Partridge, Ann H.

505 Background: Increased TILs are associated with better prognosis in triple-negative BC, including in patients (pts) age < 40. However, the role of TILs remains unclear in HR+/HER2- BC and little data exist in young pts, in whom immune microenvironment could be altered by age-related host/tumor differences. We assessed the extent and composition of immune infiltration in HR+ tumors of young women and correlated with clinicopathologic features and survival outcomes. Methods: From a prospective cohort study of women with BC diagnosed age ≤40, we identified those with stage I-III HR+/HER2- BC and available pre-treatment (tx) tumor tissue. Multiplexed immunofluorescence was used to quantify cytotoxic T (CD8+), T helper (Th, CD3+CD8-), T regulatory (Tregs, FOXP3+CD3+) and exhausted T (PD1+CD8+) cells in stroma and tumor. Univariate analyses tested associations between clinicopathologic variables and immune markers by high or low expression, divided based on median. High vs. low TILs were evaluated in Cox regression analyses for invasive breast cancer-free survival (iBCFS), distant disease-free survival (DDFS) and overall survival (OS). Results: In 390 pts, median age was 37 years (21-40), most had grade 2 (51%), T1 (65%), N0 (63%) tumors and 67% received adjuvant chemotherapy. Black pts (n = 17) had higher expression of stromal CD8+ ( P= .010), FOXP3+CD3+ ( P= .027) and PD1+CD8+ TILs ( P= .043); intratumoral TILs did not differ by race. Older age (36-40) was associated with high expression of CD8+ ( P= .033) and PD1+CD8+ TILs ( P= .031) within stroma and CD3+CD8- TILs within tumor ( P= .046). Grade 3 tumors had higher stromal and intratumoral expression of CD3+CD8- ( P= .002; P< .001) and FOXP3+CD3+ TILs ( P= .020; P< .001). No differences in TILs were seen according to recency of pregnancy, BRCA1/2 status or T/N stage. Over a median follow up of 8 years, 85 iBCFS events, 64 DDFS events and 37 deaths occurred. High stromal expression of CD3+CD8- TILs was associated with better iBCFS (HR 0.49, P= .002) and DDFS (HR 0.57, P= .046), which remained significant when adjusted for T/N stage, grade and chemotherapy (iBCFS HR 0.41, P< .001; DDFS HR 0.45, P= .008). High stromal expression of CD3+CD8- and FOXP3+CD3+ TILs was associated with better OS (HR 0.47, P= .038) and iBCFS (HR 0.58, P= .018), respectively, on adjusted analyses only. High intratumoral expression of CD3+CD8- and FOXP3+CD3+ TILs was associated with better iBCFS (HR 0.59, P= .025; HR 0.63, P= .043) after adjustment only. Conclusions: The distribution of TIL subtypes in young women’s HR+ BC varied according to race, age and grade. High stromal and intratumoral expression of Th and Tregs was associated with improved BC outcomes. Characterization of immune cell subsets could help refine the prognostic value of TILs in HR+ BC, particularly in young pts who may benefit from individualized escalated/de-escalated tx strategies.

AbstractBackgroundObesity and inactivity are poor prognostic factors in breast cancer, but less is known regarding physical activity (PA) and weight patterns in young breast cancer survivors.MethodsThe Young and Strong Study was a cluster‐randomized trial evaluating education and support interventions for young women (age <45 years) with newly diagnosed breast cancer. Sites were randomized 1:1 to a Young Women's Intervention (YWI) or a contact‐time control physical activity intervention (PAI). Changes in PA and weight were compared between groups using general estimating equations to evaluate clustered binary and Gaussian data.ResultsA total of 467 patients enrolled between July 2012 and December 2013 across 54 sites. Median age at diagnosis was 40 years (range, 22–45). At baseline, median body mass index (BMI) was 25.4 kg/m2 (range, 16.1–61.1), and participants reported a median of 0 minutes (range, 0–2190) of moderate/vigorous PA/week. PA increased significantly over time in both groups (p < .001), with no difference between groups at any time point. BMI increased modestly but significantly (p < .001) over time in both groups. Provider attention to PA was observed in 74% of participants on PAI and 61% on YWI (p = .145) and correlated with PA at 12 months (median 100 min/week of PA in participants with provider attention to PA vs. 60 min/week in those without, p = .016).ConclusionsIn a cohort of young women with breast cancer, rates of obesity and inactivity were high. PA and BMI increased over time and were not impacted by an educational PA intervention. Findings provide important information for developing lifestyle interventions for young breast cancer survivors.

