8 (0.6%) had a re-excision positive for residual malignancy. Higher age, invasive lobular carcinoma associated or not with lobular carcinoma in situ, and presence of lobular carcinoma in situ were associated with an increased risk for residual disease. Contralateral evaluation as part of postlumpectomy imaging revealed itself useful at detecting contralateral cancer, with some demographic and clinical features being associated with an increased risk for residual disease.

Age-Related Incidence and Peak Occurrence of Contralateral Breast Cancer

ImportanceYoung patients with breast cancer have higher risk for developing contralateral breast cancer (CBC) and have epidemiologic characteristics different from those of older patients.ObjectiveTo examine the incidence and peak occurrence of CBC according to age at primary breast cancer (PBC) surgery.Design, Setting, and ParticipantsThis cohort study included patients who were diagnosed with and underwent surgery for unilateral nonmetastatic breast cancer at Asan Medical Center, Korea, between January 1, 1999, and December 31, 2013, with follow-up through December 31, 2018. Data were analyzed from December 1, 2021, through April 30, 2023. Patients were divided into 2 groups according to their age at surgery for PBC: younger (≤35 years) vs older (&amp;amp;gt;35 years).Main Outcomes and MeasuresThe main outcomes were cumulative incidence and hazard rate of CBC in the entire study population and in subgroups divided by cancer subtype, categorized according to hormone receptor (HR) and ERBB2 status.ResultsA total of 16 251 female patients with stage 0 to III breast cancer were analyzed; all patients were Korean. The mean (SD) age was 48.61 (10.06) years; 1318 patients (8.11%) were in the younger group, and 14 933 (91.89%) were in the older group. Median follow-up was 107 months (IQR, 79-145 months). Compared with the older group, the younger group had significantly higher incidence of CBC (10-year cumulative incidence, 7.1% vs 2.9%; P &amp;amp;lt; .001) and higher risk (hazard ratio, 2.10; 95% CI, 1.62-2.74) of developing CBC. The hazard rate, which indicates risk for developing CBC at a certain time frame, differed according to the subtype of primary cancer. In patients with the HR+/ERBB2– subtype, the risk increased continuously in both age groups. In patients with the triple negative subtype, the risk increased until approximately 10 years and then decreased in both age groups. Meanwhile, in the HR−/ERBB2+ subtype, risk peaked earlier, especially in the younger group (1.7 years since first surgery in the younger group and 4.8 years in the older group).Conclusions and RelevanceIn this cohort study, patients aged 35 years or younger with breast cancer had a higher risk of developing CBC than older patients. Moreover, young patients with the HR−/ERBB2+ subtype tended to have a shorter interval for developing CBC. These findings might be useful in guiding treatment decisions, such as contralateral prophylactic mastectomy.

Risk factors of developing contralateral breast cancer after first primary breast cancer treatment.

Breast cancer (BC) is the most common cancer among women worldwide. Increased survival of primary BC (PBC) has increased contralateral breast cancer (CBC) and become a health problem. This study aimed to determine the effect of disease-free interval (DFI), risk factors and PBC characteristics on the progression of CBC within primary BC survivors. This retrospective study identified 5003 women diagnosed with breast cancer between 2000 and 2020 in the cancer research center. The study included 145 CBC and 4858 PBC survivors, with CBC diagnosed at least 6 months after the detection of primary BC. ER+, PR+, and HER2+ were reported in 72.13%, 66.67%, and 30% of CBC patients. Invasive ductal carcinoma (IDC) BC was reported in 69.57% of patients, and 81.90% and 83.64% of the patients were treated with adjuvant chemotherapy and external radiotherapy. The Kaplan-Meier method indicated that the median time interval between PBC and CBC was 3.92 years, and the 5-year DFI was 97%. The Cox proportional hazard regression model indicated that although more than half of the participants had no family history of BC (69.57%), women 60 years and older were negatively associated with CBC. This study provides the first investigation of CBC and DFI risk factors among PBC survivors in Iran. Age was found to be negatively associated with CBC development particularly after the age of 60, indicating the necessity of tracking CBC survivors carefully in this age group.

Endocrine therapy initiation among women diagnosed with ductal carcinoma in situ breast cancer from 2001-2016.

