Incidence Of Contralateral Breast Cancer Research Articles

Long-term oncologic outcomes of unselected triple-negative breast cancer patients according to BRCA1/2 mutations

Triple-negative breast cancer (TNBC) patients are more likely to have BRCA1/2 mutations, with a prevalence rate of about 10–20%. Although several studies have analyzed the oncologic outcomes between BRCA1/2 carriers and non-carriers, the impact on breast cancer patients is still unclear. A retrospective review was performed to determine the long-term outcomes of TNBC patients, focusing on the impact of BRCA1/2 mutations. A total of 953 TNBC patients who underwent primary breast cancer surgery from June 2008 to January 2016 were included. We examined long-term outcomes, including contralateral breast cancer (CBC) incidence, recurrence patterns, and survival rates over a median follow-up of 80.9 months (range 3–152 months). 122 patients (12.8%) had BRCA1/2 mutations. BRCA1/2 mutation carriers were significantly younger at diagnosis and more likely to have a family history of breast/ovarian cancer. CBC incidence at 60, 120, and 150 months was significantly higher in BRCA1/2 mutation carriers compared to non-carriers (P = 0.0250, 0.0063, and 0.0184, respectively). However, there were no significant differences in disease-free survival, overall survival, breast cancer-specific survival, or distant-metastasis-free survival between the two groups. BRCA1/2 mutation status was a significant risk factor for CBC (HR = 6.242, P < 0.0001). Interestingly, among 29 patients with CBC recurrence, 24 patients (82.8%) had recurring TNBC subtype and among the CBC recurrence patients, 19 patients (65.5%) resumed chemotherapy. In the TNBC subtype, appropriate genetic testing and counseling are pivotal for surgical decisions like risk-reducing mastectomy (RRM). Furthermore, long-term surveillance is warranted, especially in BRCA1/2 carriers who did not receive RRM.

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.

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.

Locoregional Recurrence Patterns in Patients With Different Molecular Subtypes of Breast Cancer

While numerous studies have consistently reported that the molecular subtypes of breast cancer (BC) are associated with different patterns of distant metastasis, few studies have investigated the association of tumor subtypes with locoregional recurrence. To investigate the patterns of ipsilateral breast tumor recurrence (IBTR), regional recurrence (RR), and contralateral BC (CBC) according to tumor subtypes. This retrospective cohort study used the clinical records of patients who underwent BC surgery at a single institution in South Korea between January 2000 and December 2018. Data were analyzed from May 1, 2019, to February 20, 2023. Ipsilateral breast tumor recurrence, RR, and CBC events. The primary outcome was differences in annual incidence patterns of IBTR, RR, and CBC according to tumor subtypes. Hormone receptor (HR) status was assessed by immunohistochemical staining assay, and ERBB2 status was evaluated according to American Society of Clinical Oncology and College of American Pathologists guidelines. A total of 16 462 female patients were included in the analysis (median age at time of operation, 49.0 years [IQR, 43.0-57.0 years]). The 10-year IBTR-, RR-, and CBC-free survival rates were 95.9%, 96.1%, and 96.5%, respectively. On univariate analysis, HR-/ERBB2+ tumors had the worst IBTR-free survival (vs HR+/ERBB2- subtype: adjusted hazard ratio, 2.95; 95% CI, 2.15-4.06), while the HR-/ERBB2- subtype had the worst RR- and CBC-free survival among all subtypes (vs HR+/ERBB2- subtype, RR: adjusted hazard ratio, 2.95; 95% CI, 2.37-3.67; CBC: adjusted hazard ratio, 2.12; 95% CI, 1.64-2.75). Subtype remained significantly associated with recurrence events in Cox proportional hazards regression analysis. Regarding the annual recurrence pattern, the IBTR patterns of HR-/ERBB2+ and HR-/ERBB2- subtypes showed double peaks, while HR+/ERBB2- tumors showed a steadily increasing pattern without distinguishable peaks. Additionally, the HR+/ERBB2- subtype seemed to have a steady RR pattern, but other subtypes showed the highest RR incidence at 1 year following surgery, which then gradually decreased. The annual recurrence incidence of CBC gradually increased among all subtypes, and patients with the HR-/ERBB2- subtype had a higher incidence than patients with other subtypes over 10 years. Younger patients (age ≤40 years) had greater differences in IBTR, RR, and CBC patterns between subtypes than did older patients. In this study, locoregional recurrence occurred with different patterns according to BC subtypes, with younger patients having greater differences in patterns among subtypes than older patients. The findings suggest that tailoring surveillance should be recommended regarding differences in locoregional recurrence patterns according to tumor subtypes, particularly for younger patients.

Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Recurrence in Breast Noninvasive Neoplasia: A 10-Year Follow-Up of TAM-01 Study.

Five-year data of the phase III trial TAM-01 showed that low-dose tamoxifen at 5 mg once daily administered for 3 years in women with intraepithelial neoplasia (IEN) reduced by 52% the recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), without additional adverse events over placebo. Here, we present the 10-year results. We randomly assigned 500 women with breast IEN (atypical ductal hyperplasia, lobular carcinoma in situ [LCIS], or hormone-sensitive or unknown DCIS) to low-dose tamoxifen or placebo after surgery with or without irradiation. The primary end point was the incidence of invasive breast cancer or DCIS. The TAM-01 population included 500 women (20% atypical ductal hyperplasia, 11% LCIS, and 69% DCIS). The mean (±SD) age at the start of treatment was 54 ± 9 years, and 58% of participants were postmenopausal. After a median follow-up of 9.7 years (IQR, 8.3-10.9 years), 66 breast cancers (15 in situ; 51 invasive) were diagnosed: 25 in the tamoxifen group and 41 in the placebo group (annual rate per 1,000 person-years, 11.3 with tamoxifen v 19.5 with placebo; hazard ratio [HR], 0.58; 95% CI, 0.35 to 0.95; log-rank P = .03). Most recurrences were invasive (77%) and ipsilateral (59%). Regarding contralateral breast cancer incidence, there were six events in the tamoxifen arm and 16 in the placebo arm (HR, 0.36; 95% CI, 0.14 to 0.92; P = .025). The number needed to be treated to prevent one case of breast event with tamoxifen therapy was 22 in 5 years and 14 in 10 years. The benefit was seen across all patient subgroups. There was a significant 50% reduction of recurrence with tamoxifen in the DCIS cohort, which represents 70% of the overall population (HR, 0.50; 95% CI, 0.28 to 0.91; P = .02). No between-group difference in the incidence of serious adverse events was reported during the prolonged follow-up period. Tamoxifen 5 mg once daily for 3 years significantly prevents recurrence from noninvasive breast cancer after 7 years from treatment cessation without long-term adverse events.

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.

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.

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.

Surgical Management and Contralateral Breast Cancer Risk in Women with History of Radiation Therapy for Hodgkin Lymphoma: Results from a Population-Based Cohort.

Women with history of chest irradiation for Hodgkin lymphoma are at increased risk of developing bilateral breast cancer, although contralateral breast cancer risk estimates in this population remain undefined. We queried the SEER database for women treated with radiation therapy for Hodgkin lymphoma prior to age 30 years and were diagnosed with a subsequent breast cancer between 1990-2016. Trends in surgical management and the 5- and 10-year cumulative incidence of contralateral breast cancer were evaluated. The cohort included 295 women with a median age of 22 years (range 8-30 years) at Hodgkin lymphoma diagnosis, and 42 years (range 22-65 years) at breast cancer diagnosis. Overall, 263 (89.2%) presented with unilateral breast cancer, while 32 (10.8%) presented with synchronous bilateral breast cancer. Breast-conserving surgery was performed in 17.3% of patients, while mastectomy was performed in 82.7%. In 263 patients presenting with unilateral breast cancer, 50 (19.0%) underwent breast-conserving surgery and 213 (81.0%) underwent mastectomy. Subgroup analysis of mastectomy patients demonstrated a 40.5% bilateral mastectomy rate. The 5-year incidence of contralateral breast cancer in women who underwent unilateral surgery was 9.4% [95% confidence interval (CI), 5.6-15.4%], increasing to 20.2% (95% CI, 13.7-29.2%) at 10-year and 29.9% (95% CI, 20.8-41.9%) at 15-year follow-up. Women with a history of prior chest radiation for Hodgkin lymphoma with a diagnosis of breast cancer have a 10-year contralateral breast cancer risk of 20%. These findings support consideration of contralateral prophylactic mastectomy during surgical decision-making for management of this high-risk patient population.

Comparison of Outcomes Between BRCA Pathogenic Variant Carriers Undergoing Breast-Conserving Surgery Versus Mastectomy.

