Omission of Axillary Dissection in Node Positive Breast Cancer After Neoadjuvant Systemic Therapy.

INTRODUCTION: Guidelines recommend axillary lymph node dissection (ALND) for ypN + positive patients as patients receiving neoadjuvant systemic therapy (NST) were excluded from trials omitting ALND in pN + patients. We sought to characterize trends in omission of ALND in patients with ypN + disease. METHODS: Adult women with invasive breast carcinoma in the National Cancer Database between 2012 and 2019 who received NST (chemotherapy or endocrine) and had ypN + disease were included. Patients were excluded if they did not have definitive surgery within eight months of diagnosis. The primary study outcome was completion of ALND versus omission. Differences in demographics, tumor characteristics, and treatment were identified using bivariate and multivariate logistic regression models. RESULTS: In total, 103,121 women were included. Most had cT1 (26%) or cT2 (45%) tumors, cN + disease (71%), and ductal histology (83%). 69% of patients received neoadjuvant chemotherapy and 31% neoadjuvant endocrine without chemotherapy (30% both). ALND was performed in 77% of patients. Omission of ALND became more prevalent each year from 2012 (14%) to 2019 (34%). On multivariate modeling, year of diagnosis, black race, cN status, higher grade, estrogen receptor+/HER2-receptor subtype, and mastectomy were associated with increased prevalence of ALND. Age, Charlson/Deyo comorbidity index score, endocrine versus chemotherapy, and adjuvant radiation were not associated with receipt of ALND. CONCLUSIONS: Despite guidelines recommending ALND, omission is common in patients with ypN + breast cancer after NST. Omission of ALND increased significantly over time and is associated with clinical and demographic factors. Future study is needed to determine the oncologic safety of this approach.

Analysis of Specimen Mammography with Artificial Intelligence to Predict Margin Status.

BACKGROUND: Intraoperative specimen mammography is a valuable tool in breast cancer surgery, providing immediate assessment of margins for a resected tumor. However, the accuracy of specimen mammography in detecting microscopic margin positivity is low. We sought to develop an artificial intelligence model to predict the pathologic margin status of resected breast tumors using specimen mammography. METHODS: A dataset of specimen mammography images matched with pathologic margin status was collected from our institution from 2017 to 2020. The dataset was randomly split into training, validation, and test sets. Specimen mammography models pretrained on radiologic images were developed and compared with models pretrained on nonmedical images. Model performance was assessed using sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC). RESULTS: The dataset included 821 images, and 53% had positive margins. For three out of four model architectures tested, models pretrained on radiologic images outperformed nonmedical models. The highest performing model, InceptionV3, showed sensitivity of 84%, specificity of 42%, and AUROC of 0.71. Model performance was better among patients with invasive cancers, less dense breasts, and non-white race. CONCLUSIONS: This study developed and internally validated artificial intelligence models that predict pathologic margins status for partial mastectomy from specimen mammograms. The models' accuracy compares favorably with published literature on surgeon and radiologist interpretation of specimen mammography. With further development, these models could more precisely guide the extent of resection, potentially improving cosmesis and reducing reoperations.

Diversity, equity, and inclusion in genitourinary clinical trials leading to FDA novel drug approval: An assessment of the FDA center for drug evaluation and research drug trials snapshot.

To determine the distribution of race and ethnicity among genitourinary oncology trial participants leading to FDA approval of novel molecular entities/biologics. Secondarily, we evaluated whether the proportion of Black participants in clinical trials increased over time. We quired the FDA Center for Drug Evaluation and Research Drug Trials Snapshot (DTS) between 2015 and 2020 for urologic oncology clinical trials leading to FDA approval of novel drugs. Enrollment data was stratified by race and ethnicity. Cochran-Armitage Trend tests were used to examine changes in Black patient participation over years. Nine clinical trials were identified that led to FDA approval of 5 novel molecular entities for prostate and 4 molecular entities for urothelial carcinoma treatment. Trials for prostate cancer included 5202 participants of which 69.8% were White, 4.0% Black, 11.0% Asian, 3.6% Hispanic, <1% American Indian/Alaska Native or Native Hawaiian/Pacific Islander, 3% other. Trials in urothelial carcinoma had 704 participants of which 75.1% were male, 80.8% White, 2.3% Black, 2.4% Hispanic, <1% American Indian/Alaska Native or Native Hawaiian/Pacific Islander, 5% other. Black participation rates over time did not change for urothelial (P = 0.59) or the combined cancer cohort (P = 0.29). Prostate cancer enrollment trends among Black participant declined over time (P = 0.03). Participants in genitourinary clinical trials leading to FDA approval of novel drugs are overwhelmingly white. Involving stakeholders who represent the needs and interests of underrepresented populations in the design and implementation of clinical trials of novel agents may be a strategy to increase diversity, equity, and inclusion among genitourinary clinical trials.

Computer Vision Analysis of Specimen Mammography to Predict Margin Status.

