Risk Of Contralateral Breast Cancer Research Articles

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.

Breast Cancer Risk and Breast-Cancer-Specific Mortality following Risk-Reducing Salpingo-Oophorectomy in BRCA Carriers: A Systematic Review and Meta-Analysis

Risk-reducing salpingo-oophorectomy (RRSO) is the gold standard method of ovarian cancer risk reduction, but the data are conflicting regarding the impact on breast cancer (BC) outcomes. This study aimed to quantify BC risk/mortality in BRCA1/BRCA2 carriers after RRSO. We conducted a systematic review (CRD42018077613) of BRCA1/BRCA2 carriers undergoing RRSO, with the outcomes including primary BC (PBC), contralateral BC (CBC) and BC-specific mortality (BCSM) using a fixed-effects meta-analysis, with subgroup analyses stratified by mutation and menopause status. RRSO was not associated with a significant reduction in the PBC risk (RR = 0.84, 95%CI: 0.59-1.21) or CBC risk (RR = 0.95, 95%CI: 0.65-1.39) in BRCA1 and BRCA2 carriers combined but was associated with reduced BC-specific mortality in BC-affected BRCA1 and BRCA2 carriers combined (RR = 0.26, 95%CI: 0.18-0.39). Subgroup analyses showed that RRSO was not associated with a reduction in the PBC risk (RR = 0.89, 95%CI: 0.68-1.17) or CBC risk (RR = 0.85, 95%CI: 0.59-1.24) in BRCA1 carriers nor a reduction in the CBC risk in BRCA2 carriers (RR = 0.35, 95%CI: 0.07-1.74) but was associated with a reduction in the PBC risk in BRCA2 carriers (RR = 0.63, 95%CI: 0.41-0.97) and BCSM in BC-affected BRCA1 carriers (RR = 0.46, 95%CI: 0.30-0.70). The mean NNT = 20.6 RRSOs to prevent one PBC death in BRCA2 carriers, while 5.6 and 14.2 RRSOs may prevent one BC death in BC-affected BRCA1 and BRCA2 carriers combined and BRCA1 carriers, respectively. RRSO was not associated with PBC or CBC risk reduction in BRCA1 and BRCA2 carriers combined but was associated with improved BC survival in BC-affected BRCA1 and BRCA2 carriers combined and BRCA1 carriers and a reduced PBC risk in BRCA2 carriers.

Abstract GS4-04: Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2

Abstract Purpose To estimate the risk of contralateral breast cancer (CBC) among women in the general population with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Methods Among 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer, a subset of 14,237 women were identified from population-based studies. The risk of CBC was estimated for PV carriers in each gene compared to women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor status. Results Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (Hazard ratio ≥ 1.9, p&amp;lt; 0.05) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks. In contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 15-year cumulative incidence of CBC was &amp;gt;20% for BRCA1, BRCA2 and CHEK2 PV carriers with breast cancer, and for PALB2 PV carriers with ER-negative breast cancer. The 15-year cumulative incidence of CBC among postmenopausal PV carriers was &amp;lt; 20% for PV carriers in any of the 5 genes. Conclusions Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk-reduction strategies. Citation Format: Siddhartha Yadav, Nicholas J. Boddicker, Jie Na, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan D. Gnanaolivu, Nicole Larson, Carolyn Dunn, Susan Holtegaard, Huaizhi Huang, Lauren R. Teras, Alpa V. Patel, James V. Lacey Jr., Susan Neuhausen, Leslie Bernstein, Elena Martinez, Christopher Haiman, Fei Chen, Kathryn Ruddy, Janet Olson, Esther John, Allison W. Kurian, Dale P. Sandler, Katie M. O’Brien, Jack A. Taylor, Clarice R. Weinberg, Hoda Anton-Culver, Argyrios Ziogas, Gary R. Zirpoli, David E. Goldgar, Katherine L. Nathanson, Susan Domchek, Julie R. Palmer, Jeffrey Weitzel, Peter Kraft, Fergus J. Couch. Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-04.