Although outcomes are similar following breast-conserving surgery (BCS) or mastectomy among sporadic breast cancer patients, data are mixed for women with a germline BRCA mutation. We sought to compare outcomes among a modern cohort of BRCA mutation carriers undergoing BCS versus mastectomy. Women with a BRCA mutation and an index breast cancer from 2006-2015 were retrospectively identified from institutional databases. Factors, including date of genetic testing, clinicopathologic details, and treatment characteristics, were identified. Subsequent locoregional recurrence (LRR), distant recurrence, contralateral breast cancer (CBC), breast cancer-specific survival (BCSS), and overall survival (OS) events were compared between groups. A total of 395 BRCA mutation carriers with 424 cancers were identified. Surgical treatment included BCS for 99 cancers and mastectomy for 325 cancers. Patients choosing mastectomy were more likely to have bilateral breast cancer, be younger/premenopausal, and be aware of their genetic status before surgery, and were less likely to receive radiation therapy (p < 0.001). At 7.9 years median follow-up, LRR, distant recurrence, BCSS, and OS rates did not differ between groups. CBC occurred in 5 versus 0 women treated with unilateral versus bilateral surgery, respectively, resulting is a 10-year estimated CBC risk of 14% among unilateral breast surgery patients (p < 0.001). With nearly 8 years follow-up, we report no difference in LRR, BCSS, and OS among BRCA mutation carriers who underwent BCS or mastectomy; however, we report a higher incidence of CBC among those undergoing unilateral breast surgery. These data support BCS as an option for BRCA mutation carriers willing to continue high-risk screening.

Abstract PD7-07: Surgical management and contralateral breast cancer risk in women with a history of radiation therapy for Hodgkin lymphoma: Results from a population-based cohort

Abstract Background: Women with a history of chest radiation for Hodgkin lymphoma are at an increased risk of developing breast cancer. Although mastectomy has historically been recommended for surgical treatment of breast cancers in women with prior radiation exposure, surgical management trends and contralateral breast cancer risk in this population remain undefined. Methods: We performed a population-based retrospective study using the Surveillance, Epidemiology, and End Results (SEER) database from 1990-2016. Our cohort included women who received radiation for Hodgkin lymphoma prior to 30 years old and were diagnosed with a subsequent breast cancer. We evaluated trends in local therapy including rates of breast conserving surgery (BCS) and mastectomy. In those undergoing unilateral surgery, the Kaplan-Meier method was used to estimate the 5- and 10-year cumulative incidence of contralateral breast cancer. Results: Our final cohort included 295 women with a median age of 22 years (range, 8-30 years) at Hodgkin lymphoma diagnosis, and 42 years (range, 22-65 years) at breast cancer diagnosis. Of these patients, 263 (89.2%) presented with unilateral breast cancer, while 32 (10.8%) presented with synchronous bilateral breast cancer. Overall, BCS was performed in 17.3% of patients and mastectomy was performed in 82.7%. In the 263 patients presenting with unilateral breast cancer, 50 (19.0%) underwent BCS and 213 (81.0%) underwent mastectomy. Subgroup analysis of mastectomy patients with surgical laterality information available demonstrated a 40.5% bilateral mastectomy rate. In the entire cohort, the 5-year incidence of contralateral breast cancer in women who underwent unilateral surgery was 9.4% (95% CI, 5.6-15.4), increasing to 20.2% (95% CI, 13.7-29.2) at 10-years of follow up. Hormone receptor status of the index breast cancer was not associated with significant differences in the incidence of contralateral breast cancer (p=0.13). Conclusions: Women with a history of prior chest radiation for Hodgkin Lymphoma with a diagnosis with breast cancer have a 10-year contralateral breast cancer risk of 20%. These findings support consideration of contralateral prophylactic mastectomy during surgical decision-making in this high-risk patient population. Citation Format: Elisheva R Eisenberg, Anna Weiss, Ipshita Prakash, Sonia Skamene, Mark Basik, Jean Francois Boileau, Lissa Ajjamada, Michael Pollak, Stephanie M Wong. Surgical management and contralateral breast cancer risk in women with a history of radiation therapy for Hodgkin lymphoma: Results from a population-based cohort [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD7-07.