Intra-operative specimen mammography is a valuable tool in breast cancer surgery, providing immediate assessment of margins for a resected tumor. However, the accuracy of specimen mammography in detecting microscopic margin positivity is low. We sought to develop a deep learning-based model to predict the pathologic margin status of resected breast tumors using specimen mammography. A dataset of specimen mammography images matched with pathology reports describing margin status was collected. Models pre-trained on radiologic images were developed and compared with models pre-trained on non-medical images. Model performance was assessed using sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC). The dataset included 821 images and 53% had positive margins. For three out of four model architectures tested, models pre-trained on radiologic images outperformed domain-agnostic models. The highest performing model, InceptionV3, showed a sensitivity of 84%, a specificity of 42%, and AUROC of 0.71. These results compare favorably with the published literature on surgeon and radiologist interpretation of specimen mammography. With further development, these models could assist clinicians with identifying positive margins intra-operatively and decrease the rate of positive margins and re-operation in breast-conserving surgery.

Racial-ethnic variations in phyllodes tumors among a multicenter United States cohort.

BACKGROUND AND OBJECTIVES: Previous studies have identified racial-ethnic differences in the diagnostic patterns and recurrence outcomes of women with phyllodes tumors (PT). However, these studies are generally limited in size and generalizability. We therefore sought to explore racial-ethnic differences in age, tumor size, subtype, and recurrence in a large US cohort of women with PT. METHODS: We performed an 11-institution retrospective review of women with PT from 2007 to 2017. Differences in age at diagnosis, tumor size and subtype, and recurrence-free survival according to race-ethnicity. RESULTS: Women of non-White race or Hispanic ethnicity were younger at the time of diagnosis with phyllodes tumor. Non-Hispanic Other women had a larger proportion of malignant PT. There were no differences in recurrence-free survival in our cohort. CONCLUSIONS: Differences in age, tumor size, and subtype were small. Therefore, the workup of young women with breast masses and the treatment of women with PT should not differ according to race-ethnicity. These conclusions are supported by our finding that there were no differences in recurrence-free survival.

Molecular classification and biomarkers of clinical outcome in breast ductal carcinoma in situ: Analysis of TBCRC 038 and RAHBT cohorts.

Ductal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We perform multiscale, integrated molecular profiling of DCIS with clinical outcomes by analyzing 774 DCIS samples from 542 patients with 7.3 years median follow-up from the Translational Breast Cancer Research Consortium 038 study and the Resource of Archival Breast Tissue cohorts. We identify 812 genes associated with ipsilateral recurrence within 5 years from treatment and develop a classifier that predicts DCIS or IBC recurrence in both cohorts. Pathways associated with recurrence include proliferation, immune response, and metabolism. Distinct stromal expression patterns and immune cell compositions are identified. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.

Omission of Radiation in Conservative Treatment for Breast Cancer: Opportunity for De-escalation of Care.

INTRODUCTION: De-escalation of breast cancer treatment aims to reduce patient and financial toxicity without compromising outcomes. Level I evidence and National Comprehensive Cancer Network guidelines support omission of adjuvant radiation in patients aged >70 y with hormone-sensitive, pT1N0M0 invasive breast cancer treated with endocrine therapy. We evaluated radiation use in patients eligible for guideline concordant omission of radiation. METHODS: Subgroup analysis of patients eligible for radiation omission from two pooled randomized controlled trials, which included stage 0-III breast cancer patients undergoing breast conserving surgery, was performed to evaluate factors associated with radiation use. RESULTS: Of 631 patients, 47 (7.4%) met radiation omission criteria and were treated by 14 surgeons at eight institutions. The mean age was 75.3 (standard deviation + 4.4) y. Majority of patients identified as White (n = 46; 97.9%) and non-Hispanic (n = 44; 93.6%). The mean tumor size was 1.0 cm; 37 patients (88.1%) had ductal, 4 patients (9.5%) had lobular, and 17 patients (40.5%) had low-grade disease. Among patients eligible for radiation omission, 34 (72.3%) patients received adjuvant radiation. Those who received radiation were significantly younger than those who did not (74 y, interquartile range = 4 y, versus 78 y, interquartile range = 11 y, P = 0.03). There was no difference in radiation use based on size (P = 0.4), histology (P = 0.5), grade (P = 0.7), race (P = 1), ethnicity (P = 0.6), institution (P = 0.1), gender of the surgeon (P = 0.7), or surgeon (P = 0.1). CONCLUSIONS: Fewer than 10% of patients undergoing breast conservation met criteria for radiation omission. Nearly three-quarters received radiation therapy with younger age being a driver of radiation use, suggesting ample opportunity for de-escalation, particularly among younger eligible patients.

Pathologic complete response and survival after neoadjuvant chemotherapy in cT1-T2/N0 HER2+ breast cancer.