487 Background: Endocrine therapy (ET) initiation in people within 1 year of diagnosis of estrogen-receptor-positive (ER+) ductal carcinoma in situ (DCIS) has ranged from 21-45% in prior studies; however, these studies did not evaluate initiation post-2011 and may not reflect current patterns of use. ET use following ER+ DCIS diagnosis can reduce the relative risks of recurrence and contralateral breast cancer by 30-50%. We evaluated ET initiation over time and by demographic, tumor, and treatment characteristics in the Kaiser Permanente Breast Cancer Survivors Study between 2001-2016. Methods: We included people aged 20+ years diagnosed with unilateral DCIS with at least 1 year of cancer-free follow-up from three U.S. integrated health systems. We excluded people with ER-negative disease, no surgery, and those who received chemotherapy or unknown radiation therapy. ET dispensings (tamoxifen and aromatase inhibitors) were extracted from electronic pharmacy records within 1 year of a person’s initial DCIS breast cancer diagnosis. Using generalized linear models with a log link and Poisson distribution, we estimated relative rates (RRs) of ET use (vs none) over time and by demographic, tumor, and other treatment characteristics. Results: Among 1,782 pre- and postmenopausal people, 577 (32%) initiated ET within 1 year of diagnosis. From 2001-2016, ET use did not change over time (34% vs 36%), tamoxifen use declined slightly (34% vs 29%), and aromatase inhibitor use increased slightly (0% vs 7%). People were less likely to initiate ET if they were ≥65 years, Black, had borderline or unknown ER status, were not tested for ER, had breast conserving surgery (BCS) without radiation, or had a unilateral mastectomy. Conclusions: Only one-third of people with DCIS diagnosed in a community healthcare setting and potentially eligible for ET, initiated treatment within 1 year of their diagnosis. Previous studies have shown long-term benefits of ET use in people with DCIS; however, we saw no increase in use over time. Concerns about side-effects, overdiagnosis and overtreatment of DCIS, and confusion about treatment guidelines may explain relatively low ET initiation.[Table: see text]

Risk of contralateral breast cancer among Asian/Pacific Islander women in the United States.

While breast cancer studies often aggregate Asian/Pacific Islander (API) women, as a single group or exclude them, this population is heterogeneous in terms of genetic background, environmental exposures, and health-related behaviors, potentially resulting in different cancer outcomes. Our purpose was to evaluate risks of contralateral breast cancer (CBC) among subgroups of API women with breast cancer. We conducted a retrospective cohort study of women ages 18 + years diagnosed with stage I-III breast cancer between 2000 and 2016 in the Surveillance, Epidemiology and End Results registries. API subgroups included Chinese, Japanese, Filipina, Native Hawaiian, Korean, Vietnamese, Indian/Pakistani, and other API women. Asynchronous CBC was defined as breast cancer diagnosed in the opposite breast 12 + months after first primary unilateral breast cancer. Multivariable-adjusted subdistribution hazard ratios (SHR) and 95% confidence intervals (CI) were estimated and stratified by API subgroups. From a cohort of 44,362 API women with breast cancer, 25% were Filipina, 18% were Chinese, 14% were Japanese, and 8% were Indian/Pakistani. API women as an aggregate group had increased risk of CBC (SHR 1.15, 95% CI 1.08-1.22) compared to NHW women, among whom Chinese (SHR 1.23, 95% CI 1.08-1.40), Filipina (SHR 1.37, 95% CI 1.23-1.52), and Native Hawaiian (SHR 1.69, 95% CI 1.37-2.08) women had greater risks. Aggregating or excluding API patients from breast cancer studies ignores their heterogeneous health outcomes. To advance cancer healthequity among API women, future research should examine inequities within the API population to design interventions that can adequately address their unique differences.

Prophylactic Salpingo-Oophorectomy and Survival After BRCA1/2 Breast Cancer Resection