Abstract Purpose: Young women’s breast cancers (YBCs), defined herein as breast cancer (BC) diagnosed at age ≤ 40 years, are etiologically and biologically distinct from postmenopausal BCs, demonstrating a higher proportion of estrogen receptor (ER) negative subtypes and a worse prognosis. Studies have not assessed whether risk factors such as recent parity and body mass index (BMI) are linked to protein expression profiles in YBCs. Accordingly, we examined protein expression assessed with GeoMx® Digital Spatial Profiling (DSP) in 640 YBCs prepared as tissue microarrays (TMAs) in the Young Women’s BC Study (YWBCS). Methods: The YWBCS is a multi-institutional cohort of 1,297 women with incident BC diagnosed at age &lt;40 years identified through medical record review, with risk factor data collected via questionnaires. TMAs including 1,505 cores of 640 YBCs that were collected prior to therapy and were suitable for molecular analysis were evaluated for 72 markers with NanoString GeoMx DSP. Associations of log-transformed biomarker expression with BMI and time from last live birth to BC diagnosis were carried out using linear mixed modeling approaches, accounting for multiple tumor tissue cores per individual. Results: Mean age at BC was 35.5 years (range 17-40). Tumor subtypes based on clinical immunostaining were the following: luminal B 46%; luminal A 36%; triple negative 12% and HER2+ 6%. Of 72 biomarkers tested, 53 (74%) were evaluable after QC and normalization. GeoMx ER and PR protein levels were higher in luminal A and luminal B YBCs than in HER2+ and TNBC (p=2x10-94 and 2x10-52, respectively), supporting the accuracy of the GeoMx assay. Compared to nulliparas or those with most recent birth &gt; 3 years before BC, those who gave birth ≤ 3 years prior to BC had tumors with higher expression of PR (8x10-6) and ER (p=0.006), and lower expression of BCL-2 (p=0.006). In contrast, women with last birth ≥ 6 years prior to BC had higher expression of CD8 (p=0.006) and PD-1 (p=0.001) than nulliparas and those with more recent births. Compared to women with BMI between 18.5 and 29.9, those with higher or lower BMIs had higher expression of CD34 (p=0.0003), CD4 (p=0.0009) and CD14 (p=0.001). BCL-2 expression was higher among women with BMI &lt; 18.5 compared to those with higher values (p=0.005). Women with BMI of 30+ had higher β2-microglobulin levels than those with lower BMIs (p=0.003). Inverse dose-response associations (with higher BMI related to lower levels) were observed for expression of ER (p=0.01), pan cytokeratin (p=0.004) and four proteins in the p13K/AKT signaling pathway (p ≤ 0.01 for each). Conclusions: Preliminarily, we identify differences in hormonal and immune markers in YBCs in relation to timing of births and BMI, suggesting that these factors may contribute to etiologic heterogeneity. Multivariate modeling is ongoing to incorporate molecular subtype and other risk factors. Citation Format: Robert A. Vierkant, Laura M. Pacheco-Spann, Stacey J. Winham, Jennifer M. Kachergus, Ji Shi, Craig Snow, Fergus J. Couch, Janet E. Olson, Chen Wang, Derek C. Radisky, Amy C. Degnim, E. Aubrey Thompson, Laura C. Collins, Kathryn J. Ruddy, Ann H. Partridge, Mark E. Sherman. Associations of parity and body mass index with NanoString digital spatial protein profiling in early onset breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1000.

PURPOSE Breast-conserving therapy (BCT) is the preferred treatment for unifocal breast cancer (BC). The oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC) has not been demonstrated in a prospective study. ACOSOG Z11102 (Alliance) is a phase II, single-arm, prospective trial designed to evaluate oncologic outcomes in patients undergoing BCT for MIBC. PATIENTS AND METHODS Women age 40 years and older with two to three foci of biopsy-proven cN0-1 BC were eligible. Patients underwent lumpectomies with negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary end point was cumulative incidence of local recurrence (LR) at 5 years with an a priori rate of clinical acceptability of <8%. RESULTS Among 270 women enrolled between November 2012 and August 2016, there were 204 eligible patients who underwent protocol-directed BCT. The median age was 61 years (range, 40-87 years). At a median follow-up of 66.4 months (range, 1.3-90.6 months), six patients developed LR for an estimated 5-year cumulative incidence of LR of 3.1% (95% CI, 1.3 to 6.4). Patient age, number of sites of preoperative biopsy–proven BC, estrogen receptor status and human epidermal growth factor receptor 2 status, and pathologic T and N categories were not associated with LR risk. Exploratory analysis showed that the 5-year LR rate in patients without preoperative magnetic resonance imaging (MRI; n = 15) was 22.6% compared with 1.7% in patients with a preoperative MRI (n = 189; P = .002). CONCLUSION The Z11102 clinical trial demonstrates that breast-conserving surgery with adjuvant radiation that includes lumpectomy site boosts yields an acceptably low 5-year LR rate for MIBC. This evidence supports BCT as a reasonable surgical option for women with two to three ipsilateral foci, particularly among patients with disease evaluated with preoperative breast MRI.

AbstractBackgroundRisk‐stratified follow‐up guidelines that account for the absolute risk and timing of recurrence may improve the quality and efficiency of breast cancer follow‐up. The objective of this study was to assess the relationship of anatomic stage and receptor status with timing of the first recurrence for patients with local‐regional breast cancer and generate risk‐stratified follow‐up recommendations.MethodsThe authors conducted a secondary analysis of 8007 patients with stage I–III breast cancer who enrolled in nine Alliance legacy clinical trials from 1997 to 2013 (ClinicalTrials.gov identifier NCT02171078). Patients who received standard‐of‐care therapy were included. Patients who were missing stage or receptor status were excluded. The primary outcome was days from the earliest treatment start date to the date of first recurrence. The primary explanatory variable was anatomic stage. The analysis was stratified by receptor type. Cox proportional‐hazards regression models produced cumulative probabilities of recurrence. A dynamic programming algorithm approach was used to optimize the timing of follow‐up intervals based on the timing of recurrence events.ResultsThe time to first recurrence varied significantly between receptor types (p < .0001). Within each receptor type, stage influenced the time to recurrence (p < .0001). The risk of recurrence was highest and occurred earliest for estrogen receptor (ER)‐negative/progesterone receptor (PR)‐negative/Her2neu‐negative tumors (stage III; 5‐year probability of recurrence, 45.5%). The risk of recurrence was lower for ER‐positive/PR‐positive/Her2neu‐positive tumors (stage III; 5‐year probability of recurrence, 15.3%), with recurrences distributed over time. Model‐generated follow‐up recommendations by stage and receptor type were created.ConclusionsThis study supports considering both anatomic stage and receptor status in follow‐up recommendations. The implementation of risk‐stratified guidelines based on these data has the potential to improve the quality and efficiency of follow‐up.

Background: The potential gonadotoxicity of anti-HER2 agents remains largely unknown, and limited, conflicting evidence exists for taxanes. Antimüllerian hormone (AMH) is an established biomarker of ovarian reserve that may aid in quantifying anticancer treatment–induced gonadotoxicity. Patients and Methods: The present biomarker analysis of the randomized phase III neoadjuvant NeoALTTO trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early breast cancer with available frozen serum samples at baseline (ie, before anticancer treatments), at week 2 (ie, the “biological window” of anti-HER2 therapy alone), and/or at the time of surgery (ie, after completing paclitaxel + anti-HER2 therapy, before starting adjuvant chemotherapy). Results: The present analysis included 130 patients with a median age of 38 years (interquartile ratio [IQR], age 33–42 years). AMH values at the 3 time points differed significantly (P<.001). At baseline, median AMH levels were 1.29 ng/mL (IQR, 0.56–2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median, 1.10 ng/mL; IQR, 0.45–2.09 ng/mL; P<.001). At surgery, a larger significant decline in AMH levels was observed (median, 0.01 ng/mL; IQR, 0.01–0.03 ng/mL; P<.001). Although the type of anti-HER2 treatment (trastuzumab and/or lapatinib) did not seem to impact the results, age and pretreatment ovarian reserve had a major influence on treatment-induced gonadotoxicity risk. Conclusions: This NeoALTTO biomarker analysis showed that anti-HER2 therapies alone had limited gonadotoxicity but that the addition of weekly paclitaxel resulted in marked AMH decline with possible negative implications for subsequent ovarian function and fertility.

Importance Both tumor-infiltrating lymphocytes (TILs) assessment and immune-related gene expression signatures by RNA profiling predict higher pathologic complete response (pCR) and improved event-free survival (EFS) in patients with early-stage ERBB2/HER2-positive breast cancer. However, whether these 2 measures of immune activation provide similar or additive prognostic value is not known. Objective To examine the prognostic ability of TILs and immune-related gene expression signatures, alone and in combination, to predict pCR and EFS in patients with early-stage ERBB2/HER2-positive breast cancer treated in 2 clinical trials. Design, Setting, and Participants In this prognostic study, a correlative analysis was performed on the Cancer and Leukemia Group B (CALGB) 40601 trial and the PAMELA trial. In the CALGB 40601 trial, 305 patients were randomly assigned to weekly paclitaxel with trastuzumab, lapatinib, or both for 16 weeks. The primary end point was pCR, with a secondary end point of EFS. In the PAMELA trial, 151 patients received neoadjuvant treatment with trastuzumab and lapatinib for 18 weeks. The primary end point was the ability of the HER2-enriched subtype to predict pCR. The studies were conducted from October 2013 to November 2015 (PAMELA) and from December 2008 to February 2012 (CALGB 40601). Data analyses were performed from June 1, 2020, to January 1, 2022. Main Outcomes and Measures Immune-related gene expression profiling by RNA sequencing and TILs were assessed on 230 CALGB 40601 trial pretreatment tumors and 138 PAMELA trial pretreatment tumors. The association of these biomarkers with pCR (CALGB 40601 and PAMELA) and EFS (CALGB 40601) was studied by logistic regression and Cox analyses. Results The median age of the patients was 50 years (IQR, 42-50 years), and 305 (100%) were women. Of 202 immune signatures tested, 166 (82.2%) were significantly correlated with TILs. In both trials combined, TILs were significantly associated with pCR (odds ratio, 1.01; 95% CI, 1.01-1.02; P = .02). In addition to TILs, 36 immune signatures were significantly associated with higher pCR rates. Seven of these signatures outperformed TILs for predicting pCR, 6 of which were B-cell related. In a multivariable Cox model adjusted for clinicopathologic factors, including PAM50 intrinsic tumor subtype, the immunoglobulin G signature, but not TILs, was independently associated with EFS (immunoglobulin G signature–adjusted hazard ratio, 0.63; 95% CI, 0.42-0.93; P = .02; TIL-adjusted hazard ratio, 1.00; 95% CI, 0.98-1.02; P = .99). Conclusions and Relevance Results of this study suggest that multiple B-cell–related signatures were more strongly associated with pCR and EFS than TILs, which largely represent T cells. When both TILs and gene expression are available, the prognostic value of immune-related signatures appears to be superior.

Objective: We sought to evaluate local/regional recurrence rates after breast-conserving surgery in a cohort of patients enrolled in legacy trials of the Alliance for Clinical Trials in Oncology and to evaluate variation in recurrence rates by receptor subtype. Background: Multiple randomized controlled trials have demonstrated equivalent survival between breast conservation and mastectomy, albeit with higher local/regional recurrence rates after breast conservation. However, absolute rates of local/regional recurrence have been declining with multi-modality treatment. Methods: Data from 5 Alliance for Clinical Trials in Oncology legacy trials that enrolled women diagnosed with breast cancer between 1997 and 2010 were included. Women who underwent breast-conserving surgery and standard systemic therapies (n=4,404) were included. Five-year rates of local/regional recurrence were estimated from Kaplan-Meier curves. Patients were censored at the time of distant recurrence (if recorded as the first recurrence), death, or last follow-up. Multivariable Cox proportional hazards models were used to identify factors associated with time to local/regional recurrence, including patient age, tumor size, lymph node status, and receptor subtype. Results: Overall 5-year recurrence was 4.6% (95% CI=4.0-5.4%). Five-year recurrence rates were lowest in those with ER+ or PR+ tumors (Her2+ 3.4% [95% CI 2.0-5.7%], Her2- 4.0% [95% CI 3.2-4.9%]) and highest in the triple-negative subtype (7.1% [95% CI 5.4-9.3%]). On multivariable analysis, increasing nodal involvement and triple-negative subtype were positively associated with recurrence (P<0.0001). Conclusions: Rates of local/regional recurrence after breast conservation in women with breast cancer enrolled in legacy trials of the Alliance for Clinical Trials in Oncology are significantly lower than historic estimates. This data can better inform patient discussions and surgical decision-making.

Abstract Background: Young women with DCIS are at increased risk of recurrence and second BC compared to older women and may derive the greatest benefit from risk reduction strategies. Little is known about treatment decision-making, engagement in preventive behaviors, or fear of recurrence among young DCIS survivors. Thus, we sought to investigate treatment and prevention issues in this population. Methods: Using a multicenter prospective cohort that enrolled 1302 women with stage 0-IV BC at age ≤40, we identified participants with DCIS only who completed surveys in the year following diagnosis (dx). Surveys assessed treatment decisions, lifestyle factors (alcohol, smoking, physical activity [PA]), and fear of recurrence (Lasry Scale). Data was summarized with descriptive statistics and groups were compared with Fisher’s exact test. Results: Among 87 patients (median age 38, range 26-40), 75 had available treatment decision data, 19 (25%) of whom had breast-conserving surgery (BCS), 11 (15%) unilateral mastectomy (UM), and 45 (60%) bilateral mastectomy (BM). Most (77%) indicated their doctor said BCS was an option or recommended, including 34 (59%) who had BM. Of 40 patients who reported a patient-driven surgical decision, 73% had BM, 13% UM, and 15% BCS. Among 15 patients who reported the decision as doctor-driven, none had BM, 27% UM, and 73% BCS. Those who had BM were more likely to be extremely confident about the decision (80% vs. 73% UM vs. 53% BCS, p=0.022). Adjuvant tamoxifen was used by 10/27 (37%) patients with ER+ DCIS who had BCS/UM. Most who took tamoxifen reported this decision was shared with their doctor (90%); 1 reported the decision was made on her own. Of the 17 patients who did not take tamoxifen, 88% indicated their doctor said endocrine therapy was an option or recommended. Among all 87 patients, 31 (36%) were former and 3 (4%) were current smokers at baseline assessment (median 5 months post-dx); 51 (59%) never smoked. Overall, 4 quit within 1 year of dx. Most patients (83%) were current drinkers at baseline, though 79% consumed &lt;5 alcoholic beverages/week; 8% reported lower consumption at 1 year. Regarding PA at 1 year, 73% (58/80) reported ≥150 minutes of moderate-intensity PA/week. Overall, 41% of young survivors were at least moderately concerned about their BC coming back, with concern varying numerically by surgery (65% post-BCS, 50% post-UM, 29% post-BM, p=0.053). Conclusions: BC recurrence concerns were frequent among young DCIS patients, particularly among those with remaining breast tissue. BM decisions were largely patient-driven and made with high confidence, reflecting preferences towards surgical prevention. While adherence to survivorship lifestyle guidelines was high, including not smoking, consumption of ≤7 drinks/week, and engaging in PA, tamoxifen use was low, even when offered by a provider. Young DCIS survivors appear motivated to lower future BC risk through surgery and maintenance of healthy behaviors, and less so with tamoxifen; such values should be considered during treatment and survivorship counseling. Citation Format: Megan E. Tesch, Julia S. Wong, Laura Dominici, Kathryn J. Ruddy, Rulla Tamini, Lidia Schapira, Virginia F. Borges, Ellen Warner, Steven E. Come, Karen Sepucha, Laura C. Collins, Ann H. Partridge, Shoshana M. Rosenberg. Breast cancer (BC) risk reduction in young women with ductal carcinoma in situ (DCIS) [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 PR009.

Abstract Clonal hematopoiesis of indeterminate potential (CHIP), an emerging biomarker for personalized risk-directed interventions, is increased in cancer survivors. However, little is known about patient preferences for CHIP testing. We surveyed participants in a prospective cohort study of young women with breast cancer (BC). The emailed survey included an introduction to CHIP and a vignette eliciting participants’ preferences for CHIP testing, considering sequentially: population-based 10-year risk of BC recurrence, hematologic malignancy, and heart disease; increased CHIP-associated risks; current CHIP management; dedicated CHIP clinic; and hypothetical CHIP treatment. Preference changes were evaluated using the McNemar test. The survey response rate was 82.2% (528/642). Median age at time of survey was 46 years and median time from diagnosis was 108 months. Only 5.9% had prior knowledge of CHIP. After vignette presentation, most survivors (87.1%) recommended CHIP testing for the vignette patient. Presented next with CHIP-independent, population-based risks, 11.1% shifted their preference from testing to not testing. After receiving information about CHIP-associated risks, an additional 10.1% shifted their preference to testing. Preference for testing increased if vignette patient was offered a CHIP clinic or hypothetical CHIP treatment, with 7.2% and 14.1% switching preferences toward testing, respectively. Finally, 75.8% of participants desired CHIP testing for themselves. Among participants, 28.2% reported that learning about CHIP caused at least moderate anxiety. Most young survivors favored CHIP testing, with preferences influenced by risk presentation and potential management strategies. Our findings highlight the importance of risk communication and psychosocial support when considering biomarkers for future risk in cancer survivors. This trial has been registered at www.clinicaltrials.gov as #NCT01468246.