Abstract P3-04-11: Longitudinal Changes of Contralateral Breast Mammographic Artificial Intelligence Algorithms Score in Ductal Carcinoma In Situ patient with Tamoxifen

Abstract Background Mammographic Artificial intelligence (AI) algorithms (Lunit insight MMG) draws attention as a diagnostic support tool for breast cancer detection. Lunit insight MMG provides a location suspected of breast cancer with a heatmap and a score reflecting the probability of the presence of suspicious areas. We investigated whether the Lunit insight MMG score is relevant for predicting the response to adjuvant tamoxifen. Methods Patients diagnosed with DCIS and underwent treatment at Seoul National University Hospital in 2010 were retrospectively enrolled. Clinical characteristics, tamoxifen use, survival data, and mammography images were extracted from the electronic medical records, and Lunit insight MMG scores were calculated retrospectively. We classified two groups according to tamoxifen treatment and compared the score change of contralateral breast from baseline to 5 years after surgery for DCIS. Change categories of Lunit insight MMG score included maintaining high risk, maintaining low risk, increasing from low risk to high risk, and decreasing from high risk to low risk. Results Of 100 patients, 50 (50%) had undergone tamoxifen treatment (group 1) and 50 (50%) had not (group 2). The median age of the patients was 48.4 years for group 1 and 51.5 years for group 2 (p=0.172). The median follow-up duration was 8.7 years for the whole cohort. Using Lunit insight MMG score, more patients in group 1 decreased in contralateral breast cancer (CBC) risk compared with group 2 (6.0% vs. 2.0%; P=.008). No patients in group 1 had an increase in CBC risk while 9 patients increased in group 2 (0% vs. 18.0%; P =.008). There was no ipsilateral breast cancer recurrence for the whole cohort, and two patients experienced contralateral invasive breast cancer in group 2. In two patients with CBC, the Lunit insight MMG score increased five years after surgery, one year and three years before the CBC diagnosis. Conclusions Longitudinal Changes of Mammographic AI algorithms Score may be a predictive surrogate marker for response to tamoxifen therapy in hormone receptor-positive DCIS. Citation Format: Changjin Lim, Eun Kyung Park, Hong-Kyu Kim, Eunhye Kang, Ji-Jung Jung, Hyunsu Yeoh, Jang-il Kim, Jung Whan Chun, Han-Byoel Lee, Hyeong-Gon Moon, Wonshik Han. Longitudinal Changes of Contralateral Breast Mammographic Artificial Intelligence Algorithms Score in Ductal Carcinoma In Situ patient with Tamoxifen [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-04-11.

Abstract P6-02-14: Contralateral breast cancer risk in patients with or without BRCA mutation

Abstract Background: Patients who carry mutated BRCA1 or BRCA2 genes have a significantly increased risk of breast cancer and developing contralateral breast cancer (CBC). In this study, we aimed to investigate the acceptance rate of BRCA1/2 testing in Korean breast cancer patients and to determine the risk of CBC in Korean patients with BRCA 1/2 germline mutations. Methods: This study included 13,109 patients with first primary breast cancer who were treated at Seoul National University Hospital from January 2005 to December 2018. These patients were divided into high-risk for BRCA1/2 mutation group and low-risk group. High risk patients were defined as those who were eligible for BRCA testing per Korean National Health Insurance Service. The high-risk group was further classified into three groups; BRCA1/2 mutation carrier, BRCA 1/2 non carrier and BRCA/12 untested. Results: Among the 4,446 high-risk patients, 962 (21.7%) patients underwent BRCA1/2 testing. The testing rate varied among different indications (47.8% of patients with a family history, 23.3% of patients under 40 years of age, and 13.0% of patients with triple negative breast cancer). The risk of the CBC in BRCA mutation group was higher than other groups (p value &amp;lt; 0.001). The 10-year cumulative risk of CBC was 11.0% BRCA1 mutation carrier and 7.4% for BRCA2 mutation carrier. In the BRCA1/2 non-carriers, the cumulative risk of CBC was 5.7%. Interestingly, the CBC risk for BRCA1/2 non-carriers significantly higher than BRCA1/2 untested group and the low-risk group (p &amp;lt; 0.001). When compared to the BRCA1/2 untested group, the relative risk for CBC was 6.7-fold increase for the BRCA1/2 mutation carrier group (95% CI = 3.65-12.22, p &amp;lt; 0.001), and 2.3-fold increase for the BRCA1/2 non-carriers group (95% CI = 1.44-3.83, p &amp;lt; 0.001). The relative risk for CBC in high-risk group also depended on subtype of breast cancer and family history. Hormone receptor negative breast cancer patients had a 1.5-fold (95% CI = 1.02-2.31, p = 0.04) increased risk of CBC and patients with one or more 1st degree relative with breast cancer had 2.4-fold increased risk (95% CI = 1.55-3.67, p &amp;lt; 0.001). Conclusion: About one out of five Korean breast cancer patients, who are eligible for the BRCA1/2 testing, undergo testing for BRCA1/2 germline mutations. We observed increased CBC risk not only for the BRCA1/2 mutation carriers but also for the BRCA1/2 non-carriers. At present, we are conducting multi-gene panel testing for the BRCA1/2 non-carriers to understand the mechanisms of the increased CBC risk. Citation Format: Eunhye Kang, Ji-Jung Jung, Hyunsu Yeoh, Changjin Lim, Jang-il Kim, Jung Whan Chun, Hong-Kyu Kim, Han-Byoel Lee, Wonshik Han, Hyeong-Gon Moon. Contralateral breast cancer risk in patients with or without BRCA mutation [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-14.