Few studies have investigated whether prophylactic salpingo-oophorectomy (PSO) for patients with previously resected breast cancer who carry pathogenic germline BRCA1 or BRCA2 variants is associated with a reduced risk of cancer-specific death. To assess the association of PSO and prophylactic mastectomy (PM) with prognosis after quadrantectomy or mastectomy as primary treatment for patients with BRCA1 or BRCA2 breast cancer. This retrospective cohort study was performed in a single-institution, tertiary referral center. Consecutive patients with invasive breast cancer treated surgically between 1972 and 2019 were recruited and followed up prospectively after they were found to carry the BRCA1 or BRCA2 gene variant. The data analysis was performed between April 2022 and July 2023. Following breast surgery, some patients underwent PSO, PM, or both, whereas others did not. The primary study end point was overall survival as measured by the Kaplan-Meier method. Secondary end points were crude cumulative incidence of breast cancer-specific mortality, ipsilateral breast tumor recurrence (IBTR), contralateral breast cancer, ovarian cancer, and ovarian cancer-specific mortality. Of 480 patients included in the cohort (median age at initial surgery, 40.0 years; IQR, 34.0-46.0 years), PSO was associated with a significantly reduced risk of death (hazard ratio [HR], 0.40; 95% CI, 0.25-0.64; P < .001). This reduction was most evident for patients carrying the BRCA1 variant (HR, 0.35; 95% CI, 0.20-0.63; P = .001), those with triple-negative disease (HR, 0.21; 95% CI, 0.09-0.46; P = .002), and those with invasive ductal carcinoma (HR, 0.51; 95% CI, 0.31-0.84; P = .008). Prophylactic salpingo-oophorectomy was not associated with risk of contralateral breast cancer or IBTR. Initial or delayed PM was associated with a reduced risk of IBTR but not with overall survival or breast cancer-specific mortality. The study findings suggest that PSO should be offered to all patients with BRCA1/2 breast cancer who undergo surgery with curative intent to reduce risk of death. In particular, PSO should be offered to patients with the BRCA1 variant at the time of breast surgery.

Adherence to hormonal therapy after surgery among older women with ductal carcinoma in situ: Implications for breast cancer-related adverse health events.

Evidence from randomized clinical trials (RCTs) shows that receipt of hormonal therapy after surgery for estrogen receptor-positive ductal carcinoma in situ (DCIS) reduces the risk of DCIS and contralateral invasive breast cancer (IBC) but not death from breast cancer. RCTs examined homogeneous samples, and therefore whether this evidence can be generalized to diverse populations is unclear. Population-based data from four state cancer registries (California, New Jersey, New York, and Texas) were analyzed on women aged 65 years and older newly diagnosed with DCIS who underwent surgery with or without radiation during the years 2006-2013. Registry records were merged with Medicare enrollment in Parts A and/or B and D (prescription drugs) and associated claims. Whether adherence to hormonal therapy was associated with adverse breast cancer-related health events was analyzed. Achieving excellent adherence did not affect death from breast cancer. In contrast, the risk of developing a subsequent breast tumor was 6.24 percentage points (breast-conserving surgery [BCS] with radiation therapy [RT]) and 10.54 percentage points (BCS alone) lower for women with excellent versus low adherence (p<.00001). For excellent versus good adherence, the reduced risk among women who had BCS with and without RT was approximately 3 and 5 percentage points, respectively. A similar pattern emerged for the risk of IBC among women who achieved excellent versus good or low adherence, whereas good versus low adherence comparisons were not significant. This analysis of a diverse population-based cohort of women with DCIS demonstrates that achieving excellent adherence to hormonal therapy is critical to minimizing the occurrence of developing subsequent breast tumors. Our analysis of a diverse population-based cohort of women with ductal carcinoma in situ demonstrates that achieving excellent adherence to hormonal therapy is critical to minimizing the occurrence of developing subsequent breast tumors.

Contralateral breast cancer risk with radiation therapy in BRCA mutation carriers: what do we tell patients?

Contralateral breast cancer risk with radiation therapy in BRCA mutation carriers: what do we tell patients?

Trends in Radiation Dose to the Contralateral Breast During Breast Cancer Radiation Therapy.

