Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). Results Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E−08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E−07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E−08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E−08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.

Outcome of patients with an ultralow risk 70-gene signature in the MINDACT trial.

500 Background: Gene signatures have proven successful in identifying patients with a low risk of distant recurrence who could forego chemotherapy (CT) and are currently included in international treatment guidelines for breast cancer. For the 70-gene signature (MammaPrint) an additional threshold was established within the low risk category to identify patients with an ultralow risk of distant recurrence. In independent cohorts, these patients had excellent breast cancer specific survival at 15 years, suggesting that ultralow risk cancers represent indolent disease (Esserman, JAMA Oncol 2017, Delahaye, BC Res Treat 2017). Here we evaluate survival of patients with an ultralow risk 70-gene signature who participated in the randomized phase 3 MINDACT trial (Piccart, Lancet Oncol 2021). Methods: Of the 6,693 patients enrolled in the MINDACT trial (EORTC 10041/BIG 3-04) between 2007-2011, profiling revealed an ultralow risk 70-gene signature in 1,000 patients (15%). We assessed 5- and 8-year distant metastasis free interval (DMFI) and breast cancer specific survival (BCSS) in patients stratified by 70-gene signature result (high, low, ultralow), and within the ultralow risk group stratified by clinical risk. For these exploratory analyses, we used Kaplan-Meier estimates for time to event endpoints and Cox-regression models to calculate hazard ratio’s (HR). Results: Median follow-up was 8.7 years. Among the ultralow risk patients (n = 1,000), 67% were ≥50 years, 81% had tumors < 2cm, 80% were lymph node negative, 96% had grade 1 or 2 tumors and 99% were ER-positive. Systemic therapy was received by 83% of patients (69% endocrine therapy (ET), 14% ET + CT) and 16% received no adjuvant systemic treatment (AST). Survival estimates for all endpoints are shown in the table; 8-year DMFI was 97.0% (95% CI 95.8-98.1) for ultralow risk. The 8-year DMFI in ultralow risk patients who received no AST or ET only was 97.8% (95% CI 95.3-100) and 97.4% (95% CI 96.1-98.7), respectively. The HR for DMFI was 0.66 (95% CI 0.46-0.95) for ultralow vs low risk, after adjusting for tumor and treatment characteristics (preliminary results). Conclusions: In this prospective study, patients with an ultralow risk 70-gene signature have an excellent prognosis with 8-year BCSS above 99% regardless of clinical risk status, and with an 8-year DMFI of 95-98%.[Table: see text]

Breast Cancer Incidence and Early Diagnosis in a Family History Risk and Prevention Clinic: 33-Year Experience in 14,311 Women

Purpose:Women at increased familial breast cancer risk have been offered screening starting at an earlier age and increased frequency than national Screening Programmes for over 30years. There are limited data on longer-term largescale implementation of this approach on cancer diagnosis.Methods:Women at our institution at ≥17% lifetime breast cancer risk have been offered enhanced screening with annual mammography starting at age 35 or 5-years younger than youngest affected relative, with upper age limit 50 for moderate and 60 for high-risk. Breast cancer pathology, stage and receptor status were assessed as well as survival from cancer diagnosis by Kaplan-Meier analysis.Results:Overall 14,311 women were seen and assessed for breast cancer risk, with 649 breast cancers occurring in 129,119.5 years follow up (post-prevalent annual incidence=4.55/1,000). Of 323/394 invasive breast cancers occurring whilst on enhanced screening, most were LN negative (72.9%), T1 (≤20mm,73.2%) and stage-1 (61.4%). Ten-year breast cancer specific survival was 91.3%(95%CI=87.4–94.0) significantly better than the 75.9%(95%CI=74.9-77.0) published for England in 2013-2017. As expected, survival was significantly better for women with screen detected cancers(p<0.001). Ten-year survival was particularly good for those with diagnosed ≤40 at 93.8% (n=75;95%CI=84.2–97.6). Women with lobular breast cancers had worse 10-year survival at 85.9% (95%CI=66.7–94.5). Breast cancer specific survival was good for 119 BRCA1/2 carriers with 20-year survival in BRCA1:91.2%(95%CI=77.8-96.6) and 83.8% (62.6-–93.5) for BRCA2Conclusions:Targeted breast screening in women aged 30-60 years at increased familial risk is associated with good long-term survival that is substantially better than expected from population data.

Breast cancer risk factors and their effects on survival: a Mendelian randomisation study

Background Observational studies have investigated the association of risk factors with breast cancer prognosis. However, the results have been conflicting and it has been challenging to establish causality due to potential residual confounding. Using a Mendelian randomisation (MR) approach, we aimed to examine the potential causal association between breast cancer-specific survival and nine established risk factors for breast cancer: alcohol consumption, body mass index, height, physical activity, mammographic density, age at menarche or menopause, smoking, and type 2 diabetes mellitus (T2DM). Methods We conducted a two-sample MR analysis on data from the Breast Cancer Association Consortium (BCAC) and risk factor summary estimates from the GWAS Catalog. The BCAC data included 86,627 female patients of European ancestry with 7054 breast cancer-specific deaths during 15 years of follow-up. Of these, 59,378 were estrogen receptor (ER)-positive and 13,692 were ER-negative breast cancer patients. For the significant association, we used sensitivity analyses and a multivariable MR model. All risk factor associations were also examined in a model adjusted by other prognostic factors. Results Increased genetic liability to T2DM was significantly associated with worse breast cancer-specific survival (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.03–1.17, P value [P] = 0.003). There were no significant associations after multiple testing correction for any of the risk factors in the ER-status subtypes. For the reported significant association with T2DM, the sensitivity analyses did not show evidence for violation of the MR assumptions nor that the association was due to increased BMI. The association remained significant when adjusting by other prognostic factors. Conclusions This extensive MR analysis suggests that T2DM may be causally associated with worse breast cancer-specific survival and therefore that treating T2DM may improve prognosis.

Survival Differences in Chinese Versus White Women With Breast Cancer in the United States: A SEER-Based Analysis

PURPOSE The affect of race on breast cancer prognosis is not well understood. We compared crude and adjusted breast cancer survival rates of Chinese women versus White women in the United States. METHODS We conducted a cohort study of Chinese and White women with breast cancer diagnosed between 2004 to 2015 in the SEER 18 registries database. We abstracted information on age at diagnosis, tumor size, grade, lymph node status, receptor status, surgical treatment, receipt of radiotherapy and chemotherapy, and death. We compared crude breast cancer–specific mortality between the two ethnic groups. We calculated adjusted hazard ratios (HRs) in a propensity-matched design using the Cox proportional hazards model. P < .05 was considered statistically significant. RESULTS There were 7,553 Chinese women (1.8%) and 414,618 White women (98.2%) with stage I-IV breast cancer in the SEER database. There were small differences in demographics, nodal burden, and clinical stage between Chinese and White women. Ten-year breast cancer–specific survival was 88.8% for Chinese women and 85.6% for White women (HR, 0.73; 95% CI, 0.67 to 0.80; P < .0001). In a propensity-matched analysis among women with stage I–IIIC breast cancer, the HR was 0.71 (95% CI, 0.62 to 0.81; P < .0001). Annual mortality rates in White women exceeded those in Chinese women for the first 9 years after diagnosis. CONCLUSION Chinese women in the United States have superior breast cancer–specific survival compared with White women. The reason for the observed difference is not clear. Differences in demographic and tumor features between Chinese and White women with breast cancer may contribute to the disparity, as may the possibility of intrinsic biologic differences.

Survival and prognostic factors of patients with breast cancer in the state of São Paulo

Introduction Breast cancer is a public health problem worldwide, being the most common malignant neoplasm in the female population. Objectives To estimate 5- and 10-year breast cancer-specific survival probabilities of patients included in the hospital-based cancer registry (HBCR) of the Fundação Oncocentro de São Paulo (FOSP, in Portuguese) and to assess the prognostic factors for this neoplasm. Methods Historical cohort study that included women with breast cancer included in HBCR-FOSP and diagnosed between 2002 and 2012. The event of interest was breast cancer-specific mortality. Living cases at the end of follow-up (December 31, 2017), loss to follow-up and death other than that due to breast cancer were considered censored on the date of the last contact or date of death. Descriptive analysis and survival analysis were performed using the Kaplan-Meyer method. Survival curves were compared using the log-rank test. Hazard ratios (HR) and their 95%CI were estimated using Cox's proportional hazards model. The study was approved by the Human Research Ethics Committee of the Botucatu Medical School, São Paulo State University, Brazil. Results 53,146 cases of invasive breast cancer were registered at HBCR-FOSP between 2002-2012. The median age at diagnosis was 55.9 years. By the end of the follow-up, 20,683 patients died, and 71.4% were due to breast cancer. The 5- and 10-year breast cancer-specific survival for the entire cohort was 76.1% (95%CI 75.7-76.5%) and 64.8% (95% CI 64.2-65.3%), respectively. In the multivariate analysis, the factors associated with prognosis were age at diagnosis, year of diagnosis, educational level, clinical stage, and histological type. Conclusions These findings may contribute to the development of policies for the identification of breast tumors at earlier stages. Key messages Breast cancer is an important public health problem in Brazil and worldwide. The findings of this study may contribute to the development of public policies for the control of breast cancer in the state of São Paulo.

Circulating sphingomyelins on estrogen receptor-positive and estrogen receptor-negative breast cancer-specific survival

Aim: This study aims to determine whether a causal relationship exists between circulating sphingomyelins and breast cancer-specific survival, since, if one does, sphingomyelins could be studied as a therapeutic target in the management of breast cancer. Patients/materials & methods: Mendelian randomization is used here to investigate whether higher levels of circulating sphingomyelins impact breast cancer-specific survival for estrogen receptor-negative (ER–) and estrogen receptor-positive (ER+) patients. Results: The results suggest a null effect of sphingomyelins for ER– breast cancer-specific survival and a protective effect for ER+ breast cancer-specific survival. Sensitivity analyses implicate low-density lipoprotein cholesterol as a potential confounder. Conclusion: Future studies should replicate and triangulate the present findings with other methods and tease out the roles of sphingomyelins and low-density lipoprotein cholesterol on breast cancer-specific survival.