The impact of coding germline variants on contralateral breast cancer risk and survival

Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70-4.87), 2.31 (1.39-3.85), 8.29 (2.53-27.21), 2.25 (1.55-3.27), and 2.67 (1.33-5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13-2.07), 2.08 (0.95-4.57), and 1.39 (1.13-1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.

Associations of a Breast Cancer Polygenic Risk Score With Tumor Characteristics and Survival.

A polygenic risk score (PRS) consisting of 313 common genetic variants (PRS313) is associated with risk of breast cancer and contralateral breast cancer. This study aimed to evaluate the association of the PRS313 with clinicopathologic characteristics of, and survival following, breast cancer. Women with invasive breast cancer were included, 98,397 of European ancestry and 12,920 of Asian ancestry, from the Breast Cancer Association Consortium (BCAC), and 683 women from the European MINDACT trial. Associations between PRS313 and clinicopathologic characteristics, including the 70-gene signature for MINDACT, were evaluated using logistic regression analyses. Associations of PRS313 (continuous, per standard deviation) with overall survival (OS) and breast cancer-specific survival (BCSS) were evaluated with Cox regression, adjusted for clinicopathologic characteristics and treatment. The PRS313 was associated with more favorable tumor characteristics. In BCAC, increasing PRS313 was associated with lower grade, hormone receptor-positive status, and smaller tumor size. In MINDACT, PRS313 was associated with a low risk 70-gene signature. In European women from BCAC, higher PRS313 was associated with better OS and BCSS: hazard ratio (HR) 0.96 (95% CI, 0.94 to 0.97) and 0.96 (95% CI, 0.94 to 0.98), but the association disappeared after adjustment for clinicopathologic characteristics (and treatment): OS HR, 1.01 (95% CI, 0.98 to 1.05) and BCSS HR, 1.02 (95% CI, 0.98 to 1.07). The results in MINDACT and Asian women from BCAC were consistent. An increased PRS313 is associated with favorable tumor characteristics, but is not independently associated with prognosis. Thus, PRS313 has no role in the clinical management of primary breast cancer at the time of diagnosis. Nevertheless, breast cancer mortality rates will be higher for women with higher PRS313 as increasing PRS313 is associated with an increased risk of disease. This information is crucial for modeling effective stratified screening programs.

Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2.

To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2. Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

The Contribution of Germline Pathogenic Variants in Breast Cancer Genes to Contralateral Breast Cancer Risk in BRCA1/BRCA2/PALB2-Negative Women.

Contralateral breast cancer (CBC) is associated with younger age at first diagnosis, family history and pathogenic germline variants (PGVs) in genes such as BRCA1, BRCA2 and PALB2. However, data regarding genetic factors predisposing to CBC among younger women who are BRCA1/2/PALB2-negative remain limited. In this nested case-control study, participants negative for BRCA1/2/PALB2 PGVs were selected from the WECARE Study. The burden of PGVs in established breast cancer risk genes was compared in 357 cases with CBC and 366 matched controls with unilateral breast cancer (UBC). The samples were sequenced in two phases. Whole exome sequencing was used in Group 1, 162 CBC and 172 UBC (mean age at diagnosis: 42 years). A targeted panel of genes was used in Group 2, 195 CBC and 194 UBC (mean age at diagnosis: 50 years). Comparisons of PGVs burdens between CBC and UBC were made in these groups, and additional stratified sub-analysis was performed within each group according to the age at diagnosis and the time from first breast cancer (BC). The PGVs burden in Group 1 was significantly higher in CBC than in UBC (p = 0.002, OR = 2.5, 95CI: 1.2-5.6), driven mainly by variants in CHEK2 and ATM. The proportions of PGVs carriers in CBC and UBC in this group were 14.8% and 5.8%, respectively. There was no significant difference in PGVs burden between CBC and UBC in Group 2 (p = 0.4, OR = 1.4, 95CI: 0.7-2.8), with proportions of carriers being 8.7% and 8.2%, respectively. There was a significant association of PGVs in CBC with younger age. Metanalysis combining both groups confirmed the significant association between the burden of PGVs and the risk of CBC (p = 0.006) with the significance driven by the younger cases (Group 1). In younger BRCA1/BRCA2/PALB2-negative women, the aggregated burden of PGVs in breast cancer risk genes was associated with the increased risk of CBC and was inversely proportional to the age at onset.