Over 4 million survivors of breast cancer live in the United States, 35% of whom were treated before 2009. Approximately half of patients with breast cancer receive radiation therapy, which exposes the untreated contralateral breast to radiation and increases the risk of a subsequent contralateral breast cancer (CBC). Radiation oncology has strived to reduce unwanted radiation dose, but it is unknown whether a corresponding decline in actual dose received to the untreated contralateral breast has occurred. The purpose of this study was to evaluate trends in unwanted contralateral breast radiation dose to inform risk assessment of second primary cancer in the contralateral breast for long-term survivors of breast cancer. Individually estimated radiation absorbed doses to the four quadrants and areola central area of the contralateral breast were estimated for 2,132 women treated with radiation therapy for local/regional breast cancers at age <55 years diagnosed between 1985 and 2008. The two inner quadrant doses and two outer quadrant doses were averaged. Trends in dose to each of the three areas of the contralateral breast were evaluated in multivariable models. The population impact of reducing contralateral breast dose on the incidence of radiation-associated CBC was assessed by estimating population attributable risk fraction (PAR) in a multivariable model. The median dose to the inner quadrants of the contralateral breast was 1.70 Gy; to the areola, 1.20 Gy; and to the outer quadrants, 0.72 Gy. Ninety-two percent of patients received ≥1 Gy to the inner quadrants. For each calendar year of diagnosis, dose declined significantly for each location, most rapidly for the inner quadrants (0.04 Gy/year). Declines in dose were similar across subgroups defined by age at diagnosis and body mass index. The PAR for CBC due to radiation exposure >1 Gy for women <40 years of age was 17%. Radiation dose-reduction measures have reduced dose to the contralateral breast during breast radiation therapy. Reducing the dose to the contralateral breast to <1 Gy could prevent an estimated 17% of subsequent radiation-associated CBCs for women treated under 40 years of age. These dose estimates inform CBC surveillance for the growing number of breast cancer survivors who received radiation therapy as young women in recent decades. Continued reductions in dose to the contralateral breast could further reduce the incidence of radiation-associated CBC.

Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.

Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)]. Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Contralateral breast cancer risk in patients with breast cancer and a germline-BRCA1/2 pathogenic variant undergoing radiation.

Radiation-induced secondary breast cancer (BC) may be a concern after radiation therapy (RT) for primary breast cancer (PBC), especially in young patients with germline (g)BRCA-associated BC who already have high contralateral BC (CBC) risk and potentially increased genetic susceptibility to radiation. We sought to investigate whether adjuvant RT for PBC increases the risk of CBC in patients with gBRCA1/2-associated BC. The gBRCA1/2 pathogenic variant carriers diagnosed with PBC were selected from the prospective International BRCA1/2 Carrier Cohort Study. We used multivariable Cox proportional hazards models to investigate the association between RT (yes vs no) and CBC risk. We further stratified for BRCA status and age at PBC diagnosis (<40 and >40 years). Statistical significance tests were 2-sided. Of 3602 eligible patients, 2297 (64%) received adjuvant RT. Median follow-up was 9.6 years. The RT group had more patients with stage III PBC than the non-RT group (15% vs 3%, P < .001), received chemotherapy more often (81% vs 70%, P < .001), and received endocrine therapy more often (50% vs 35%, P < .001). The RT group had an increased CBC risk compared with the non-RT group (adjusted hazard ratio [HR] = 1.44; 95% confidence interval [CI] = 1.12 to 1.86). Statistical significance was observed in gBRCA2 (HR = 1.77; 95% CI = 1.13 to 2.77) but not in gBRCA1 pathogenic variant carriers (HR = 1.29; 95% CI = 0.93 to 1.77; P = .39 for interaction). In the combined gBRCA1/2 group, patients irradiated when they were younger than or older than 40 years of age at PBC diagnosis showed similar risks (HR = 1.38; 95% CI = 0.93 to 2.04 and HR = 1.56; 95% CI = 1.11 to 2.19, respectively). RT regimens minimizing contralateral breast dose should be considered in gBRCA1/2 pathogenic variant carriers.

How to close the care gap: Factors hindering the use of BRCA mutation profiling of patients with breast cancer and ovarian cancer in a real world setting.

