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BACKGROUND: Rates of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for breast cancer have improved, especially among human epidermal growth factor 2-positive (HER2+) and triple-negative subtypes. The frequency and significance of biomarker profile change in residual disease are unclear. This study aimed to determine the rate of biomarker profile changes after NAC and the impact on clinical outcomes in a contemporary cohort. METHODS: Upon institutional review board approval, the study identified 634 consecutive patients treated with NAC between 2010 and 2022 at two academic institutions. The study cohort was focused on patients with residual disease who underwent biomarker profile retesting. Biomarker profile change for each subtype was compared across groups using Fisher-Irwin tests. Cox Proportional Hazards Model and Kaplan-Meier plots were performed to evaluate the association of changed versus unchanged biomarker profile with event-free survival. RESULTS: Biomarker retesting was performed for 259 (61.4 %) of 422 patients with residual disease. Biomarker profile change occurred in 18.1 % overall and was significantly higher among those with pre-NAC HER2+ disease (32.7 %, 17/52) than among those with HER2-disease (14.5 %, 30/207) (p = 0.004). Conversion of pre-NAC biomarker profiles of HR+HER2- and HR+HER2+ to triple-negative breast cancer (TNBC) post-NAC may be associated with worse event-free survival, hazard ratios of 2.23 (95 % confidence interval [CI], 0.90-5.53; p = 0.08), trending toward significance, and 36.7 (95 % CI, 2.2-610.8; p = 0.01), respectively. CONCLUSIONS: The results from one of the largest contemporary cohorts demonstrated that biomarker profile change in patients with residual disease after NAC was common. Furthermore, specific biomarker profile change in residual disease may have prognostic value. These findings strengthen the rationale for routine re-testing of biomarkers in residual disease after NAC.

BACKGROUND: Invasive lobular carcinoma (ILC) of the breast grows in a diffuse pattern, resulting in a high risk of positive margins at surgical resection. Oncoplastic approaches have been shown to reduce this risk, but concerns persist around the safety of immediate oncoplastic surgery for those with ILC. This study evaluated the short- and long-term oncologic outcomes of immediate oncoplastic surgery for patients with ILC. METHODS: This study retrospectively analyzed an institutional database of stages I to III ILC patients who underwent breast-conserving surgery (BCS) with or without immediate oncoplastic surgery (oncoplastic closure or oncoplastic reduction mammoplasty [ORM]). The study compared positive margin rates, rates of successful BCS, and recurrence-free survival (RFS) by type of surgery. RESULTS: For 494 patients the findings showed that the use of immediate ORM was associated with significantly lower odds of positive margins (odds ratio [OR], 0.34; 95 % confidence interval [CI], 0.17-0.66; p = 0.002). Both lumpectomy with oncoplastic closure and ORM were significantly associated with higher rates of successful BCS than standard lumpectomy (94.2 %, 87.8 %, and 73.9 %, respectively; p < 0.001). No difference in RFS was observed between those undergoing immediate oncoplastic surgery and those undergoing standard lumpectomy alone. CONCLUSIONS: The patients with stages I to III ILC who underwent immediate oncoplastic surgery had significant benefits including lower odds of positive margins and higher rates of successful BCS, with both types of immediate oncoplastic surgery showing similar RFS compared with lumpectomy alone. This supports the oncologic safety of immediate oncoplastic surgery for diffusely growing tumors such as ILC, providing it an ideal option for patients desiring BCS.

Endocrine therapies (ET) with cyclin-dependent kinase 4/6 (CDK4/6) inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of patient-derived xenografts (PDXs) from patients with 22 ER+ breast cancer demonstrated that protein kinase, membrane-associated tyrosine/threonine one (PKMYT1), a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53. In vitro the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX-derived organoids and PDXs, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.

BACKGROUND: Invasive lobular carcinoma (ILC) is the second most common subtype of breast cancer. Although mammography is known to have low sensitivity for ILC, there are no data to guide the optimal surveillance after treatment. We explored surveillance strategies after breast-conserving surgery (BCS) for ILC and determined the proportion of imaging-detected recurrences versus interval cancers. METHODS: From an institutional database of 813 women, we retrospectively identified patients who underwent BCS for stage I-III ILC and subsequently had a recurrence. We categorized patients by surveillance strategy and determined the modality of recurrence detection. Interval cancer rates for local recurrences were compared across surveillance strategies using the Chi-square test. We evaluated overall survival with the log-rank test and a Cox proportional hazards model. RESULTS: We included 58 patients with ILC who had a recurrence after BCS. Of these, 22 (37.9%) had local recurrence, 27 (46.6%) had distant recurrence, and 9 (15.5%) had both local and distant recurrence. Most patients underwent routine mammographic surveillance (65.2%), with 19.6% having supplemental breast magnetic resonance imaging (MRI) and 15.2% having no surveillance. The interval cancer rate was significantly higher in the mammographic surveillance group compared with the MRI surveillance group (61.9% vs. 16.7%; p

BACKGROUND: For patients with clinically node-positive (cN+) breast cancer undergoing neoadjuvant chemotherapy (NAC), retrieving previously clipped, biopsy-proven positive lymph nodes during sentinel lymph node biopsy [i.e., targeted axillary dissection (TAD)] may reduce false negative rates. However, the overall utilization and impact of clipping positive nodes remains uncertain. PATIENTS AND METHODS: We retrospectively analyzed cN+ ISPY-2 patients (2011-2022) undergoing axillary surgery after NAC. We evaluated trends in node clipping and associations with type of axillary surgery [sentinel lymph node (SLN) only, SLN and axillary lymph node dissection (ALND), or ALND only] and event-free survival (EFS) in patients that were cN+ on a NAC trial. RESULTS: Among 801 cN+ patients, 161 (20.1%) had pre-NAC clip placement in the positive node. The proportion of patients that were cN+ undergoing clip placement increased from 2.4 to 36.2% between 2011 and 2021. Multivariable logistic regression showed nodal clipping was independently associated with higher odds of SLN-only surgery [odds ratio (OR) 4.3, 95% confidence interval (CI) 2.8-6.8, p < 0.001]. This was also true among patients with residual pathologically node-positive (pN+) disease. Completion ALND rate did not differ based on clip retrieval success. No significant differences in EFS were observed in those with or without clip placement, both with or without successful clip retrieval [hazard ratio (HR) 0.85, 95% CI 0.4-1.7, p = 0.7; HR 1.8, 95% CI 0.5-6.0, p = 0.3, respectively]. CONCLUSION: Clip placement in the positive lymph node before NAC is increasingly common. The significant association between clip placement and omission of axillary dissection, even among patients with pN+ disease, suggests a paradigm shift toward TAD as a definitive surgical management strategy in patients with pN+ disease after NAC.

PURPOSE: To report patient outcomes and local tumor control rates in a cohort of patients with biopsy-proven HER-2 positive breast cancer treated with stereotactic radiosurgery (SRS) for brain metastases (BM). METHODS: This international, retrospective, multicenter study, included 195 female patients with 1706 SRS-treated BM. Radiologic and clinical outcomes after SRS were determined and prognostic factors identified. RESULTS: At SRS, median patient age was 55 years [interquartile range (IQR) 47.6-62.0], and 156 (80%) patients had KPS ≥ 80. The median tumor volume was 0.1 cm3 (IQR 0.1-0.5) and the median prescription dose was 16 Gy (IQR 16-18). Local tumor control (LTC) rate was 98%, 94%, 93%, 90%, and 88% at six-, 12-, 24-, 36- and 60-months post-SRS, respectively. On multivariate analysis, tumor volume (p =

ObjectiveAlthough supervised machine learning is popular for information extraction from clinical notes, creating large annotated datasets requires extensive domain expertise and is time-consuming. Meanwhile, large language models (LLMs) have demonstrated promising transfer learning capability. In this study, we explored whether recent LLMs could reduce the need for large-scale data annotations.Materials and methodsWe curated a dataset of 769 breast cancer pathology reports, manually labeled with 12 categories, to compare zero-shot classification capability of the following LLMs: GPT-4, GPT-3.5, Starling, and ClinicalCamel, with task-specific supervised classification performance of 3 models: random forests, long short-term memory networks with attention (LSTM-Att), and the UCSF-BERT model.ResultsAcross all 12 tasks, the GPT-4 model performed either significantly better than or as well as the best supervised model, LSTM-Att (average macro F1-score of 0.86 vs 0.75), with advantage on tasks with high label imbalance. Other LLMs demonstrated poor performance. Frequent GPT-4 error categories included incorrect inferences from multiple samples and from history, and complex task design, and several LSTM-Att errors were related to poor generalization to the test set.DiscussionOn tasks where large annotated datasets cannot be easily collected, LLMs can reduce the burden of data labeling. However, if the use of LLMs is prohibitive, the use of simpler models with large annotated datasets can provide comparable results.ConclusionsGPT-4 demonstrated the potential to speed up the execution of clinical NLP studies by reducing the need for large annotated datasets. This may increase the utilization of NLP-based variables and outcomes in clinical studies.

BACKGROUND: After treatment of pregnancy-associated breast cancer (PABC), some women desire future pregnancy. While safety of pregnancy after breast cancer has been demonstrated, the same cannot be said about women with PABC. OBJECTIVE: The aim of this study was to describe the incidence and outcomes of patients with PABC with subsequent pregnancies compared with those without another pregnancy. METHODS: A retrospective chart review identified patients diagnosed with breast cancer during pregnancy or within 5 years postpartum between 2011 and 2023. Patients were then screened for further pregnancy. Clinicopathologic variables, oncologic outcomes, and pregnancy outcomes were recorded. The Chi-square test and t-test were used to compare patients with subsequent pregnancy with those without. Kaplan-Meier method and log-rank test were used to estimate 5-year disease-free survival (DFS). RESULTS: Overall, 75 patients with PABC were identified, 58 of whom had PABC and no further pregnancies (NSP-PABC) and 17 with subsequent pregnancy (SP-PABC). Compared with patients with NSP-PABC, patients with SP-PABC were significantly younger (p = 0.015) and less likely to have prior pregnancies (p

BackgroundMany adolescent and young adult (AYA) patients with breast cancer (BC) receive adjuvant therapy as initial treatment, with long-term bone marrow suppression as a potential complication, but no studies have evaluated the impact of race/ethnicity on the development of bone marrow suppression in AYA BC survivors.Patients and methodsFemale patients ages 15-39 years diagnosed with BC (2006-2018) and surviving ≥ 2 years were identified from the California Cancer Registry and linked to statewide hospitalization data. We estimated the cumulative incidence of developing late effects of bone marrow suppression, such as leukopenia, anemia, thrombocytopenia, bleeding, and infection/sepsis, during hospital discharge diagnoses present ≥ 2 years after diagnosis. We examined the impact of sociodemographic and clinical factors on late effects using multivariate Cox proportional hazards regression.ResultsOf 11,293 patients, 42.8% were non-Hispanic (nH) White, 28.8% Hispanic, 19.5% nH Asian/Pacific Islander, and 7.5% nH Black. In multivariable analyses, nH Blacks had the highest risk (versus nH Whites) of anemia [hazard ratio (HR) 1.72, 95% confidence interval (CI) 1.47-2.02], leukopenia (HR 1.56, CI 1.14-2.13), thrombocytopenia (HR 1.46, CI 1.08-1.99), major infection/sepsis (HR 1.64, CI 1.4-1.92), and bleeding (HR 1.89, CI 1.39-2.58). Hispanics had a higher risk of developing anemia (HR 1.17, CI 1.04-1.32), bleeding (HR 1.4, CI 1.12-1.76), and major infections/sepsis (HR 1.36, CI 1.21-1.52). Asian/Pacific Islanders had only a higher risk of developing bleeding (HR 1.33, CI 1.03-1.72). Patients from a low neighborhood socioeconomic status had a 20% higher risk of infection/sepsis (HR 1.21, CI 1.1-1.34), but there were no associations for the other late effects.ConclusionsWe identified that AYAs of nH Black, Hispanic, and Asian/Pacific Islander race/ethnicity are at an increased risk of several late effects after adjuvant therapy compared with nH White patients. From these data, providers can implement early/frequent screening of hematologic late effects in these high-risk survivors.

BACKGROUND: The TROPiCS-02 study (NCT03901339) demonstrated that sacituzumab govitecan (SG) has superior clinical outcomes over treatment of physicians choice (TPC) chemotherapy in patients with hormone receptor-positive, human epidermal growth factor 2 receptor-negative (HR+/HER2-) metastatic breast cancer (mBC). Here, we present health-related quality of life (HRQoL) patient-reported outcome (PRO) findings from this study. PATIENTS AND METHODS: Eligible adults with HR+/HER2- mBC who previously received a taxane, endocrine-based therapy, a CDK4/6 inhibitor, and 2-4 lines of chemotherapy were randomized 1:1 to receive SG or TPC until progression or unacceptable toxicity. PROs were assessed at baseline and on day 1 of each cycle, using the European Organization for Research and Treatment of Cancer Quality-of-Life Core 30 (EORTC QLQ-C30), EQ-5D-5L, and PRO Common Terminology Criteria for Adverse Events (PRO-CTCAE). RESULTS: Compared to TPC, overall least square mean change from baseline was significantly better for SG for physical functioning and dyspnea, but worse for diarrhea. Time to first clinically meaningful worsening or death was significantly longer for SG in global health status/quality of life, physical functioning, fatigue, emotional functioning, dyspnea, insomnia, and financial difficulties of the EORTC QLQ-C30 and the EQ-VAS, but longer for TPC in diarrhea. Few patients in both arms reported experiencing any worsening to level 3 or 4 treatment-related symptomatic events during treatment, as assessed by 16 PRO-CTCAE items, except for diarrhea frequency and amount of hair loss, which favored TPC. CONCLUSIONS: SG was associated with an HRQoL benefit in most symptoms and functioning, compared with TPC. This supports the favorable profile of SG as a treatment option for patients with pretreated HR+/HER2- mBC.

BACKGROUND: The incidence of breast and colorectal cancer (CRC) in younger-than-average-age patients is rising and poorly understood. This is the largest study on patients with both cancers who are less than 60 years old and aims to characterize demographic, clinicopathologic, and genetic features and describe therapeutic dilemmas and management strategies. MATERIALS AND METHODS: This is a retrospective medical records review of patients at the University of California San Francisco with both primary breast and CRC before age 60. RESULTS: Fifty-one patients were identified; 41 had detailed medical records. Median age of diagnosis with breast cancer was 43 (range 27-59) and CRC was 50 (28-59). Most were Caucasian (38, 74.5%) and never smokers (23, 56.1%); about half were current alcohol consumers (20, 48.8%) and about one-third had sedentary jobs (14, 34.1%). Average BMI was 25.8 (range: 14-49), and 30% were overweight or obese. Breast was the first cancer diagnosed in 36 patients (70.6%) and 44 (86.3%) had a metachronous CRC diagnosis. Breast cancer was early stage (0-2) in 32 (78.0%) patients whereas CRC was split between early stage (1-2) in 14 (34.1%) and later stage (3-4) in 19 (46.2%). Ten patients (24.3%) had a known germline mutation, although 23 (56.1%) had a family history of cancer in a first-degree relative. CONCLUSION: Younger patients with both breast and CRC are a unique cohort, often without known risk factors. Alcohol consumption and sedentary jobs were the most common risk factors, and about one-quarter had a known genetic predisposition. Comanagement of both cancers requires individualized, multidisciplinary care.

Only a handful of somatic alterations have been linked to endocrine therapy resistance in hormone-dependent breast cancer, potentially explaining ∼40% of relapses. If other mechanisms underlie the evolution of hormone-dependent breast cancer under adjuvant therapy is currently unknown. In this work, we employ functional genomics to dissect the contribution of cis-regulatory elements (CRE) to cancer evolution by focusing on 12 megabases of noncoding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Parallel epigenetic perturbation (CRISPRi) in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies a limited set of noncoding changes potentially involved in therapy resistance. Overall, our data uncover how endocrine therapies trigger the emergence of transient features which could ultimately be exploited to hinder the adaptive process. Significance: This study shows that cells adapting to endocrine therapies undergo changes in the usage or regulatory regions. Dormant cells are less vulnerable to regulatory perturbation but gain transient dependencies which can be exploited to decrease the formation of dormant persisters.

PURPOSE: Patients with invasive lobular carcinoma (ILC) face high rates of positive margins and completion mastectomy, which can be improved with the use of specific techniques, such as oncoplastic surgery. However, prior studies have shown that type of breast cancer surgery performed is also associated with patient factors such as elevated body mass index (BMI). Thus, this study investigates whether BMI impacts the type of surgical interventions in patients with ILC. METHODS: A retrospective analysis of 705 patients with stage I-III ILC from an institutional database was conducted. Patients were stratified by BMI (underweight, normal weight, overweight, obese). Pearsons Chi-square, ANOVA, and multivariable logistic regression were used to evaluate the relationship between BMI and surgical procedures. RESULTS: Breast-conserving surgery (BCS) was the initial operation in 60% of patients, with no significant difference by BMI. Among those undergoing BCS, patients with obese BMI were significantly more likely to undergo oncoplastic surgery (46.9% vs. 7.7%, 37.3%, and 33.6% for underweight, normal, and overweight, respectively, p = 0.032). Obese BMI patients undergoing mastectomy were less likely to have reconstruction compared to those with underweight, normal weight, and overweight BMI (44.2% vs. 50%, 71.1%, and 64.1%, p = 0.002). CONCLUSION: Overweight/obese BMI patients with ILC underwent different surgical interventions compared to those with lower BMI. While initial BCS rates were similar, overweight/obese patients had higher oncoplastic surgery rates in BCS and lower reconstruction rates in mastectomy. Further research is needed to understand BMIs impact on surgical decisions and outcomes in ILC.