Effects of chemotherapy on contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers: A nationwide cohort study

AimBRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers. Patients and methodsBRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression. ResultsWe included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% [95%CI: 5.1–8.6] and 16.7% [95%CI: 10.8–23.7] in BRCA1 and 4.8% [95%CI: 2.7–7.8] and 16.0% [95%CI: 9.3–24.4] in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29–0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29–1.39). In BRCA1, risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17–0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17–0.68 and HR: 0.22, 95%CI: 0.08–0.62, respectively). ConclusionRisk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers.

Risk of contralateral breast cancer according to first breast cancer characteristics among women in the USA, 1992\u20132016

BackgroundEstimates of contralateral breast cancer (CBC) risk in the modern treatment era by year of diagnosis and characteristics of the first breast cancer are needed to assess the impact of recent advances in breast cancer treatment and inform clinical decision making.MethodsWe examined CBC risk among 419,818 women (age 30–84 years) who were diagnosed with a first unilateral invasive breast cancer and survived ≥ 1 year in the US Surveillance, Epidemiology, and End Results program cancer registries from 1992 to 2015 (follow-up through 2016). CBC was defined as a second invasive breast cancer in the contralateral breast ≥ 12 months after the first breast cancer. We estimated standardized incidence ratios (SIRs) of CBC by year of diagnosis, age at diagnosis, and tumor characteristics for the first breast cancer. Cumulative incidence of CBC was calculated for women diagnosed with a first breast cancer in the recent treatment era (2004–2015, follow-up through 2016).ResultsOver a median follow-up of 8 years (range 1–25 years), 12,986 breast cancer patients developed CBC. Overall, breast cancer patients had approximately twice the risk of developing cancer in the contralateral breast when compared to that expected in the general population (SIR = 2.21, 95% CI = 2.17–2.25). SIRs for CBC declined by year of first diagnosis, irrespective of age at diagnosis and estrogen receptor (ER) status (p-trends < 0.001), but the strongest decline was after an ER-positive tumor. The 5-year cumulative incidence of CBC ranged from 1.01% (95% CI = 0.90–1.14%) in younger women (age < 50 years) with a first ER-positive tumor to 1.89% (95% CI = 1.61–2.21%) in younger women with a first ER-negative tumor.ConclusionDeclines in CBC risk are consistent with continued advances in breast cancer treatment. The updated estimates of cumulative incidence inform breast cancer patients and clinicians on the risk of CBC and may help guide treatment decisions.

Abstract PD10-02: The influence of pathogenic variants in breast cancer predisposition genes on secondary breast cancer events in a prospectively collected cohort of breast cancer patients