e18636 Background: The majority of hereditary breast and ovarian cancers are linked to BRCA1/2 mutations. However, in patients with a suggestive personal or family history, a specific predisposing gene is identified in &lt; 30% of cases. Mutation testing is recommended for individual genes in the appropriate clinical setting with a high suspicion index for a specific mutated gene. The risk of contralateral breast cancer increases with the time since the first breast cancer, reaching 20%–30% at ten years of follow-up and 40%–50% at 20 years, depending on the gene involved. Methods: The study assessed the prevalence of BRCA testing among young breast cancer women (age less than 50 years) and explored the factors hindering the performance of the BRCA mutation test. Among the 3400 breast cancers reported from 2017 to 2022, 46.17% (n = 1570) of young breast cancer women were advised for BRCA testing. We administered the questionnaire on factors influencing the BRCA mutation profiling performance to all the young breast cancer women (n = 1532). The data was collected from the electronic medical records and the department of molecular oncology. We performed regression analysis to predict the act of BRCA mutation profile testing. Results: Among them (n = 1570), only 17.70% (n = 278) performed BRCA1/2 genetic testing. In 278 patients who had undergone BRCA testing, pathogenic or likely pathogenic BRCA1/2/HRR mutations were detected in 52 patients (18.7%). 38 (13.7%) with BRCA 1, 14(5%) with BRCA2. Somatic with HRR testing was done in 13(4.6%), Somatic testing in 37(13.3%) and germline testing was done in 228 (82%). BRCA mutation was detected in 18 (34.6%) patients with breast cancer, 32(61.5%) patients with ovarian cancer. The factors influencing not performing the BRCA testing were the higher Cost of the test (83.4%), delay in getting the result (32.4%), unawareness of the importance of the test (52.6%), and not being advised by the physician as a mandatory test to perform (47.6%) and male spouse as a decision maker (31.8%). Conclusions: BRCA mutation profile test is mandatory to know their recurrence risk and treatment decisions for opting for PARP inhibitor. But the Cost of the test is the main barrier to performing this in a low-middle-income country setting. Female gender and related decision-making conflict could be the other reasons not to perform the test.

Cancer risk and characteristics in older female BRCA1/2 mutation carriers.

10610 Background: Cancer risk and characteristics in older females with BRCA1/2 mutations are less well studied, and the role of risk-reducing strategies in this population remains unclear. Methods: From a database of 1070 female carriers of BRCA1/2 pathogenic (PV) or likely pathogenic variants (LPV) seen at Nancy and James Grosfeld Cancer Genetics Center in Beaumont Health from January 2006 to December 2021, we identified 283 females who lived to age 65 or older. We analyzed cancer risk and clinical characteristics, focusing on females with cancer diagnosed at age 65 or older. Results: Of the 283 BRCA1/2 carriers, 229 (81%) had a cancer diagnosis, out of which 84 (37%) were diagnosed at age 65 or older. Of all the breast cancer diagnoses (n = 173), 45 (26%) were diagnosed at age 65 or older. Among these 45 patients, median age at diagnosis was 69 years (65-87); majority were BRCA2 carriers (62%), with invasive ductal carcinoma (80%), ER-positive (58%), PR-negative (55%), HER2-negative (97%), high grade (55%) and had stage I or II disease (78%). Fifteen patients (38%) were triple-negative. A minority (32%) received adjuvant chemotherapy, 43% received adjuvant endocrine therapy, and 54% received adjuvant radiation. During a median follow-up of 205 months for all breast cancers (n = 173), there were 52 recurrences, 28 of these (54%) were diagnosed at age 65 or older, of which 13 were contralateral (median time to recurrence: 140 months); 5 were local/regional (median time: 186 months) and 10 were metastatic (median time: 76 months). Ten of the 13 contralateral recurrences (77%) were in BRCA1 carriers. Of the ovarian cancer diagnoses (n = 69), 27 (39%) were diagnosed at age 65 or older. Among these 27 patients, median age at diagnosis was 71 years (65-87); majority were BRCA2 carriers (74%), had serous carcinoma (84%), with stage III or IV disease (96%). Of all ovarian cancers (n = 69), there were 15 recurrences (22%), 9 of them (60%) were diagnosed at age 65 or older. Of the 8 pancreatic cancers, 6 were diagnosed at age 65 or older. Of the 283 BRCA1/2 carriers, 249 still had at least one breast at the time of genetic testing, and 34% elected for risk-reducing mastectomy (RRM). Of the 177 patients with intact ovaries, 71% opted for risk-reducing salpingo-oophorectomy (RRSO). Compared to BRCA carriers with cancer diagnosed under age 65, a smaller proportion of those diagnosed at age 65 or older opted to undergo RRM (26% vs. 40%) or RRSO (67% vs. 78%). Conclusions: Our study reveals that female BRCA1/2 mutation carriers over age 65 continue to retain a significant risk of cancer, including breast, contralateral breast, ovarian, and pancreatic cancer. This finding supports the importance of continued high-risk surveillance and risk-reducing interventions in this growing demographic. Further studies are needed to better define the cancer risks and optimal management of older females with BRCA1/2 mutations.