BRCA-CRisk: A Contralateral Breast Cancer Risk Prediction Model for BRCA Carriers.

The absolute cumulative risk of contralateral breast cancer (CBC) for patients with BRCA1/2 variants is unknown. The purpose of this study was to develop a CBC risk prediction model for assessing CBC risk for BRCA1/2 carriers. The primary cohort of 491 patients with BRCA1/2 variants was derived from a large series of unselected patients with breast cancer. A nomogram was established on the basis of the results of a multivariate Cox regression analysis from this cohort. This model, named BRCA-CRisk, was further validated by an independent cohort of 205 patients with BRCA1/2 variants. Discrimination and calibration of the model were assessed. In the primary cohort of 491 patients, 66 developed contralateral breast cancer after a median follow-up of 7.0 years. Four variables were significantly associated with risk of CBC and were incorporated in the establishment of the BRCA-CRisk prediction model: younger age at first breast cancer (with continuous variable, P = .002), positive first-degree family history of breast and/or ovarian cancer (hazard ratio [HR], 1.89; 95% CI, 1.16 to 3.08; P = .011), variant located near the 3' region of BRCA (HR, 2.01; 95% CI, 1.23 to 3.30; P = .006), and endocrine therapy (HR, 0.54; 95% CI, 0.33 to 0.88; P = .013). The area under the time-dependent curves for the 5- and 10-year cumulative risks of CBC were 0.775 and 0.702, respectively. The model was well validated in the independent cohort of 205 BRCA1/2 carriers, with area under the curves of 0.750 and 0.691 for 5 and 10 years, respectively. BRCA-CRisk model provides a useful tool for assessing the absolute cumulative risk of CBC for BRCA1/2 carriers and may help carriers and clinicians optimally select risk-reducing strategies on the basis of individual CBC risk.

Abstract IA027: DCIS or cancer? Why all the confusion?

Abstract Many women diagnosed with DCIS in the United States report they are confused about their chances of developing an invasive breast cancer or metastatic cancer. They are told that DCIS is not cancer but it holds the possibility of becoming a cancer. Nevertheless, DCIS is treated in much the same way as a small invasive cancer. Surgical options include lumpectomy alone, lumpectomy with radiotherapy, unilateral or bilateral mastectomy. Much of the confusion is generated by the current paradigm that separates DCIS and invasive cancer into distinct conditions. The mortality of DCIS is 3% over 20 years and that prevention of local invasive recurrence post-DCIS does not reduce breast cancer mortality. If the invasive recurrence were the real cancer then preventing it would reduce the risk of dying but this has not been shown. Further, the risk of an invasive in-breast recurrence following DCIS is the same as the risk of an invasive in-breast recurrence following invasive breast cancer. In the Banting database, the 15-year risk of invasive local recurrence following DCIS was 15.6%, following stage I breast cancer was 15.3% and following stage II breast cancer was 15.9%. In the Banting database, the 15-year risk of ipsilateral invasive recurrence was 14% for DCIS patients who receives radiotherapy and was 29% for DCIS patients who did not received radiotherapy – a difference of 15%. In the Banting database, the 15-year risk of ipsilateral invasive recurrence was 14% for Stage I/II patients who received radiotherapy and was 27% for Stage I/II patients who did not receive radiotherapy – a difference of 13%. The benefit of radiotherapy is the same in both groups. Similarly, the benefit of unilateral mastectomy versus lumpectomy on preventing local invasive recurrence is the same for DCIS patients as it is for early-stage invasive breast cancer patients. In our SEER-based analysis of 812,851 women with breast cancer, the 25-year actuarial risk of contralateral invasive breast cancer was 10.1% for patients with DCIS and was 9.9% for patients with invasive breast cancer. Based on this finding, the benefit of performing a contralateral mastectomy at the time of diagnosis is the same for both groups. We accept lumpectomy as standard of care for invasive breast cancer even though the risk of invasive ipsilateral recurrence is much higher after lumpectomy than after mastectomy. We consider contralateral mastectomy as an option for women with invasive cancer, but as overtreatment for women with DCIS even though the risk of contralateral breast cancer is almost exactly the same. The benefit of radiotherapy is the same for patients with DCIS and stage I/II breast cancer, but we are more likely to consider it overtreatment for DCIS patients. Much of the confusion can be resolved if we consider both types of cancer to be different points on the spectrum. Breast cancer is heterogeneous; DCIS is one end of the spectrum. Accepting this fact will make the rationale behind treatment decisions easier to explain. Citation Format: Steven A. Narod. DCIS or cancer? Why all the confusion? [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr IA027.

Abstract A003: Risks of ductal carcinoma in situ of the breast associated with pathogenic variants in cancer predisposition genes

Abstract Introduction: The relationship between germline pathogenic variants (PVs) in cancer predisposition genes and ductal carcinoma in situ (DCIS) is not well established. The objective of this study is to determine the risks of DCIS and contralateral breast cancer among women with DCIS associated with germline PVs in cancer predisposition genes. Methods: Associations between pathogenic variants in 11 cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MSH6, PALB2, RAD51C, and RAD51D) and DCIS were determined in case control analyses of a population-based cohort of 3876 women with DCIS and age-matched unaffected women, and in a clinical cohort of 9887 DCIS cases undergoing clinical genetic testing at Ambry Genetics and unaffected reference controls. The incidence of contralateral breast cancer risk in BRCA1, BRCA2, and PALB2 PV carriers with DCIS was also evaluated in a time-to-event analysis. Results: The mean age at diagnosis of DCIS was 50 years in the clinical testing cohort and 59 years in the population-based cohort. The frequency of PVs in 11 predisposition genes among DCIS cases was 6.9% in the clinical testing cohort and 4.9% in the population-based cohort. PVs in ATM, BRCA1, BRCA2, CHEK2, MSH6, PALB2, and RAD51D were associated with significantly increased risks (Odds Ratio (OR) &amp;gt;2) of DCIS in the clinical testing cohort whereas only PVs in BRCA1, CHEK2, PALB2, and ATM were associated with significantly increased risks of DCIS in the population-based cohort. The cumulative incidence of contralateral breast cancer among BRCA1, BRCA2, and PALB2 PV carriers with DCIS was 11% in 5-years and 20% in 15-years. Conclusions: This study provides new insights into PVs that predispose to DCIS. In addition, it establishes an increased risk of contralateral breast cancer risk among women with DCIS who are carriers of PVs in BRCA1, BRCA2, or PALB2. These findings will guide surveillance and risk reducing strategies in germline PV carriers with DCIS. Citation Format: Huaizhi Huang, Ronan E. Couch, Holly LaDuca, Siddhartha Yadav, Eric C. Polley, Nicholas J. Boddicker, Jie Na, Rohan D. Gnanaolivu, David E. Goldgar, Tina Pesaran, Steven N. Hart, Jill S. Dolinsky, Julie R. Palmer, Lauren Teras, Alpa V. Patel, Kathryn J. Ruddy, Janet E. Olson, Celine M. Vachon, Peter Kraft, Song Yao, Amy Trentham-Dietz, Katherine L. Nathanson, Jeffrey N. Weitzel, Susan M. Domchek, Fergus J. Couch, Chunling Hu. Risks of ductal carcinoma in situ of the breast associated with pathogenic variants in cancer predisposition genes [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr A003.

Accelerated Partial Breast Irradiation (APBI) Using Five Daily Fractions: A Prospective, Phase II, Multi-Center Trial of Cosmetic Outcomes and Toxicity: Final Results