Abstract Background: About 10-20% of breast cancers (BC) are hereditary. Patients (pts) with BC and pathogenic variants (PVs) in the BRCA1 or BRCA2 gene are at increased risk of contralateral breast cancer (CBC). However, risks of CBC and recurrent BC associated with PVs in other established BC predisposition genes (e.g. PALB2, CHEK2, ATM) are less well established. We performed research genetic testing of over 4000 pts with BC treated at Mayo Clinic. Because most pts were unaware of their mutation status prior to selection of therapy, this cohort provides a unique opportunity to evaluate the natural history of BC recurrence after treatment of the index BC in pts with a deleterious mutation in predisposition genes. Methods: Women diagnosed and treated for BC at Mayo Clinic between 2001-2016 were enrolled in an IRB-approved research cohort. Pts were not selected for age of diagnosis or family history. Coding regions and consensus splice sites of established BC predisposition genes were subjected to amplicon-based deep sequencing using the QIAseq method in germline DNA extracted from peripheral blood or buccal samples. PVs in the genes were identified using GATK haplotype caller and Vardict. Patient, tumor, oncologic management and follow up data were reviewed. Herein we report on the differences in the incidence of local recurrence and CBC, among carriers and non- carriers and by predisposition gene using the cumulative incidence estimator and Fine and Gray regression to account for competing risks. Results: Of 4272 women with BC (median age 57, range 21-94), a PV in a BC predisposition gene was identified in 287 (6.7%). The most common PVs were seen in CHEK2 (67, 1.6%), BRCA1 (62, 1.5%), BRCA2 (60, 1.4%), ATM (47, 1.1%); 8 (0.2%) patients had more than one PV. Pts with any PVs presented at younger age (median 51 vs 58 years, p&amp;lt;0.001), were more likely to have stage IV disease (4.5% vs 2.3%, p=0.02), estrogen receptor (ER) negative BC (19.5% vs 13.5%, p=0.005), and bilateral cancer (8.8% vs 4.3%, p&amp;lt;0.001). ER- BC proportion varied by gene - 38.9% in pts with PVs associated with ER- BC (BRCA1, BARD1, BRIP1, RAD51C, RAD51D) and 11.9% in those with PVs associated with ER+ BC (BRCA2, ATM, CDH1, CHEK2), p&amp;lt;0.001. NCCN criteria for genetic testing were assessed for 3763, with 69.9% of those with PVs qualifying for testing compared to 46.3% of those without PVs (p&amp;lt;0.001). Among 3973 pts (249 with PVs, 3724 without) with unilateral stage 0-III cancer, 168 pts developed local recurrence, 131 pts developed CBC and 248 pts developed distant disease with median 5 years of follow-up. Patients with any PV had higher rates of local recurrence after breast conserving surgery (HR 2.3, 95% CI: 1.2-4.2, p=0.01) but overall did not have significantly higher risk of CBC if contralateral prophylactic mastectomy was not performed (HR 1.7, 95% CI: 0.9-3.2, p=0.11). Specifically, pts with PVs in genes other than BRCA1 or BRCA2 did not have a higher risk of CBC compared to pts with no PV (HR 1.0, 95% CI: 0.4-2.7, p=0.96); the comparison of CBC risk in BRCA1 or BRCA2 versus those with no PV was HR 2.9 (95% CI: 1.3-6.5, p=0.01), while BRCA1 or BRCA2 compared to those with other PVs was HR 2.7 (95% CI: 0.8-9.3, p=0.13). In pts with CHEK2 PVs, the probability of CBC at 10-years follow-up was 5.4%, which was similar to pts without a mutation (5.3%), p=0.47. Conclusion: While PVs in known BC predisposition genes increase risk of BC development, risk of CBC in carriers of PVs in non-BRCA predisposition genes with BC are not as high as seen with BRCA1 or 2 PV carriers. This information regarding future BC will be helpful in personalizing decisions on the extent of surgery in carriers of PVs in BC predisposition genes. Citation Format: Judy C. Boughey, Tanya L. Hoskin, Siddhartha Yadav, Fergus J. Couch. The influence of pathogenic variants in breast cancer predisposition genes on secondary breast cancer events in a prospectively collected cohort of breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-02.

Contralateral Breast Primary in Breast Cancer Survivors-An Experience from a Tertiary Care Centre in Thiruvananthapuram, Kerala, India

Introduction: Improved life expectancy after breast cancer treatment has led to increased incidence of contralateral breast cancers. There are no well established guidelines for the management of these cancers. There is a paucity of Indian data regarding contralateral breast cancers. Aim: To describe the clinicopathological profile and prognostic outlook of patients with contralateral breast cancers. Materials and Methods: This was a retrospective cross-sectional study in which all patients who underwent surgery for non metastatic breast cancer between January 2006-December 2010 at Regional Cancer Centre, Thiruvananthapuram, Kerala, India, were identified. The follow-up data of these patients (6240 patients) were retrieved from medical records division in January 2020. The medical records of all these patients who developed contralateral breast cancer were analysed. Results: A total of 98 patients (1.57%) developed contralateral breast cancer. Most of the second breast cancers were presented at a lower stage than index cancer. Twenty five patients (25.51%) contralateral breast cancers were detected after five years. A total of 58 patients (59.18%) had interval cancer. Among them, 32 (55.17%) were detected by the treating doctor and 26 patients (44.83%) were symptomatic. The median duration of follow-up was 98 months (range 24-150 months). The five year Overall Survival (OS) was 80.5% and five year Disease Free Survival (DFS) was 62.8%. The patients who developed contralateral breast cancer within three years had lower five year OS when compared to those who developed after three years (75.5% vs 86.7% p=0.85). Five year OS was 74.8%, 81% and 85% for patient reported interval cancer, physician detected interval cancers and mammogram detected cancers respectively (p=0.9). Conclusion: Most contralateral breast cancers presented in a lower stage than index cancer. Contralateral breast cancer has got a reasonably good five year OS. There is no significant OS difference between mammogram detected second cancer and interval cancer. There was a need for more frequent clinical breast examination even after five years to detect contralateral primary in an early stage. Cost effectiveness of frequent follow- up mammogram examinations compared to clinical examination should be evaluated in future prospective studies.

Contralateral breast cancer risk and endocrine therapy use in patients with ductal carcinoma in situ treated with unilateral mastectomy in the modern era

BackgroundIn patients with ductal carcinoma in situ (DCIS), the risk of developing contralateral breast cancer (CBC) and the role of adjuvant endocrine therapy (ET) in decreasing CBC risk is not well understood. MethodsA retrospective review was performed on patients with DCIS who underwent a unilateral mastectomy (UM) from 2000 to 2010. CBC incidence, time to CBC and disease free survival were evaluated for women who took ET versus those who did not. Results176 patients underwent a UM for DCIS, 72% were ER positive and 16% of patients took ET. At a median of 12 year follow up, 15 patients experienced CBC. Women over 63 years had highest incidence of CBC. CBC risk was not different between those who took ET versus those who did not. ConclusionThe overall incidence of CBC was 9% in our DCIS cohort and was not significantly different among patients who took ET versus those who did not.

Contralateral breast cancer risk in patients with ductal carcinoma in situ and invasive breast cancer

We aimed to assess contralateral breast cancer (CBC) risk in patients with ductal carcinoma in situ (DCIS) compared with invasive breast cancer (BC). Women diagnosed with DCIS (N = 28,003) or stage I–III BC (N = 275,836) between 1989 and 2017 were identified from the nationwide Netherlands Cancer Registry. Cumulative incidences were estimated, accounting for competing risks, and hazard ratios (HRs) for metachronous invasive CBC. To evaluate effects of adjuvant systemic therapy and screening, separate analyses were performed for stage I BC without adjuvant systemic therapy and by mode of first BC detection. Multivariable models including clinico-pathological and treatment data were created to assess CBC risk prediction performance in DCIS patients. The 10-year cumulative incidence of invasive CBC was 4.8% for DCIS patients (CBC = 1334). Invasive CBC risk was higher in DCIS patients compared with invasive BC overall (HR = 1.10, 95% confidence interval (CI) = 1.04–1.17), and lower compared with stage I BC without adjuvant systemic therapy (HR = 0.87; 95% CI = 0.82–0.92). In patients diagnosed ≥2011, the HR for invasive CBC was 1.38 (95% CI = 1.35–1.68) after screen-detected DCIS compared with screen-detected invasive BC, and was 2.14 (95% CI = 1.46–3.13) when not screen-detected. The C-index was 0.52 (95% CI = 0.50–0.54) for invasive CBC prediction in DCIS patients. In conclusion, CBC risks are low overall. DCIS patients had a slightly higher risk of invasive CBC compared with invasive BC, likely explained by the risk-reducing effect of (neo)adjuvant systemic therapy among BC patients. For support of clinical decision making more information is needed to differentiate CBC risks among DCIS patients.

14P BRCA mutation and clinical outcomes in breast cancer focusing on survivals and failure patterns: A long-term follow-up study of Koreans

The purpose of this study was to evaluate the effect of BRCA mutation on survival and recurrence rate, focusing on risk of ipsilateral recurrence and contralateral breast cancer in breast cancer patients who underwent genetic screening for BRCA1/2 mutation and were treated at Samsung Medical Center. We retrospectively reviewed medical records of 300 patients with breast cancer who underwent genetic screening for BRCA1/2 genes and were treated at Samsung Medical Center between January 1, 2000 and December 31, 2010. Ultimately, clinical outcomes of 273 patients were analyzed. The median follow-up duration was 102 months (range, 1 to 220 months). BRCA1/2-mutated tumors had shorter 10-year disease-free survival (DFS) rate compared to those with non-mutated tumors (62.8% vs. 80.0%, p = 0.02). Regarding failure patterns, BRCA1/2-mutated tumors showed higher incidence of contralateral breast cancer than non-mutated tumors (BRCA1/2 non-mutated vs. mutated tumors: 4.9% vs. 26.0%, p < 0.001). BRCA mutation status remained a significant prognostic factor for contralateral breast recurrence-free survival (HR: 4.155, 95% CI: 1.789-9.652; p = 0.001). Korean patients having BRCA mutation showed inferior DFS compared to those without BRCA mutation. BRCA mutation status is a strong predictor of recurrence in contralateral breast. Strategies such as prophylactic treatment and active surveillance should be discussed with breast cancer patients who have BRCA mutations.