Risk of second primary cancer among women in the Kaiser Permanente Breast Cancer Survivors Cohort

BackgroundBreast cancer survivors are living longer due to early detection and advances in treatment and are at increased risk for second primary cancers. Comprehensive evaluation of second cancer risk among patients treated in recent decades is lacking.MethodsWe identified 16,004 females diagnosed with a first primary stage I-III breast cancer between 1990 and 2016 (followed through 2017) and survived ≥ 1 year at Kaiser Permanente (KP) Colorado, Northwest, and Washington. Second cancer was defined as an invasive primary cancer diagnosed ≥ 12 months after the first primary breast cancer. Second cancer risk was evaluated for all cancers (excluding ipsilateral breast cancer) using standardized incidence ratios (SIRs), and a competing risk approach for cumulative incidence and hazard ratios (HRs) adjusted for KP center, treatment, age, and year of first cancer diagnosis.ResultsOver a median follow-up of 6.2 years, 1,562 women developed second cancer. Breast cancer survivors had a 70% higher risk of any cancer (95%CI = 1.62–1.79) and 45% higher risk of non-breast cancer (95%CI = 1.37–1.54) compared with the general population. SIRs were highest for malignancies of the peritoneum (SIR = 3.44, 95%CI = 1.65–6.33), soft tissue (SIR = 3.32, 95%CI = 2.51–4.30), contralateral breast (SIR = 3.10, 95%CI = 2.82–3.40), and acute myeloid leukemia (SIR = 2.11, 95%CI = 1.18–3.48)/myelodysplastic syndrome (SIR = 3.25, 95%CI = 1.89–5.20). Women also had elevated risks for oral, colon, pancreas, lung, and uterine corpus cancer, melanoma, and non-Hodgkin lymphoma (SIR range = 1.31–1.97). Radiotherapy was associated with increased risk for all second cancers (HR = 1.13, 95%CI = 1.01–1.25) and soft tissue sarcoma (HR = 2.36, 95%CI = 1.17–4.78), chemotherapy with decreased risk for all second cancers (HR = 0.87, 95%CI = 0.78–0.98) and increased myelodysplastic syndrome risk (HR = 3.01, 95%CI = 1.01–8.94), and endocrine therapy with lower contralateral breast cancer risk (HR = 0.48, 95%CI = 0.38–0.60). Approximately 1 in 9 women who survived ≥ 1 year developed second cancer, 1 in 13 developed second non-breast cancer, and 1 in 30 developed contralateral breast cancer by 10 years. Trends in cumulative incidence declined for contralateral breast cancer but not for second non-breast cancers.ConclusionsElevated risks of second cancer among breast cancer survivors treated in recent decades suggests that heightened surveillance is warranted and continued efforts to reduce second cancers are needed.

Caveolin-1 genotypes as predictor for locoregional recurrence and contralateral disease in breast cancer

PurposeCaveolin-1 (CAV1) has been implicated in breast cancer oncogenesis and metastasis and may be a potential prognosticator, especially for non-distant events. CAV1 functions as a master regulator of membrane transport and cell signaling. Several CAV1 SNPs have been linked to multiple cancers, but the prognostic impact of CAV1 SNPs in breast cancer remains unclear. Here, we investigated CAV1 polymorphisms in relation to clinical outcomes in breast cancer.MethodsA cohort of 1017 breast cancer patients (inclusion 2002–2012, Sweden) were genotyped using Oncoarray by Ilumina. Patients were followed for up to 15 years. Five out of six CAV1 SNPs (rs10256914, rs959173, rs3807989, rs3815412, and rs8713) passed quality control and were used for haplotype construction. CAV1 genotypes and haplotypes in relation to clinical outcomes were assessed with Cox regression and adjusted for potential confounders (age, tumor characteristics, and adjuvant treatments).ResultsOnly one SNP was associated with lymph node status, no other SNPs or haplotypes were associated with tumor characteristics. The CAV1 rs3815412 CC genotype (5.8% of patients) was associated with increased risk of contralateral breast cancer, adjusted hazard ratio (HRadj) 4.26 (95% CI 1.86–9.73). Moreover, the TTACA haplotype (13% of patients) conferred an increased risk for locoregional recurrence HRadj 2.24 (95% CI 1.24–4.04). No other genotypes or haplotypes were associated with clinical outcome.ConclusionCAV1 polymorphisms were associated with increased risk for locoregional recurrence and contralateral breast cancer. These findings may identify patients that could derive benefit from more tailored treatment to prevent non-distant events, if confirmed.