Women with small HER2+ breast cancers may have excellent prognosis with adjuvant single-agent chemotherapy and HER2-targeted therapy. The role of de-escalated therapy in the neoadjuvant setting, however, remains uncertain. We conducted a cohort study of adult women with T1-2/cN0 HER2+ breast cancer diagnosed 2013-2016 in the National Cancer Database treated with neoadjuvant chemotherapy (NAC) and HER2-targeted therapy. Factors associated with pathologic complete response (pCR) and overall survival were examined. In total, 6994 patients were included, 32% cT1 and 68% cT2. Multi-agent NAC was given to 90% of women while single-agent NAC was given to 10% of women. pCR was achieved in 46% of cT2 patients and 43% of cT1, and in 46% of patients treated with multi-agent versus 38% single agent. Patients receiving multi-agent chemotherapy were younger, had fewer comorbidities, and had higher cT stage and grade. In all patients, pCR was associated with improved survival (p < 0.01). Multi-agent chemotherapy (OR 1.3, p = 0.003), hormone receptor negative (OR 2.6, p < 0.001), higher grade (OR 2.2, p < 0.001), younger age (OR 1.4, p = 0.011), and later year of diagnosis (OR 1.3, p = 0.005) were associated with achieving pCR. Multi-agent chemotherapy was associated with higher likelihood of pCR, but this effect was modest compared to other factors. Single-agent NAC with HER2-directed therapy in selected patients may provide excellent outcome with reduced toxicity, while allowing escalated therapy in the adjuvant setting for patients with residual disease. Prospective studies are needed to determine effects of de-escalation in the neoadjuvant setting on survival and optimal selection strategies.

The impact of age and nodal status on variations in oncotype DX testing and adjuvant treatment.

Oncotype DX (ODX) recurrence score (RS) is a validated tool to guide the use of adjuvant chemotherapy (AC) in hormone receptor+/HER2- breast cancer. In this analysis, we examine (1) characteristics associated with ODX testing and (2) the association between ODX RS and receipt of AC across age and nodal status. Women with HR+/HER2-, early-stage (T1-2, N0-1) breast cancers from 2010-2017 in the National Cancer Database were included. 530,125 met inclusion and 255,971 received ODX testing. Older women were less likely to receive testing; however, nodal positivity increased use of testing. High ODX RS was associated with increased mortality, though the association was not consistent across age and was most strongly associated with mortality among younger, node-negative women. Older women with high ODX RS, regardless of nodal status, were less likely to receive AC. Clinicians may be employing ODX RS to support treatment decisions against the receipt of AC.

Prospective Evaluation of Radar-Localized Reflector-Directed Targeted Axillary Dissection in Node-Positive Breast Cancer Patients after Neoadjuvant Systemic Therapy.

BACKGROUND: This is a prospective, single-institution study to evaluate feasibility and accuracy of radar-localized reflector (RLR)-targeted axillary dissection (TAD) in node-positive breast cancer patients after neoadjuvant systemic therapy (NST). METHODS: Patients with biopsy-proven T1-2, N1-3 disease were eligible. Before NST, a marker clip and/or RLR was placed into the positive node. After NST, RLR was inserted if not placed previously. All patients underwent RLR TAD followed by axillary lymph node dissection (ALND). Primary end points of the trial were feasibility of RLR TAD and false negative rate (FNR). RESULTS: Between 2017 and 2021, 101 patients with N1-3 disease underwent NST. Five patients withdrew from the study, 1 was ineligible, and there were 9 technical failures, thus our final study cohort comprised 86 patients. RLR TAD was performed with probe guidance and confirmed with intraoperative specimen radiograph. After RLR TAD, ALND was performed. Median number of RLR TAD nodes removed was 2 (range 1-10), and the RLR TAD nodes remained positive in 56 patients. Median number of ALND nodes removed was 18 (range 4-46). Accounting for 9 technical failures, feasibility was 90%. All technical failures occurred with attempted placement of RLR after NST. Feasibility rate was 100% when RLR placement occurred at diagnosis. Of the evaluable 86 patients, RLR TAD accurately predicted axillary status in 83 patients, with FNR of 5.1%. CONCLUSION: We demonstrate high accuracy of RLR TAD, especially when RLR is placed before NST. For patients who present with N1-3 disease, this is another step towards axillary surgery de-escalation strategies.

Non-oncology clinical trial engagement in a nationally representative sample: Identification of motivators and barriers.

BACKGROUND: Enrollment in non-oncology clinical trials is often challenging and social determinants that may serve as motivators or barriers to clinical trial enrollment are largely unexplored. We sought to assess engagement in non-oncology clinical trials with a focus on social determinants of health as barriers or motivators toward participation. METHODS: A cross-sectional analysis of non-cancer respondents was conducted using the Health Information National Trends Survey (HINTS) administered in 2020. Our analytic cohort was comprised of respondents with no reported history of cancer. Our primary outcome of interest was trial engagement defined as receiving an invitation to participate in a clinical trial. