Breast Cancer-specific Survival Research Articles

Do we need reshape rTNM staging system for ipsilateral breast tumor recurrence of breast cancer? A population-based, propensity score matched cohort study.

The aim of the study was to explore the role of recurrent TNM (rTNM) staging in predicting prognosis for ipsilateral breast tumor recurrence (IBTR) and determine the optimal treatment strategy for IBTR. IBTR cases were identified from the Surveillance, Epidemiology, and End Results (SEER) database spanning the years 2000-2018. Cox proportional hazards analysis was performed to examine factors associated with overall survival (OS) and breast cancer-specific survival (BCSS). Propensity score matching (PSM) was employed to match IBTR with primary early breast cancer (EBC) based on clinicopathological characteristics. Investigations into the impact of different therapies were also included. Of the 4375 IBTR cases included in the study, the 5-year OS was 87.1%, 71.6% and 58.7% in rTNM stages I, II and III, respectively. After PSM, while IBTR patients had worse survival to primary EBC patients, prognosis of IBTR for different rTNM stage always closely aligned with the corresponding stage of primary EBC. Repeat breast-conserving surgery (BCS) with radiation therapy was equivalent to mastectomy with respect to OS and BCSS. Chemotherapy was favorable for OS and BCSS in estrogen receptor (ER)-negative IBTR or IBTR occurring within a 60-month interval. rTNM staging system has an outstanding prognostic value for survival outcome of patients with IBTR, and IBTR and primary EBC may have potentially analogous features in the context of TNM staging. BCS plus radiation therapy may be an alternative. IBTR cases who have experienced recurrence with short intervals and with ER-negative tumors might benefit from chemotherapy.

CD163+ macrophages in the triple-negative breast tumor microenvironment are associated with improved survival in the Women’s Circle of Health Study and the Women’s Circle of Health Follow-Up Study

BackgroundTumor-associated macrophages (TAMs) are a prominent immune subpopulation in the tumor microenvironment that could potentially serve as therapeutic targets for breast cancer. Thus, it is important to characterize this cell population across different tumor subtypes including patterns of association with demographic and prognostic factors, and breast cancer outcomes.MethodsWe investigated CD163+ macrophages in relation to clinicopathologic variables and breast cancer outcomes in the Women’s Circle of Health Study and Women’s Circle of Health Follow-up Study populations of predominantly Black women with breast cancer. We evaluated 611 invasive breast tumor samples (507 from Black women, 104 from White women) with immunohistochemical staining of tissue microarray slides followed by digital image analysis. Multivariable Cox proportional hazards models were used to estimate hazard ratios for overall survival (OS) and breast cancer-specific survival (BCSS) for 546 cases with available survival data (median follow-up time 9.68 years (IQR: 7.43–12.33).ResultsWomen with triple-negative breast cancer showed significantly improved OS in relation to increased levels of tumor-infiltrating CD163+ macrophages in age-adjusted (Q3 vs. Q1: HR = 0.36; 95% CI 0.16–0.83) and fully adjusted models (Q3 vs. Q1: HR = 0.30; 95% CI 0.12–0.73). A similar, but non-statistically significant, association was observed for BCSS. Macrophage infiltration in luminal and HER2+ tumors was not associated with OS or BCSS. In a multivariate regression model that adjusted for age, subtype, grade, and tumor size, there was no significant difference in CD163+ macrophage density between Black and White women (RR = 0.88; 95% CI 0.71–1.10).ConclusionsIn contrast to previous studies, we observed that higher densities of CD163+ macrophages are independently associated with improved OS and BCSS in women with invasive triple-negative breast cancer.Trial registrationNot applicable.

Abstract PO5-06-03: Impact of curative-intent treatment on survival for metastatic breast cancer limited to distant lymph nodes

Abstract BACKGROUND: Metastatic breast cancer limited to distant lymph nodes is classified as stage IV but potentially represents an anatomically distinct entity amenable to curative treatment. Its optimal management is unclear, with existing studies limited by small sample sizes and short follow-up durations. We sought to investigate the impact of curative-intent treatment on breast cancer-specific survival (BCSS) and overall survival (OS) for patients with this diagnosis. METHODS: Three cohorts of patients diagnosed with breast cancer from 2010 to 2019 were identified from the Surveillance, Epidemiology, and End Results 17 registries database. The curative cohort consisted of patients with metastatic breast cancer involving only distant lymph nodes who received a combination of chemotherapy, surgery to the primary site, and radiotherapy (curative-intent treatment). The palliative cohort included patients who underwent chemotherapy but not curative-intent treatment. The N3c cohort was comprised of patients with ipsilateral supraclavicular lymph node metastases but no distant metastases who received curative-intent treatment. Weighting based on covariate balancing propensity scores was performed to balance age, sex, race, median household income, year of diagnosis, T stage, histology, pathological grade, and ER/PR/HER2 status between the cohorts. Weight-adjusted multivariable Cox regression models with the same covariates were then used to compare the BCSS and OS of the three cohorts. RESULTS: A total of 2,089 patients with a median follow-up of 37 months were eligible for analysis, of whom 577 (27.6%) were in the curative cohort, 905 (43.3%) were in the palliative cohort, and 607 (29.1%) were in the N3c cohort. After propensity score weighting, the maximal standardized mean difference for all covariates was less than 0.1. Five-year BCSS for patients in the weight-adjusted curative, palliative, and N3c cohorts were 63.0% (95% CI 58.1-68.3), 46.7% (42.4-51.4), and 66.4% (61.4-71.8), respectively; and five-year OS were 57.9% (53.0-63.2), 41.2% (37.2-45.7), and 62.2% (57.3-67.6), respectively. Compared to the palliative cohort, the curative cohort exhibited better BCSS (HR 0.47, 95% CI 0.38-0.57; P< 0.001) and OS (HR 0.48, 95% CI 0.40-0.58; P< 0.001). In contrast, the N3c cohort had similar BCSS (HR 0.93, 95% CI 0.73-1.17; P=0.53) and OS (HR 0.96, 95% CI 0.77-1.19; P=0.68) to the curative cohort. CONCLUSIONS: Patients treated curatively for metastatic breast cancer limited to distant lymph nodes had higher BCSS and OS than those receiving palliative chemotherapy and similar BCSS and OS to patients receiving curative-intent treatment for ipsilateral supraclavicular lymph node metastases. These results support the use of aggressive multimodal therapy for select stage IV breast cancer patients with only distant nodal metastases and, if confirmed, suggest that a substantial portion of such patients may be undertreated. Citation Format: Yang Xu. Impact of curative-intent treatment on survival for metastatic breast cancer limited to distant lymph nodes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-06-03.

Abstract PO4-06-02: Frequency of presentation and outcomes of stage IV breast cancer over the past decade: a population-based study

Abstract Background: Over the past decade, there have been major advances for the treatment of patients (pts) with metastatic breast cancer (MBC). For pts with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative MBC, newer treatments include CDK 4/6 inhibitors among other targeted therapies; for HER2+ MBC, we have seen the development of antibody-drug conjugates (ADC) and other anti-HER2 agents; and for triple-negative breast cancer (TNBC) options include immunotherapy, ADCs, and PARP inhibitors. The aims of this study were to evaluate time trends in clinical characteristics, frequency of presentation and outcomes of pts with stage IV breast cancer over the past decade. Methods: Using data from the Surveillance, Epidemiology, and End Results (SEER) program, we identified pts diagnosed with breast cancer between 2010-2020. Pts required to have known HR and HER2 status and known stage at diagnosis. We described the proportion of stage IV disease overall for each tumor subtype and evaluated trends in the proportion of stage IV over time. Outcomes were evaluated by breast cancer-specific survival (BCSS) using Kaplan-Meier. Among stage IV pts, we conducted multivariable cox models to assess changes in BCSS over time, stratified by tumor subtype and adjusted for age at diagnosis, race and ethnicity, sex, tumor grade, histology, surgery, radiation therapy, chemotherapy, sites of distant metastases, marital status, median household income, rurality and US region. We evaluated overall survival as a secondary endpoint. Results: We included 443,631 pts of whom 24,788 (5.59%) had stage IV disease at diagnosis. Pts with stage IV breast cancer had a median age of 61 years and a median follow up of 57 months (IQR 28 – 89 months). When compared to stage I-III, stage IV pts were more often of Black race (10.4% for stage I-III vs 15.7% for stage IV), less often married (56.7% vs 43.5%, respectively) and less often HR+/HER2- (74.1% vs 59.9%, respectively); all p < 0.001. Among pts with stage IV, the frequency of each metastatic site at initial diagnosis was: bone 66.45%, lung 30.47%, liver 25.79%, and brain 7.9%. Across all years (2010-2020), the proportion of stage IV disease varied significantly by tumor subtype: 4.6% in HR+/HER2-, 8.5% in HR+/HER2+, 11.3% in HR-/HER2+, and 7.1% in TNBC; p < 0.001. The proportion of stage IV increased modestly during 2010-2020 in HR+/HER2- tumors (4.6% in 2010 to 5.1% in 2020, p for trend = 0.01), in HR-/HER2+ (10% in 2010 to 13.7% in 2020, p for trend < 0.001), and in TNBC (6.9% in 2010 to 7.8% in 2020, p for trend = 0.001). No significant difference was observed in the proportion of stage IV over time in HR+/HER2+ (p for trend = 0.76). Rate of BCSS at 5 years was: 32.51% for HR+/HER2-, 43.92% for HR+/HER2+, 37.28% for HR-/HER2+, and 10.97% for TNBC; p < 0.001. In adjusted Cox models, BCSS improved significantly over time for each additional year in HR+/HER2- (adjusted Hazard Ratio [HzR] 0.982, p = 0.01), in HR+/HER2+ (adjusted HzR 0.945, p < 0.001), and in HR-/HER2+ (adjusted HzR 0.959, p = 0.03). The improvement in BCSS over time in TNBC was not significant (adjusted HzR 0.982, p = 0.15). Overall survival results were similar to those of BCSS both in 5-year rates as well as Cox model results. Conclusions: In this population-based study, we saw that the proportion of pts presenting with de-novo stage IV varied significantly by tumor subtype, being as low as 4.6% in HR+/HER2- and as high as 11.3% in HR-/HER2+ disease. These proportions have unfortunately increased over time in most subtypes, highlighting a need for additional research to identify the reasons behind these trends. BCSS improved significantly over time in HR+/HER2- and in both HER2+ subtypes, coinciding with a time period of important therapeutic advances. TNBC remains a highly unmet medical need and further follow up is needed to assess the impact of newer treatments. Citation Format: Jorge Avila, Julieta Leone, Nabihah Tayob, Carlos Vallejo, Michael Hassett, Nancy Lin, Sara Tolaney, Jose Leone. Frequency of presentation and outcomes of stage IV breast cancer over the past decade: a population-based study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-06-02.

Abstract PO3-03-02: Effect of Surgery on Breast Cancer-Specific Mortality in Elderly Patients with Hormone Receptor-Positive, HER2-Negative Breast Cancer

Abstract Background: The number of elderly patients with breast cancer has been increasing in Japan. Although standard treatment including surgery is desirable if the expected life expectancy is sufficient, not all elderly patients with breast cancer are eligible for surgery due to frailty and comorbidities. Endocrine therapy (ET) alone is an alternative option if surgery is not considered adequate in patients with hormone receptor-positive breast cancer. We evaluated whether ET alone was associated with inferior overall and breast cancer-specific survival compared to standard treatment including surgery in elderly patients. Methods: This study included all patients aged 75 years and over who were diagnosed with non-metastatic primary invasive hormone receptor-positive, HER2-negative breast cancer and treated at Hiraka General Hospital from July 2006 to March 2022. Patients were divided as those who received ET alone (ET alone group) and those who received surgery with other therapies (Surgery group). Survival status as on March 31, 2023 and cause of death were determined. Overall survival and breast cancer-specific survival were estimated using the Kaplan–Meier method and compared using the log-rank test. Univariate analysis and multivariate Cox proportional hazards regression model including age, Eastern Cooperative Oncology Group performance status (PS) score, clinical stage, and treatment were used to identify survival-associated factors. Propensity score matching was used to reduce the effect of selection bias on treatment type during survival comparison of the groups. Results: The study cohort comprised 128 patients, including 33 and 95 patients in the ET alone group and Surgery group, respectively. The median ages were 84.6 and 80.4 years in the ET alone group and Surgery group, respectively (p < 0.05). Ten patients (30%) in the ET alone group had poor PS (3 or 4), and no patient in the Surgery group had poor PS (p < 0.01). Also, 24.2%, 54.5%, and 21.2% of the patients in the ET alone group and 48.4%, 43.2%, and 8.4% of the patients in the Surgery group had clinical stage I, II, and III disease at diagnosis, respectively (p < 0.05). Survival status was confirmed in all patients, and the cause of death was confirmed in 52 of the 53 patients who died (98%) during the study period, including 24 and 29 patients in the ET alone group and Surgery group, respectively. Breast cancer was the cause of death in 3 patients (13%) in the ET alone group and 5 patients (17%) in the Surgery group. By univariate analysis, overall survival was significantly better in the Surgery group than in the ET alone group (median, 12.5 vs. 4.1 years; p < 0.0001). Similarly, breast cancer-specific survival was better in the Surgery group than in the ET alone group (p < 0.05). By multivariate Cox proportional hazards regression analysis, age was associated with shorter overall survival time (hazard ratio [HR] 1.07, 95% confidence interval [CI] 1.00–1.15; p = 0.04) and surgery was associated with longer overall survival (HR 0.24, 95% CI 0.12–0.47; p < 0.001). Breast cancer-specific survival was associated with age (HR 1.18, 95% CI 1.03–1.36; p = 0.02) and clinical stage (HR 8.89, 95% CI 1.05–75.5; p < 0.05) but not with treatment (HR 0.66, 95% CI 0.73–5.85; p = 0.71). After propensity score matching, overall survival was significantly better in the Surgery group than in the ET alone group (HR 0.26, 95% CI 0.09–0.73; p = 0.01) whereas breast cancer-specific survival was not significantly different between the two groups (HR 0.82, 95% CI 0.08–8.27; p = 0.86). Conclusion: Even in elderly patients, surgery should be considered if sufficient life expectancy is expected. However, most of the deaths were not related to breast cancer in the present study cohort. Therefore, for elderly patients without sufficient life expectancy, endocrine therapy alone would be an appropriate option. Citation Format: Misako Yatsuyanagi, Tomoyuki Shimada, Yuko Takeishi, Yukiko Matsuzaka, Chika ohsawa. Effect of Surgery on Breast Cancer-Specific Mortality in Elderly Patients with Hormone Receptor-Positive, HER2-Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-03-02.

Abstract GS03-02: Mammographic surveillance in early breast cancer patients aged 50 years or over: results of the Mammo-50 non-inferiority trial of annual versus less frequent mammography

Abstract Introduction: Annual surveillance mammograms for an unspecified period, after treatment for early breast cancer, are widely practised in USA and Europe and represent a significant healthcare cost. Current UK guidelines recommend annual mammograms up to 5 years, then reverts to 3 year screening without specified risk stratification. Further evidence is needed to determine the optimum frequency and duration of mammographic surveillance. Methods: A multi-centre, randomised controlled, phase III trial of annual mammography versus 2-yearly for conservation surgery and 3-yearly mammograms for mastectomy patients up to 9 years. Women were eligible if aged 50 years or over at initial diagnosis of breast cancer (invasive or DCIS), and recurrence free 3 years post curative surgery. Primary outcome was breast cancer specific survival (BCSS). Secondary outcomes include recurrence free interval (RFI) and overall survival (OS). BCSS event was defined as deaths from breast cancer and RFI as any locoregional or distant invasive recurrence or new breast primary. 5000 women were needed to detect a 3% absolute non-inferiority (NI) margin for BCSS with 2.5% one-sided alpha and at least 85% power. Analyses were carried out on intention-to-treat basis. Results: 5235 women were randomised between April 2014 and September 2018. 4347 (83%) women were aged 55-75 years, 4203 (80%) had undergone conservation surgery, 4564 (87%) had invasive disease, 1162 (22%) had node positive disease, 4330 (83%) had ER positive tumours and 3812 (73%) were taking hormone therapy at the time of randomisation. Patient characteristics were balanced across arms. With a median of 5.4 years follow-up (interquartile range 4.6-5.9), 319 women have died; 104 of breast cancer (53 on annual arm; 51 on less frequent arm). BCSS at 5 years was 98.2% (95% CI 97.5-98.6%) on annual arm and 98.3% (95% CI 97.7-98.8%) on less frequent arm. Hazard ratio (HR) was 1.04 (95% CI 0.71 -1.54), demonstrating non-inferiority of less frequent mammograms at the 3% margin (NI p< 0.0001; critical value 2.71) and the 1% margin (NI p=0.02; critical value 1.56). 320 (6%) women had a new invasive breast cancer event (55 loco-regional recurrences, 85 new breast primaries, 139 distant recurrences and 41 with multiple invasive events); 164 on the annual arm compared to 156 on the less frequent arm. Five-year RFI was 94.2% (95% CI 93.2-95.1%) for the annual arm and 94.4% (95% CI 93.4-95.3%) for the less frequent arm; HR= 1.03; (95% CI 0.83-1.28) demonstrating non-inferiority at a 2% margin (NI p=0.006; critical value 1.36). OS at 5 years was 94.9% (95% CI 93.9-95.7%) on the annual arm and 94.3% (95% CI 93.3-95.2%) on the less frequent arm. Hazard ratio (HR) was 1.18 (95% CI 0.94 -1.47), demonstrating non-inferiority of less frequent mammograms at the 3% margin (NI p=0.003; critical value 1.61) and the 2.5% margin (NI p=0.02; critical value 1.51). A total of 14987 mammograms have been performed on the annual arm and 8047 on the less frequent arm. 1967 (75%) of 2618 women on the annual arm complied with their allocated schedule compared to 1775 (68%) of 2617 women on the less frequent arm. COVID-19 pandemic affected compliance; it is estimated that 345 (7%) women missed mammograms during the pandemic. A sensitivity analysis was performed on the 72% of women who fully complied with their scheduled mammograms as per protocol, and again NI was demonstrated for BCSS, RFI and OS. Conclusions: For patients aged 50 or older and 3 years post diagnosis, Mammo-50 demonstrated that less frequent mammograms were no worse than annual mammograms. These results provide evidence for less frequent mammographic surveillance for this patient population. Citation Format: Janet Dunn, Peter Donnelly, Nada Elbeltagi, Andrea Marshall, Alastair Thompson, Riccardo Audisio, Sarah Pinder, David Cameron, Amy Campbell, Sue Hartup, Lesley Turner, Annie Young, Helen Higgins, Eila Watson, Sophie Gasson, Peter Barrett-Lee, Claire Hulme, Bethany Shinkins, Peter Hall, Andy Evans. Mammographic surveillance in early breast cancer patients aged 50 years or over: results of the Mammo-50 non-inferiority trial of annual versus less frequent mammography [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS03-02.

Abstract PO1-03-06: Older patients with Early Stage Triple Negative Breast Cancer: The Memorial Sloan Kettering Cancer Center experience

Abstract INTRODUCTION Approximately 15% cases of TNBC are diagnosed in individuals over the age of 70. Older patients remain under-represented in clinical trials. We conducted a retrospective review of patients 70 years of age and older with stage I-III TNBC who were treated at Memorial Sloan Kettering Cancer Center (MSKCC), with the goal of describing the clinical practice patterns and outcomes. MATERIAL AND METHODS A retrospective record review of patients 70 years of age and older with a diagnosis of stage I-III TNBC between January 2015-December 2019 was performed. We report the data on the utilization of systemic chemotherapy and survival analyses. We compared patient characteristics by chemotherapy type using Wilcoxon rank sum test, Pearson’s Chi-squared test, and Fisher’s exact test. Overall Survival (OS), Breast Cancer Specific Survival (BCSS), and Recurrence Free BCSS (RF-BCSS) were examined using Cox proportional hazards models. All statistical analyses were conducted using R. RESULTS A total of 147 patients were included. The median age was 75 years (range 70-96). The number of patients with stage I, II, and III disease was 64 (44%), 66 (45%), 17 (12%), respectively. Twenty-five (18%) patients underwent comprehensive geriatric assessment. Out of total patients, 93 (63%) patients received systemic Chemotherapy (C) while 54 (37%) received no chemotherapy (NC). Patients receiving C were younger (median age 74 years with C vs. 78 years with NC, p< 0.001) and had a higher disease stage (Stage II-III: 66% (C) vs. 41% (NC), p=0.005). There were no significant differences in Activities of Daily Living (ADL) difficulty between both arms. Amongst, Instrumental ADL (IADL) assessment, patients in the NC group reported statistically significant greater difficulty with meal preparation (17% in NC and 4.3% in C, p=0.016). The most common reasons for not receiving chemotherapy were low-risk disease i.e. pT1aN0 or microinvasive (33%), patient preference (29%), and frailty per the treating oncologist (19%). Rate of mastectomy was higher in the NC group (35% in NC vs. 20% in C, p=0.029). Among the 32 patients who had radiation data, breast irradiation rates were higher in the C group (70% in C and 17% in NC, p=0.003). Thirty patients (20%) received neoadjuvant chemotherapy (NAC) and 65 (44%) received adjuvant chemotherapy. Anthracycline-based chemotherapy was the most common NAC (n=17, 57%). Patients who received Cyclophosphamide-Methotrexate-5-Fluorouracil (CMF) were older (age ≥75 years: 51% (CMF) vs. 17% (ACT),p=0.010), more likely treated in an adjuvant setting (87% CMF vs. 61% ACT, p=0.017), had earlier-stage disease (Stage 1: 54% (CMF) vs. 26% (ACT), p=0.028), and reported more ADL (31% in CMF vs. 0% in ACT, p=0.002) and IADL difficulties (31% CMF vs 4.3% in ACT, p=0.021). The use of Docetaxel/Cyclophosphamide (TC) and platinum-based regimens was low (8% and 5%, respectively). In the univariate analysis between the C and NC groups, there was no difference in OS (Hazard Ratio (HR) 0.78, 95% Confidence Interval (CI) 0.42-1.43; p=0.4), BCSS (HR 1.39, 95% CI 0.57-3.39; p=0.5), and RF-BCSS (HR 1.60, 95% CI 0.67-3.83; p=0.3). There was no difference in OS (HR 0.60, 95% CI 0.23-1.55; p=0.3), BCSS (HR 0.48, 95% CI 0.17-1.32; p=0.2), and RF-BCSS (HR 0.71, 95% CI 0.30-1.73; p=0.5) in patients receiving CMF vs. ACT. CONCLUSIONS In our single institutional experience, we observed that two-thirds of older patients with early-stage TNBC received systemic polychemotherapy. A third of patients with NC were very low risk (pT1a or microinvasive disease) which could explain lack of chemotherapy benefit in our study population. Use of CMF was more prevalent in patients aged ≥75, stage I disease, ADL/IADL difficulties, and in the adjuvant setting. We observed no difference in survival outcomes between the two chemotherapy regimens. CMF remains an efficacious option and a potentially viable alternative to ACT in TNBC, especially in the setting of early stage and advanced age. Citation Format: Jasmeet Singh, Diana Lake, West Dente-Ferguson, Yuan Chen, Fiona Erlich, Beatriz Korc-Grodzicki, Mark Robson, Larry Norton, W. Iris Zhi. Older patients with Early Stage Triple Negative Breast Cancer: The Memorial Sloan Kettering Cancer Center experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-03-06.

Abstract PS09-02: Event-free Survival by Residual Cancer Burden (RCB) and Intratumor HER2 Heterogeneity after Neoadjuvant T-DM1 and Pertuzumab for Early-stage HER2-positive Breast Cancer

Abstract Background: Intratumor HER2 heterogeneity (ITH-HER2) predicates resistance to targeted anti-HER2-based therapy, and understanding its impact on response to HER2-directed therapies is particularly important with regimens that rely solely on targeted anti-HER2 therapies without chemotherapy. Methods: To determine the effect of ITH-HER2 on response to therapy, we conducted a single-arm phase II study in which patients (pts) with centrally confirmed HER2+ early-stage breast cancer received six cycles of preoperative T-DM1 plus pertuzumab. Baseline image-guided biopsies allowed central pathology evaluation of ITH HER2, defined as an area with HER2 amplification in >5% but < 50% of tumor cells or a HER2-negative area by FISH. The study met its primary endpoint by demonstrating inferior pathologic complete response (pCR) measured by Residual Cancer Burden (RCB) in the subset of ITH-HER2 pts. Single-cell ERBB2 FISH analysis identified the fraction of ERBB2 nonamplified cells as a factor associated with therapeutic resistance (Metzger et al. Cancer Discovery 2021). Secondary endpoints included event-free survival (EFS), invasive disease-free survival (iDFS), and breast cancer-specific survival (BCSS) by ITH-HER2 status and RCB scores. Results: 163 pts were enrolled and received treatment in the study from Jan 2015 to Jan 2018. Central pathology evaluation of HER2 heterogeneity was successful in 96% (157/163) of cases, with 16 classified as ITH-HER2. RCB-0 or -I rate in the ITH-HER2 vs. not was (25% v. 67%, OR = 5.6, p = 0.002). Median follow-up, including all treated pts (n =163), was 65.4 months (IQR, 60.3-76.6). The 5yr EFS, iDFS, and BCSS were 91% [86.5% - 95.6%], 89.4% [84.5% - 94.5%], and 96% [92.9% - 99.2%], respectively. ITH-HER2 was associated with numerically inferior outcomes for EFS, iDFS, and BCSS (Table 1). The subset of pts with non-ITH-HER2 at baseline (n= 141) and RCB-0 or -I (n = 95/141, 67%) had a 5-yr IDFS of 94.2% [89.3% - 99.3%]. A sensitivity analysis describing survival outcomes by chemotherapy use in the adjuvant setting will be presented at the meeting, along with translational research results evaluating the association of HER2DX assay with pCR and survival outcomes. Conclusions: The inferior pCR rates among cases classified as ITH-HER2 translated into numerically inferior outcomes for both EFS and iDFS. The number of events is small; therefore, our results are exploratory. Selecting pts whose tumors lack ITH-HER2 can increase the chances of achieving RCB 0/I with neoadjuvant TDM1 + pertuzumab. Neoadjuvant TDM1 + pertuzumab, followed by adjuvant HER2-directed therapy without classic chemotherapy agents, could represent an optimal regimen for non-ITH-HER2 pts experiencing RCB 0/I at the time of surgery and deserves further study. Table 1. 5-year survival estimates by ITH-HER2 Citation Format: Otto Metzger, Se Eun Kim, Nabihah Tayob, Giuseppe Viale, Denise Yardley, Aleix Prat, Vandana Abramson, Laura Spring, Adrienne Waks, Eileen Wrabel, Michelle DeMeo, Aditya Bardia, Patrizia Dell'Orto, Leila Russo, Tari King, Franziska Michor, Eric Winer, Kornelia Polyak, Sara Tolaney, Ian Krop. Event-free Survival by Residual Cancer Burden (RCB) and Intratumor HER2 Heterogeneity after Neoadjuvant T-DM1 and Pertuzumab for Early-stage HER2-positive Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS09-02.

Abstract PO1-28-10: Tumor Infiltrating Lymphocytes identify patients with stage I TNBC with excellent outcome without chemotherapy

Abstract Introduction International guidelines recommend chemotherapy for most patients with stage I triple negative breast cancer (TNBC), except for special histological subtypes. However, the absolute benefit of systemic treatment for all stage I TNBC patients is not well known and no tools are yet available to select patients with an excellent prognosis for whom the chemotherapy can be safely omitted. High levels of stromal tumor infiltrating lymphocytes (sTILs) are strongly associated with favorable prognosis in TNBC, however, data solely focusing on patients with stage I TNBC who did not receive chemotherapy are lacking. Methods Patients with pT1N0M0 TNBC diagnosed between 2005 and 2015 not treated with (neo)adjuvant chemotherapy were identified from the nationwide Netherlands Cancer Registry (NCR) and linked to the national pathology database (PALGA). Newly sectioned hematoxylin & eosin (H&E) slides were used for central review of the histology and sTILs scoring following the International TIL working group guidelines (www.tilsinbreastcancer.org). Cause of death was provided by Statistics Netherlands (CBS). Primary endpoint was breast-cancer specific survival (BCSS) at 5-, 10- and 15-years for prespecified sTILs cut-offs of 30%, 50% and 75% sTILs. Results sTILs were evaluated for 1,041 patients with stage I TNBC who did not receive (neo)adjuvant chemotherapy. Mean age at diagnosis was 64.4 years [range 26 – 96] and median sTILs value was 5%. Most tumors (91.5%) were invasive ductal adenocarcinomas of no special type (NST) and 6.6% were of histological special types. In 52% of the patients the tumor was >1cm (pT1cN0). Median follow-up was 9.4 years in which 335 patients had died, of whom 107 due to breast cancer. Patients with pT1abN0 tumors had a favorable prognosis compared with patients with a pT1cN0 tumor (HR 0.47, CI 0.32- 0.72). 10-year BCSS in patients with pT1ab was 91.8% and 85.8% in patients with pT1c tumors. In the overall cohort, sTILs-levels of at least 30% were associated with better BCSS compared to sTILs < 30% (HR 0.45, CI 0.26 – 0.77), with 10year-BCSS of 96% and 87%, respectively (table 1). Patients with TNBC of special histological subtype had low sTILs (median 1%). A univariate cox model showed no association between sTILs (continuous) and BCSS in TNBC of special histological subtype (p = 0.56). Next, the prognostic value of sTILs was evaluated separately for pT1ab and pT1c. High sTILs ≥50% were not associated with improved BCSS compared to low sTILs < 50% in patients with pT1ab (HR 1.35, CI 0.65 – 2.82, p = 0.42). In contrast, high sTILs ≥50% showed a strong prognostic importance over low sTILs < 50% (HR 0.27, CI 0.10 – 0.74) in patients with pT1C tumors. We found excellent 10year-BCSS of 95% for patients if sTILs ≥50%, which further increases to 98% with sTILs ≥75% contrasting 10year-BCSS of 83% for patients with sTILs < 30%. Conclusions sTILs-levels provide important prognostic information in patients with stage I TNBC who did not receive (neo)adjuvant chemotherapy. The outcome of patients with pT1c TNBC and sTILs ≥50% was excellent, with 10year-BCSS of 95%, and 98% if sTILs >75%. This large registry study provides a foundation for clinical trials in patients with stage I TNBC with high TILs to prospectively confirm their excellent survival without chemotherapy. Citation Format: Veerle Geurts, Sara Balduzzi, Hugo Horlings, Tessa G Steenbruggen, Sabine Siesling, Sylvia Adams, Gabe Sonke, Roberto Salgado, Marleen Kok. Tumor Infiltrating Lymphocytes identify patients with stage I TNBC with excellent outcome without chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-28-10.

Abstract PO1-02-14: Breast cancer in older women - long-term prognosis by age and subtype in a large population-based cohort

Abstract Background Compared to middle-aged women, older women have a higher risk of breast cancer death. Whether the increased risk of breast cancer death is present in all subgroups of older adults with breast cancer, or negligible in the subgroups receiving adequate surgical and oncological treatment, has been debated. We studied long-term prognosis by age and subtype, adjusting for stage, treatment, socioeconomic status and comorbidity, clarifying which subgroups of older patients that are at increased risk of breast cancer death. Methods In a nation-wide cohort of 45,949 women aged ≥60 years at diagnosis of breast cancer 1997-2014, we estimated crude probabilities of breast cancer death and from other causes using competing risk methods. Cox proportional hazards models were used to estimate adjusted hazard ratios (HR) with 95% confidence intervals (CI. Results In this large population-based cohort study of older women with breast cancer, we found an increasing risk of breast cancer death with increasing age at diagnosis, both at 5- and 10-year follow up. The strong association between age and breast cancer death was found for all breast cancer subtypes, being most prominent in Her2-positive breast cancer. The age effect was also significant in Luminal A breast cancer where treatment opportunities are not necessarily affected by age. High-risk tumors were equally common in all age groups above 60 years. In multivariable analysis, stage, subtype, grade and treatment were important explanatory variables to the age-related differences in survival, while comorbidity and socioeconomic status contributed minorly. After adjustments, older age remained an independent risk factor for both overall and breast cancer survival. Older women with triple-negative (60-79 years) or Her2-positive (60-84 years) tumors had a 5-year risk of breast cancer death exceeding the risk of death by other causes. Conclusions Older women had a significantly higher risk of breast cancer death irrespective of breast cancer subtype, also in Luminal A disease where treatment opportunities are not necessarily affected by age. Table 3. Crude probabilities of breast cancer specific death and death by other cause (competing cause of death) at 5, 10 and 15 years. Table 4. Multivariable analysis of prognostic factors affecting 15-year overall (OS) and breast cancer- specific survival (BCSS) Table 5. Multivariable analysis of prognostic factors affecting 15-year overall (OS) and breast cancer- specific survival (BCSS) by age at diagnosis and subtype. Citation Format: Amelia Chiorescu, Anna L V Johansson, Antonis Valachis, Alexios Matikas, Jan Frisell, Lars Holmberg, Irma Fredriksson. Breast cancer in older women - long-term prognosis by age and subtype in a large population-based cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-02-14.

Abstract PO3-09-06: Role of Obesity-Related Biomarkers on Mortality Among Black Breast Cancer Survivors in the Women’s Circle of Health Followup Study

Abstract Background: Central obesity and higher adiposity have been recently associated with higher all-cause and breast cancer-specific mortality in Black breast cancer survivors participating in the Women’s Circle of Health Followup Study. Adipose tissue is a dynamic organ producing adipocytokines, including leptin, adiponectin, adipsin, resistin, lipocalin-2/NGAL, plasminogen-activator inhibitor type 1 (PAI-1) and CXCL11, TNFα, and IL-6, which modulate inflammatory markers in obesity, including the release of proinflammatory C-reactive protein (CRP). These circulating biomarkers play important roles linking obesity with insulin resistance, hyperinsulinemia, chronic inflammation, and altered immunity, which may impact overall and breast cancer mortality. The goal of this analysis was to determine if circulating adipocytokines and obesity-related biomarkers of systemic inflammation are associated with breast cancer and overall survival in Black breast cancer survivors. Methods: Circulating biomarkers were assayed for 460 Black breast cancer survivors who provided a blood sample 2 years post-diagnosis in the Women’s Circle of Health Followup Study, a population-based cohort of Black breast cancer survivors in New Jersey enrolled within 12 months of diagnosis. Associations between biomarkers (by tertiles) and overall survival were assessed using multivariable Cox regression models. Breast cancer specific survival was assessed based on competing risk analyses using the Fine and Gray subdistribution hazard model. Multivariable models were adjusted for age, body mass index as a measure of overall adiposity, education, menopausal status, stage, grade, subtype, and chemotherapy, hormonal therapy, and radiation treatments received. All tests were two-sided at Analyses were conducted at P=0.05. Results: In multivariable analyses, lipocalin-2, CXCL11, and CRP, biomarkers of adipose tissue inflammation closely related to insulin resistance, were associated with worse overall but not breast cancer specific survival. Compared to women in the lowest tertile of lipocalin-2, women in the highest tertile had a 3-fold increased risk of dying from any cause (T3 vs T1, HR=3.08, 95% CI: 1.29-7.39, p= 0.004) and a ~2-fold increased risk of dying from breast cancer, which was not statistically significant (HR= 1.84, 95% CI: 0.59-5.79, p=0.30). Similarly, women in the highest tertile of CXCL11 were at 2-fold increased risk of dying of any cause (HR: 2.10, 95% CI: 0.96-4.57, p=0.06) but no associations were observed with risk of dying from breast cancer (HR:1.31, 0.42-4.13, p=0.64). Circulating CRP, as a marker of systemic inflammation, was also associated with worse overall survival (T3 vs T1 HR: 2.51, 95% CI: 1.07-5.89, p=0.03), showing a borderline significant association with increased breast cancer specific survival (T3 vs T1 HR: 4.32, 95% CI: 0.87-21.38, p=0.07). No associations with overall or breast cancer specific mortality were observed for any of the other adipocytokines examined. Conclusion: In this population-based cohort study of Black breast cancer survivors, biomarkers associated with adipose tissue related inflammation and insulin resistance were associated with reduced overall survival. Relationships with breast cancer survival were not significant, possibly due to limited sample size. Citation Format: Shipra Gandhi, Chi-Chen Hong, Anthony George, Kristopher Attwood, Bo Quin, Nur Zeinomar, Yong Lin, Christine Ambrosone, Kitaw Demissie, Elisa Bandera. Role of Obesity-Related Biomarkers on Mortality Among Black Breast Cancer Survivors in the Women’s Circle of Health Followup Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-09-06.

Abstract GS02-13: Pregnancy after breast cancer in young women with germline BRCA pathogenic variants: results from an international cohort study

Abstract Background: Oncofertility counseling in BRCA carriers has unique challenges due to a possible negative impact of germline pathogenic/likely pathogenic variants (PVs) on reproductive potential and the indication to undergo risk-reducing bilateral salpingo-oophorectomy. While previous studies demonstrated the safety of pregnancy in women with prior breast cancer (BC) history, limited evidence exists in BRCA carriers specifically. We report the results of the largest study to date investigating likelihood of pregnancy after BC, reproductive and disease outcomes specifically in BRCA carriers. Methods: This was an international, multicenter, hospital-based, retrospective cohort study including young BRCA carriers with history of BC (NCT03673306). Eligible patients were women harboring germline PVs in BRCA1 and/or BRCA2 and diagnosed with stage I-III invasive BC at the age of ≤ 40 years between January 2000 and December 2020. BRCA healthy carriers or patients with BRCA variants of unknown significance, non-invasive BC, lack of follow-up, prior ovarian cancer or other malignancies without history of BC were excluded. Primary endpoints were pregnancy rate and disease-free survival (DFS). Overall survival (OS), BC specific survival (BCSS), pregnancy, fetal and obstetric outcomes were secondary endpoints. To mitigate the impact of guaranteed time bias, two survival analyses were performed: 1) Extended Cox model with occurrence of pregnancy as a time-varying covariate; 2) Case-control analysis by matching 1:3 patients with and without a pregnancy for type of BRCA PV, hormone receptor status, nodal status and year at diagnosis; moreover, each control had to have a disease-free interval longer than the time occurring between BC diagnosis and conception of the matched case. Results: From 78 centers worldwide, 4,732 patients were included, of whom 659 had at least one pregnancy after BC (pregnancy cohort) and 4,073 did not (non-pregnancy cohort). Patients in the pregnancy cohort were significantly more likely to carry BRCA1 PVs, to be younger at BC diagnosis, to have node-negative and hormone receptor-negative (HR-) BC (all p< 0.01). Pregnancy rate at 10 years was 22% (95% CI 21%-24%) overall, 18% (95% CI 16%-21%) and 26% (95% CI 24%-26%) in patients with HR+ and HR- BC, respectively (p< 0.01). Median time from BC diagnosis to conception was 3.5 years (IQR 2.2-5.3 years), significantly longer in patients with HR+ than HR- BC (4.3 vs 3.2 years, p< 0.01). Among 659 patients with a pregnancy after BC, 45 (6.8%) and 63 (9.6%) experienced an induced abortion or a miscarriage, respectively. Of the 517 (78.5%) patients with completed pregnancy, 54 (10.4%) had twins and 406 (78.5%) delivered at term (delivery ≥37 weeks). Among the 571 babies born, 5 (0.9%) had congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in DFS was observed between the pregnancy and non-pregnancy cohorts (unadjusted HR 0.97, 95% CI 0.82-1.15, p=0.74; adjusted HR [aHR] 0.99, 95% CI 0.81-1.20, p=0.90). Patients in the pregnancy cohort showed significantly better BCSS (HR 0.53, 95% CI 0.38-0.74, p< 0.01; aHR 0.59, 95% CI 0.41-0.86, p< 0.01) and OS (HR 0.52, 95% CI 0.38-0.72, p< 0.01; aHR 0.58, 95% CI 0.40-0.85, p< 0.01). Similar results were obtained in the case-control analysis. Subgroup analyses of survival endpoints according to patient, tumor and treatment characteristics will be presented at the conference. Conclusions: In this global study, 1 out of 5 young BRCA carriers conceived within 10 years after a BC diagnosis, higher than rates previously reported in unselected young BC populations. Pregnancy following BC in BRCA carriers did not appear to adversely impact maternal prognosis or fetal outcomes. These findings should be incorporated into oncofertility counseling of young BRCA carriers with BC. Citation Format: Matteo Lambertini, Eva Blondeaux, Elisa Agostinetto, Anne-Sophie Hamy-Petit, Hee Jeong Kim, Camila Chiodi, Rinat Bernstein-Molho, Florentine Hilbers, Katarzyna Pogoda, Estela Carrasco Lopez, Kevin Punie, Jyoti Bajpai, Michail Ignatiadis, Halle Moore, Kelly-Anne Phillips, Angela Toss, Christine Rousset-Jablonski, Fedro Alessandro Peccatori, Tiphaine Renaud, Alberta Ferrari, Shani Paluch-Shimon, Robert Fruscio, Wanda Cui, Stephanie Wong, Claudio Vernieri, Kathryn Ruddy, Maria Vittoria Dieci, Alexios Matikas, Mariya Rozenblit, Cynthia Villareal Garza, Laura De Marchis, Lucia Del Mastro, Fabio Puglisi, Maria Del Pilar Estevez-Diz, Kenny A. Rodriguez-Wallberg, Bela Mrinakova, Sarah Meister, Luca Livraghi, Florian Clatot, Rinat Yerushalmi, Carmine De Angelis, Rodrigo Sánchez-Bayona, Icro Meattini, Natalia Cichowska-Cwalińska, Martine Berlière, Mahmoud Salama, Ugo De Giorgi, Amir Sonnenblick, Hatem Azim, Ann Partridge. Pregnancy after breast cancer in young women with germline BRCA pathogenic variants: results from an international cohort study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS02-13.

Abstract PO4-17-06: Real World Data: A single institute experience with neoadjuvant endocrine therapy for ER+ breast cancer — clinical response rates, clinical predictors of response and long-term outcomes following breast conserving surgery

Abstract Background: Neoadjuvant endocrine therapy (NET) in postmenopausal women (PMW) with large or locally advanced oestrogen receptor (ER)-rich breast cancer allows more women to be treated by breast-conserving surgery (BCS). A comprehensive analysis of the factors affecting clinical response to NET and the long-term safety of this strategy has been studied. Patients: A retrospective cohort was studied of 435 PMW (median age: 77 years; range: 50-98) with ER-positive breast cancer treated with NET (aromatase inhibition) (median duration: 6.8 months; range 3-43 months), between 2001-15. Clinical response was monitored throughout NET treatment with periodic 3D ultrasound measurements of the primary tumour. All patients went on to have surgery, 55% had adjuvant radiotherapy and all had adjuvant ET for at least 5 years. All patients had routine follow-up (median follow-up 12.3 years). To-date, this represents the largest cohort of patients treated with >3 months NET. Results: Clinical response to NET was excellent, with only 3.2% of tumours progressing on-treatment based on RECIST 1.1 criteria. Mean percentage reduction in tumour on NET was 71%. Response rate (partial/complete response) was 59% and response continued until 12 months and then levelled off. Following NET, over 92% of patients were suitable for BCS and 61% achieved clinical TNM down-staging. Multivariate analysis revealed that only ER level (response highest in patients with Allred scores 7 and 8), and percentage change in tumour volume by 6 weeks were significant predictors of overall clinical response to NET. Clinical response to NET was not associated with node status or tumour grade. BCS following NET had a local disease control rate of 89% (95%CI±0.06) at 10 years, but actuarial local recurrence at 10 years was only 7% in those having radiotherapy compared with 30% in the group who did not receive radiotherapy (P< 0.0001). In addition, the overall recurrence rate (P=0.028) was improved by radiotherapy irrespective of nodal status. Radiotherapy did not improve overall breast cancer-specific survival (BCSS). Systemic recurrence and BCSS was higher with greater nodal involvement. Most patients in this study died of other causes (14-year crude all-cause mortality was 71%). Conclusion: NET followed by BCS is an effective strategy in PMW with ER-rich breast cancer. Excellent clinical response rates are seen even in women with node-positive or high-grade disease. Less than 5% showed evidence of progression. Early response to NET predicts for long-term tumour volume reduction and NET can achieve continued tumour shrinkage for up to 1 year. NET followed by BCS appears a safe treatment approach and offers good long-term outcomes when BCS is followed by adjuvant radiotherapy. Citation Format: Arran K Turnbull, Carlos Martinez-Perez, Charlene Kay, Rebecca Swan, Lorna Renshaw, J Michael Dixon. Real World Data: A single institute experience with neoadjuvant endocrine therapy for ER+ breast cancer — clinical response rates, clinical predictors of response and long-term outcomes following breast conserving surgery [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-17-06.

Abstract PO4-08-04: Comparison of Outcomes and Prognosis between BRCA Pathogenic Variant Carriers Undergoing Breast-Conserving Surgery versus Mastectomy for Breast Cancer

Abstract Introduction: While outcomes are similar following breast-conserving surgery (BCS) or mastectomy among patients with sporadic breast cancer, data are still controversial for germline BRCA pathogenic variant carriers. We previously compared outcome following BCS between BRCA pathogenic variant carriers and non-carriers, and reported higher ipsilateral breast recurrence and comparable prognosis in the carriers. The purpose of this current study was to compare outcomes among BRCA pathogenic variant carriers undergoing BCS versus mastectomy in long-term follow-up period. Methods: Women with a BRCA pathogenic variant and a stage 0-III breast cancer who underwent definitive surgery from 1987–2021 were retrospectively identified from institutional database. Factors including clinicopathologic information and treatment characteristics were identified. Subsequent local recurrence, regional recurrence, distant recurrence, contralateral breast cancer (CBC), breast cancer-specific survival (BCSS), and overall survival (OS) rates were compared between BCS and mastectomy using Kaplan-Meier method and log-rank test. The chi-square test and t-test were used to compare patient characteristics between the two groups. Results: A total of 232 BRCA mutation carriers with 257 cancers including 25 patients with synchronous bilateral breast cancer were identified. Surgical treatment included BCS for 82 cancers and mastectomy for 175 cancers including nipple-sparing mastectomy for 51 cancers. Patient age at surgery and cancer stage did not statistically differ between BCS and mastectomy groups. Comparing to patients choosing mastectomy, patients who underwent BCS were less likely to be aware of their genetic status before surgery and were more likely to receive radiation therapy (p < 0.001). Contralateral risk reducing mastectomy was performed in 22.5% (18/80) in the BCS group and 48.7% (74/152) in the mastectomy group (p < 0.001) concurrently or at any time after the first definitive surgery. Risk reducing salpingo-oophorectomy was performed in 40% (32/80) in the BCS group and 49% (75/152) in the mastectomy group (p = 0.17). At 7.5 years median follow-up, local recurrence rate was statistically higher in the BCS group than in the mastectomy group (20.0% in BSC vs. 4.6% in mastectomy, p = 0.043). In patients who underwent nipple-sparing mastectomy, 4.0% (2/51) had local subcutaneous recurrence and no nipple-areolar recurrence was observed. Median duration from the first definitive surgery to ipsilateral local recurrence was 10.0 years in the BCS group and 2.3 years in the mastectomy group. Regional lymph node recurrence (11.2% in BCS vs. 6.4% in mastectomy, p = 0.62), distant recurrence (13.7% vs. 9.2%, p = 0.84), CBC (15.0% vs. 8.6%, p = 0.70), BCSS (88.8% vs. 94.1%, p = 0.65) and OS (87.5% vs. 94.1%, p = 0.49) rates did not statistically differ between two groups. Conclusions: With 7.5 years median follow-up, higher local recurrence rate was observed in BCS than in mastectomy among BRCA pathogenic variant carriers. Our results found no statistical difference between BCS and mastectomy in regional recurrence, distant recurrence, CBC, and prognosis, indicating relatively higher risk in BCS. While BCS could be an option for BRCA pathogenic variant carriers willing to continue high-risk breast surveillance, shared decision making should be carefully performed based on the long-term local recurrence risk. Citation Format: Kumiko Kida, Junko Takei, Misato Suzuki, Megumi Okawa, Sakurako Kazama, Sakiko Kondo, Michiko Yamanaka, Atsushi Yoshida. Comparison of Outcomes and Prognosis between BRCA Pathogenic Variant Carriers Undergoing Breast-Conserving Surgery versus Mastectomy for Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-08-04.

Abstract PO4-01-08: Co-expression of estrogen receptor (ER), progesterone receptor (PR), and Ki67 in a single breast cancer cell indicates a favorable prognosis in ER-positive breast cancer

Abstract Background: ER-positive breast cancer is biologically and clinically divided into two subtypes: luminal-A and luminal-B. This classification is mainly based on the status of cellular proliferation. At least two different pathways drive cellular proliferation in ER-positive breast cancer. One is a classical pathway where ER binds to estrogen responsive element (ERE), which leads to the expression of downstream molecules, including PR. The other is a non-classical pathway where a complex of ER and relevant factors bind to different sites than ERE. Growth factor signaling has been suggested to potentiate a non-classical pathway. We hypothesized that examining PR status in ER-positive proliferating cells could tell which pathway is more dominant in ER-positive breast cancer. Methods: To test the hypothesis, we used a newly developed triplex immunohistochemistry (IHC) that detects three molecules simultaneously under bright-field microscopy. Postmenopausal patients who were treated with neoadjuvant endocrine therapy with aromatase inhibitors from January 2007 to September 2016 at Saitama Cancer Center were included in this study. ER, PR, and Ki67 expressions were assessed in a single slide using the triplex IHC assay with anti-ER antibody (clone SP1), anti-PR antibody (clone 1E2), and anti-Ki67 antibody (clone 30-9). ER, PR and Ki67 expression was assessed in a single cell nucleus of cancer cells (567 to 4871 cells) from multiple areas in each case. An ER-positive proliferating cell was defined as an ER-positive and Ki67-positive cell. PR status in ER-positive proliferating cells was assessed. When PR was expressed in more than 50% of ER-positive proliferating cells in a clinical case, the tumor was categorized as the PR-positive group. Luminal A and luminal B breast cancers were defined based on the pre-treatment Ki67 labeling index with a cut-off of 14 %. Statistical analyses included the Mann-Whitney test, the log-rank test, and the Cox proportional hazard model. Results: Pre-treatment tissues from 55 patients were evaluated. The median age was 62 (range: 54 to 80) years. The patients were grouped into PR-positive and PR-negative groups. The two groups had no differences in age and pre-treatment T and N stages. The median pre-treatment Ki67 labeling index was 5.9 % in the PR-positive group and 9.9 % in the PR-negative group, which showed a statistically significant difference (P = 0.01). Clinical response to neoadjuvant endocrine therapy was compared, and no difference was observed. The median post-treatment Ki67 labeling index was 3.6 % in the PR-positive group and 13.1 % in the PR-negative group with a significant difference (P = 0.035). The survival was compared between the two groups. The PR-positive group showed a significantly more favorable disease-free survival (DFS) than the PR-negative group (P = 0.0079). To adjust for the background differences including Ki67 and PR status, a multivariate analysis was performed and showed that the PR-positive group had a significantly better DFS than the PR-negative group independent of clinical stage, Ki67 labeling index, and PR status (P = 0.042). Breast cancer-specific survival (BCSS) was also better in the PR-positive group than in the PR-negative group after adjusting for clinical stage, Ki67 labeling index, and PR status (P = 0.043). Interestingly, among patients with luminal A tumors, those in the PR-positive group showed a better DFS than those in the PR-negative group (P = 0.022). Conclusion: PR status in ER-positive proliferating cells was an independent prognostic factor in DFS and BCSS and divided patients with luminal A tumors further into two prognostic groups. Citation Format: Takayuki Ueno, Rie Horii, Hiroshi Matsumoto, Makiko Ono, Yurina Maeshima, Hiroaki Nitta. Co-expression of estrogen receptor (ER), progesterone receptor (PR), and Ki67 in a single breast cancer cell indicates a favorable prognosis in ER-positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-01-08.

Abstract PO3-01-04: Neoadjuvant compared to adjuvant chemotherapy combined with trastuzumab in patients with HER2-positive breast cancer: a register-based cohort study

Abstract Introduction Neoadjuvant therapy (NAT) is considered the standard of care in patients with HER2-positive breast cancer mainly due to the possibility to adjust the post-neoadjuvant treatment based on the tumor response to NAT. However, there is no convincing evidence on a survival benefit with NAT compared to adjuvant therapy (AT) for HER2-positive breast cancer. The aim of the present study was to compare the two therapeutic strategies in a register-based cohort of Swedish patients with primary operable HER2-positive breast cancer. Method The research database BCBaSe 3.0, which is based on the Swedish National Quality breast cancer register, was used to identify patients with primary operable HER2-positive breast cancer that diagnosed between 2008 and 2020 and received either NAT or AT including chemotherapy and trastuzumab. To mitigate confounding by indication bias, propensity score matching (PSM) with 1:1 matching was applied. The effectiveness of the two therapeutic strategies was investigated through analyzing distant disease-free survival (DDFS), breast-cancer specific survival (BCSS), and overall survival (OS). Multivariate Cox regression analyses were performed for the outcomes of interest to provide Hazard Ratios (HR) and corresponding 95% Confidence Intervals (CI). Results In total, 7258 patients with primary operable HER2-positive breast cancer treated with either NAT or AT were identified, 1789 (24.6%) received NAT and 5469 (75.4%) AT. After 1:1 PSM, 1258 patients in each therapeutic strategy were available for comparisons. After a median follow-up of 63 months, no statistically significant differences between NAT and AT were observed in either outcome (HR for DDFS: 0.97; 95% CI: 0.72 – 1.30; HR for BCSS: 0.69; 95% CI: 0.45 – 1.07; HR for OS: 0.72; 95% CI: 0.50 – 1.05). In subgroup analyses, estrogen-receptor status did not impact the results that remained statistically non-significant between NAT and AT whereas in patients with clinically positive lymph node status, NAT resulted in better BCSS (HR: 0.44; 95% CI: 0.22 – 0.89) and OS (HR: 0.49; 95% CI: 0.29 – 0.90). The latter trend was not evident in patients with clinically negative lymph node status. Conclusion Our study results confirm the equivalence of NAT and AT in terms of prognosis for patients with operable HER2-positive disease and imply a potential benefit of NAT compared to AT in patients with clinically positive lymph node status. Considering the emerging treatment strategies in HER2-positive breast cancer patients treated with NAT (pertuzumab as a part of NAT, T-DM1 as post-neoadjuvant therapy) that have been shown to improve survival but are not reflected in the study cohort, NAT should be considered as the strategy with the higher possibility to improve long-term prognosis for patients with HER2-positive disease. Citation Format: Servah Hosseini-Mellner, Åsa Wickberg, Antonis Valachis, Andreas Karakatsanis. Neoadjuvant compared to adjuvant chemotherapy combined with trastuzumab in patients with HER2-positive breast cancer: a register-based cohort study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-01-04.

Abstract PO4-09-01: Survival of patients harboring a germline ATM pathogenic/likely pathogenic variant and diagnosed with breast cancer: A case-control study

Abstract Introduction: Patients harboring a pathogenic/likely pathogenic variant (PV/LPV) in ATM present an increased lifetime risk of developing breast cancer (BC). The survival outcomes of these patients are not well-known. Methods: Retrospective, multicentric case-control study. Case group included patients with stage I-III breast cancer harboring a PV/LPV in ATM. Control group included patients with stage I-III breast cancer with a negative germline BC multigene panel testing including ATM gene analysis. Clinical outcomes defined as locoregional relapse-free survival (RFS), distant RFS and breast cancer specific survival were compared between cases and controls. Case group was obtained from five hereditary cancer units and control group was obtained from a sporadic clinic-based cohort. Cases and controls were matched 1:2 by stage, molecular subtype by immunohistochemistry, age at BC diagnosis and year of BC diagnosis. Baseline continuous variables were presented as mean and standard deviation and comparison was performed with Student´s t-test. Baseline categorical variables were presented with number and percentage and comparison were performed using chi-square test. Survival analyses were estimated by Kaplan-Meier curves, the comparison of survival was tested by stratified log-rank testing. Cox proportional hazards model was used to estimate the hazard ratio and confidence intervals. Results: We identified 64 patients (p) with an ATM PV/LPV and 120 controls. Median age at diagnosis was 47 years (28-84) and 46 years (25-88), respectively. The main tumoral characteristics in both groups were ductal (87.5% and 83.5%), luminal B-HER2 negative (37.5% and 45.8%) with histological grade II (54.7% and 58.5%) tumors. Majority of tumors in both groups were diagnosed at stage II (53.1% and 54.2%). Differences between groups were observed in first-degree BC family history (39p (61.9%) vs 51p (43.6%); p=0.02); frequency of multicentric/multifocal tumors (15p (25%) vs 13p (11.1%); p=0.018); contralateral breast cancer (16p (25%) vs 8p (6.7%); p=0.0004) and type of surgery (46.8% conservative surgery in cases and 69.2% in controls; p< 0.001). The result of the germline genetic study was not available for all patients before surgery. Baseline characteristics are summarized in Table 1. With a median follow-up of 6.7 years, we observed more locoregional recurrence and distant recurrence in the control group (ipsilateral local or lymphatic recurrence: 0p (0%) vs 15p (12.5%); p=0.078; metachronic contralateral breast cancer: 7p (12.7%) vs 3p (2.6%); p=0.02; distance recurrence 5p (7.8%) vs 24p (20%); p=0.03. No differences between groups were observed in BC-specific survival analysis, with a median BC-specific survival of 6.24y (4.67-12.1) in patients with ATM and 6.68y (6.12-7.94) in the control group (HR: 1.21 (0.88-1.65); p=0.24). Conclusions: Patients with BC harboring a germline ATM PV/LPV had more multifocal and multicentric disease at diagnosis; and more synchronous and metachronous contralateral BC compared to controls, with no differences in BC-specific survival. Further studies in a larger cohort are warranted to analyze sensitivity to systemic therapies. Table 1. Baseline characteristics of cases and control groups. ER (Estrogen Receptor) positive if > or equal to 1%; PR (Progesterone Receptor) positive if > or equal to 1%; HER2 (Human epidermal growth factor receptor-2); ChTh: Chemotherapy; SLNB: Sentinel Lymph Node Biopsy; AL: Axillar lymphadenectomy Citation Format: Mara Cruellas, Ariadna Roqué, Nuria Dueñas, Iris Teruel, Noemí Tuset Der-Abrain, Alejandra Rezqallah, Víctor Navarro, Laia Joval-Ramentol, Maite Torres, Cristina Saura, Joan Brunet, Judith Balmaña. Survival of patients harboring a germline ATM pathogenic/likely pathogenic variant and diagnosed with breast cancer: A case-control study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-09-01.

Abstract PO2-23-10: Obesity May Modulate the Relationship Between High Mammographic Breast Density and Neoadjuvant Chemoresistance in Early Breast Cancer

Abstract Background - An inverse association has been described in a number of studies between mammographic breast density (MBD) and pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) for early breast cancer (BC), implicating high MBD in chemotherapy resistance. However, this effect has not been seen in all there is a paucity of data exploring whether this relationship extends the relationship beyond pCR to overall survival. This study aims to validate the relationship between MBD and pCR in patients undergoing NAC for early BC as well as to assess the relation of MBD with clinical complete response (cCR), relapse-free (RFS) and BC-specific survival (BCSS). Further, this study examines these associations stratified by body mass index (BMI). Methods - MBD was measured in contralateral mammograms in 127 women before NAC, using Cumulus software. As the study spanned the transition period from film to digital mammography, film mammograms were digitised using a high-powered scanner and processed full-field digital mammograms were extracted from the imaging storage facility. Basic patient, tumour and treatment demographics were collated including BMI. Percent dense area (PDA) was correlated with patient and tumour characteristics, short-term (pCR/cCR incidences), and long-term chemotherapy outcomes (RFS and BCSS). Results - Overall rates of cCR and pCR of 49% and 21% were observed across the whole cohort. Mean PDA was higher in those not undergoing cCR (p=0.041) and relapsing patients (p=0.041) but did not significantly vary by pCR or BC-deaths. As a dichotomous variable, high PDA relative to low PDA corresponded to lower cCR (40 v 58%, p=0.027), but no significant difference was seen for pCR (17.5 v 25.0%, p=0.15), BC relapse (38 v 30%, p=0.15) or BC-death (32 v 25%, p=0.20). High PDA (relative to low PDA) in patients with obesity (BMI >30kg/m2) was associated with lower pCR (0% v 28.1%, p=0.036) and numerically higher relapse rates (56% v 28%, p=0.063) and breast cancer deaths (56 v 28%, p=0.071. No such relationship was observed in patients with a BMI< 30kg/m2. Conclusion - Higher MBD associated with lower cCR and higher relapse but not with pCR or BC death. The inferior outcomes with high MBD were confined to patients with obesity in our study. Further analysis of the relationship between MBD and outcomes, including by BMI, is warranted. Citation Format: Andrew Redfern, Veenoo Agarwal, Ellie Darcey, Lisa Spalding, Hilary Martin, Jennifer Stone. Obesity May Modulate the Relationship Between High Mammographic Breast Density and Neoadjuvant Chemoresistance in Early Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-23-10.

Abstract PO3-02-06: Predictive Factors for adjuvant radiation use in patients >70 years with pT1N0 HR+ breast cancers

Abstract Introduction: In 2004 the CALGB 9343 study reported that women >70 years of age with pT1NO hormone receptor positive breast cancer received no meaningful benefit from breast irradiation following lumpectomy. Although there was a modest reduction in local recurrence, there was no improvement in rates of mastectomy for local recurrence, distant metastases, 5-year overall survival (OS) and breast cancer specific survival therefore concluding that it was reasonable to omit radiation therapy in this group. An update of the CALGB 9343 study in 2013 with 10-year follow-up came to the same conclusion. Previous analysis of the National Cancer Database (NCDB) and the SEER database showed, however, that the majority of women with these characteristics were still receiving radiation therapy. We conducted this retrospective analysis from NCDB to identify factors associated with the use of radiation in this population. Methods: We reviewed the NCDB database and collected records of all breast cancer patients aged >70 years, who had hormone positive (HR+), pT1N0 disease between the years of 2004-2019. They were separated into radiation and non-radiation cohorts and then stratified based on ethnicity, age groups, insurance status, income quartiles, education quartiles, areas of residence, tumor size, comorbidities, diagnosis to treatment time, treatment facility type and geographic location. We then compared mortality between the two cohorts and completed a multivariate analysis to determine the demographic and clinical factors associated with the likelihood of receiving radiation. SAS was used for analysis and p-value < 0.05 was deemed as statistically significant. Results: 147,611 patients met the criteria of age > 70, pT1N0, HR+ treated with surgical lumpectomy. The majority of them were white, aged 70-75y, had Medicare, were in higher education and income quartiles and lived in metro areas (Table 1). 57.9% of the total study population received radiation. The possibility of receiving radiation decreased as age increased beyond 75 years. Uninsured patients, Medicare patients, those with comorbities, higher educational status as well as those who lived 20+ miles away from their treatment facility and treated at urban centers in central or south Atlantic areas were less likely to receive radiation. Those treated at Comprehensive community cancer programs and middle Atlantic areas were more likely to receive radiation. The possibility of radiation also progressively increased with tumor size. However, there were no differences observed when stratified by race, income status or chemotherapy use (Table 2). We also noted a small overall survival advantage for the radiation cohort (HR 0.77, p-value < 0.0001) which could be explained by the fact that patients without comorbidities were more likely to receive radiation. Discussion: Our results provide a real-world estimate of radiation use in pT1N0 HR+ early-stage breast cancer in women > 70 years. The major predictors of radiation use included younger age, low co-morbidities, insurance and institutions providing care. Lack of awareness about recent updates or concern about local recurrence could be contributing to the continued use of radiation. Although there are minor differences when stratified by demographics, it is concerning that the overall trend of radiation use has not significantly decreased over time. Since there is currently no data to support the routine use of radiation in this patient group as evidenced by randomized controlled trials, it is prudent to avoid radiation. This approach would help reduce healthcare costs, patient inconvenience and associated morbidity. Table 1 Baseline characteristics Table 2 Factors affecting radiation use Citation Format: Suma Sri Chennapragada, Runhua Shi, Shivani Sharma, Gary Burton. Predictive Factors for adjuvant radiation use in patients >70 years with pT1N0 HR+ breast cancers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-02-06.

Abstract PO5-19-10: First oncological outcomes of HypoG-01: a UNICANCER phase III trial comparing loco-regional hypo vs normo fractionated radiation therapy in early breast cancer patients

Abstract Objective Normofractionated (NF) radiation therapy (RT) is still standard for loco-regional early breast cancer (EBC) in many countries. HypoG-01, a UNICANCER, non-inferiority, open-label, multicenter, randomized phase III trial (NCT03127995), conducted in parallel with the DBCG Skagen trial 1 (NCT02384733), evaluated hypofractionated (HF) RT with 40 Gy/15 fr (2.67 Gy/fr) versus NF RT 50 Gy/25 fr (2.0 Gy/fr). This is the first report of oncological outcomes, secondary endpoints of the trial. Methods Patients (pts) ≥18 years old were operated for T1-3, N0-3, M0 breast cancer. All pts received nodal and thoracic wall or breast RT. Tumor-bed boost (sequential or simultaneous) and nodal levels treated were decided according to local guidelines. Target volumes were delineated according to the ESTRO consensus. RT technique was left at the investigator’s discretion. Stratification factors included treating center, type of surgery, number of positive nodes and body mass index. The primary endpoint, reported previously, was time to occurrence of arm lymphedema. Oncological outcomes included locoregional relapse free survival (LRFS), invasive disease-free survival (IDFS), distant disease-free survival (DDFS), breast cancer specific survival (BCSS) and overall survival (OS) as defined per DATECAN guidelines. All time to cancer related endpoints were defined as starting from the date of randomization until the event. The primary statistic test was stratified one-sided logrank test: 5% significance level in per-protocol population (PPP) with a pre-specified non-inferiority margin of 1.545. Stratified Cox model was used for calculating hazard ratios of oncological outcomes. Results In total, 1265 pts were randomized to HF versus NF RT from Sep 2016 to Mar 2020 with 1221 in the PPP (HF group 614 pts (50.3%); NF group 607 (49.7%)), 5 consent withdrawn and 39 major deviations. Median age was 58 years (range 23-91), surgery included mastectomy (501 pts; 45%) and axillary clearance (921 pts; 82.8%). Sequential (67.8%) or simultaneous integrated (32.2%) tumor-bed boost was used in 596 pts (48.8%). With a median follow-up for OS in PP analysis of 3.8 years (95% CI 3.3 to 3.9), HF was non-inferior to NF RT in terms of lymphedema (HR=1.07; 90% CI 0.86-1.34, non-inferiority p=0.003). Table 1 reports the hazard ratio and 3-year survival rates for the oncological endpoints LRFS, IDFS, DDFS, BCCS and OS. There was no sign of disadvantage for any of these endpoints comparing HF to NF. Additional analyses will be presented at the meeting. Conclusion Moderately HF loco-regional RT is non-inferior to NF RT in terms of lymphedema risk in EBC and does not show a disadvantage in terms of LRFS, IDFS, DDFS, BCCS and OS with a median follow-up of 3.8 years. Together with the Skagen 1 trial, this study provides level 1A evidence supporting the use of 40 Gy/15 fr for loco-regional radiation therapy in EBC with respect to arm lymphedema risk; Table 1: Oncological outcomes according to treatment arm in the per protocol analysis HF: Moderately hypofractionated radiation therapy; NF: Normofractionated radiation therapy; n:number of patients; N: number of events Citation Format: Sofia Rivera, Eleni Karamouza, Youlia Kirova, Séverine Racadot, Mohamed Benchalal, Jean-Baptiste Clavier, Claire Charra-Brunaud, Marie-Eve Chand-Fouche, Delphine Argo-Leignel, Karine Peignaux, Ahmed Benyoucef, David Pasquier, Philippe Guilbert, Julien Blanchecotte, Agnès Tallet, Adeline Petit, Guillemette Bernadou, Xavier Zasadny, Claire Lemanski, Jacques Fourquet, Emmanuelle Malaurie, Honorine Kouto, Carole Massabeau, Alexandre Henni, Pauline Regnault, Aurélie Belliere, Yazid Belkacemi, Magali Le Blanc-Onfroy, Julien Geffrelot, Jean-Briac Prevost, Marie Bergeaud, Assia Lamrani-Ghaouti, Amandine Ruffier, Naima Bonnet, Stephanie Wong, Christine Rossier, Thomas Brion, Pierre Maroun, Claire Petit, Guillaume Auzac, Stefan Michiels. First oncological outcomes of HypoG-01: a UNICANCER phase III trial comparing loco-regional hypo vs normo fractionated radiation therapy in early breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-10.