Germline BRCA Mutation and Clinical Outcomes in Breast Cancer Patients Focusing on Survival and Failure Patterns: A Long-Term Follow-Up Study of Koreans.

Background and Objectives: This study aimed to evaluate the effect of a BRCA mutation on survival and failure patterns, focusing on the risk of ipsilateral recurrence and contralateral breast cancer in patients. Materials and Methods: We retrospectively reviewed medical records of 300 patients with breast cancer who underwent genetic screening for BRCA1/2 genes and were treated at Samsung Medical Center between 1 January 2000 and 31 December 2010. Ultimately, clinical outcomes of 273 patients were analyzed. Results: The median follow-up duration was 102 months (range, 1 to 220 months). Patients with BRCA1/2-mutated tumors had a shorter 10-year disease-free survival (DFS) rate compared to those with non-mutated tumors (62.8% vs. 80.0%, p = 0.02). Regarding failure patterns, patients with BRCA1/2-mutated tumors showed a higher incidence of contralateral breast cancer than those with non-mutated tumors (BRCA1/2 non-mutated vs. mutated tumors: 4.9% vs. 26.0%, p < 0.001). BRCA mutation status remained a significant prognostic factor for contralateral breast recurrence-free survival (HR: 4.155; 95% CI: 1.789–9.652; p = 0.001). Korean patients with a BRCA mutation showed inferior DFS compared to those without a BRCA mutation. Conclusions: BRCA mutation status is a strong predictor of recurrence in contralateral breast cancer. Strategies such as prophylactic treatment and active surveillance should be discussed with breast cancer patients who have a BRCA mutation.

Abstract P5-12-10: Tamoxifen versus anastrozole as adjuvant therapy in early stage breast cancer in premenopausal women on ovarian function suppression: A meta-analysis of randomized clinical trials

Abstract Introduction: Different strategies have been studied in adjuvant treatment for hormone positive early stage breast cancer. The addition of ovarian function suppression (OFS) therapy to Tamoxifen in premenopausal women was proven to prolong disease-free survival and overall survival compared with Tamoxifen alone. However, trials that examined the use of anastrozole inhibitor (AI) in the presence of OFS in comparison to Tamoxifen with OFS showed contradicting results. Therefore, we conducted this meta-analysis of randomized clinical trials (RCTs) comparing these two approaches. Methods: A comprehensive search of the electronic database (PubMed) from inception to July 2019 was conducted to identify all RCTs that compared OFS with Tamoxifen versus OFS with AI in premenopausal females with breast cancer. The primary endpoint was event-free survival, defined as females without events (local or distant recurrence, cancer in the contralateral breast, secondary non-breast malignancy, or death) at the longest follow-up duration. The secondary endpoints were death, the incidence of distant metastasis, and the incidence of contralateral breast cancer. We calculated the odds ratios (ORs) and 95% confidence intervals (CIs) for all dichotomous data. Heterogeneity was explored by the Cochran Q statistic and I-squared (I2) statistic. P-values &amp;lt;0.05 were considered statistically significant. Results: We included 4 RCTs with 7,202 total patients (mean age 43.8). At baseline, T1 disease represented 53.5% and nodal positive disease was 44.5%. After a median follow-up period of 78 months, there was a non-significant reduction of event-free survival with the AI group compared with the Tamoxifen group (OR=1.13; 95% CI=0.87-1.47; P=0.37). In addition, there were no significant differences between both groups with regard to deaths (OR=1.11; 95% CI=0.50-2.47; P=0.8). The incidence of distant metastasis did not differ between both groups (OR=1.02; 95% CI=0.82-1.26; P=0.86). Similarly, there were no differences in the incidence of contralateral breast cancer between both groups (OR=1.30; 95% CI=0.86-1.96; P=0.21). Conclusions: Among premenopausal women with early breast cancer, the use of AI plus OFS versus Tamoxifen plus OFS was not associated with significantly reduced event-free survival. Given the limited number of RCTs and low events, further, adequately powered trials are needed to validate this finding. Citation Format: Shima Sidahmed, Ahmed Abdalla, Babikir Kheiri, Ghassan Bachuwa. Tamoxifen versus anastrozole as adjuvant therapy in early stage breast cancer in premenopausal women on ovarian function suppression: A meta-analysis of randomized clinical trials [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-10.