<h3>Purpose/Objective(s)</h3> To report final results of a clinical trial of APBI using intensity modulated radiotherapy (IMRT) to deliver 27 Gy in 5 daily fractions following breast conserving surgery (BCS) prospectively designed to assess the efficacy and cosmetic outcomes of a 1-week, APBI regimen among women with early breast cancer. <h3>Materials/Methods</h3> Women ≥ 50 years, with lymph node-negative, ER positive, HER-2 negative breast cancer or ductal carcinoma in situ (DCIS), ≤ 3cm diameter, following BCS with margins ≥ 2mm, and excellent or good baseline cosmesis received 27 Gy in 5 daily fractions to the seroma plus 1 cm CTV and 0.7 cm PTV margins. Clinical photographs, patient and provider cosmetic scores, breast fibrosis, telangiectasia and pain were collected prospectively, prior to RT and at 6 weeks, 1 and 2 years after RT. The primary endpoint was the proportion of women who retained Excellent or Good cosmesis at 2 years using the EORTC Cosmetic Rating System. Cosmetic failure was deterioration from Excellent or Good to Fair or Poor. A panel of 5 radiation oncologists independently assessed the cosmetic photographs. Secondary endpoints were rates and grades of breast fibrosis, telangiectasia, breast pain, ipsilateral breast tumor recurrence (IBRT), overall (OS), breast cancer-specific survival (BCSS) and subsequent mastectomy. Efficacy outcomes were assessed at clinic visits and by review of charts. ClinicalTrials.gov registration: NCT02681107. <h3>Results</h3> A total of 298 patients were treated between April 25, 2016, and October 31, 2019. At a median follow up of 48 months, the 4-year OS was 98.5% (95% CI 96.1% - 99.5%) and BCSS was 99.7% (95% CI 97.6% - 99.9%). The 4-year IBRT rate was 3.3% (95% CI 1.1% - 6.4%). There were 10 contralateral breast events for a 4-year rate of 3.9% (95% CI 2.2% - 6.9%). There were 10 ipsilateral and 6 contralateral mastectomies. Two patients died of unrelated causes prior to 2 years; 79 patients declined in-clinic attendance due to COVID or competing comorbidities and 217 women had 2-year cosmetic photographs and clinical assessments performed. Consensus of the photo-panel cosmesis at baseline was: Excellent: n=116 (53%), Good: n=102 (47%), Fair: n=1 (0.5%) and Poor: n=0. Consensus overall cosmesis at 2 years was: Excellent: n=141 (65%), Good: n=78 (35%), Fair: n=0 and Poor: n=0. Most patients had either improved (n=168; 77%) or no change (n=43; 20%) in cosmesis at 2-years. No patient had cosmetic failure but 6 (3%) had a change from Excellent to Good at 2 years. Most patients reported either no (79%) or mild (21%) pain, with no moderate or severe pain. Two patients (0.9%) had grade 2 fibrosis and 5 patients (2%) had visible telangiectasia that did not detract from overall cosmesis. <h3>Conclusion</h3> APBI using 27 Gy in 5 fractions using a conformal IMRT technique, achieved excellent 2-year cosmesis with minimal toxicity. The IBRT risk was comparable to the contralateral new breast cancer risk and to local recurrence rates of recently published early breast cancer trials.

Risk of metachronous contralateral breast cancer in patients with primary invasive lobular breast cancer: Results from a nationwide cohort.

Lobular primary breast cancer (PBC) histology has been proposed as a risk factor for contralateral breast cancer (CBC), but results have been inconsistent. We investigated CBC risk and the impact of systemic therapy in lobular versus ductal PBC. Further, CBC characteristics following these histologic subtypes were explored. We selected 74,373 women diagnosed between 2003 and 2010 with stage I-III invasive PBC from the nationwide Netherlands Cancer Registry. We assessed absolute risk of CBC taking into account competing risks among those with lobular (n= 8903), lobular mixed with other types (n= 3512), versus ductal (n= 62,230) histology. Hazard ratios (HR) for CBC were estimated in a cause-specific Cox model, adjusting for age at PBC diagnosis, radiotherapy, chemotherapy and/or endocrine therapy. Multivariable HRs for CBC were 1.18 (95% CI: 1.04-1.33) for lobular and 1.37 (95% CI: 1.16-1.63) for lobular mixed versus ductal PBC. Ten-year cumulative CBC incidences in patients with lobular, lobular mixed versus ductal PBC were 3.2%, 3.6% versus 2.8% when treated with systemic therapy and 6.6%, 7.7% versus 5.6% in patients without systemic therapy, respectively. Metachronous CBCs were diagnosed in a less favourable stage in 19%, 26% and 23% and less favourable differentiation grade in 22%, 33% and 27% than the PBCs of patients with lobular, lobular mixed and ductal PBC, respectively. In conclusion, lobular and lobular mixed PBC histology are associated with modestly increased CBC risk. Personalised CBC risk assessment needs to consider PBC histology, including systemic treatment administration. The impact on prognosis of CBCs with unfavourable characteristics warrants further evaluation.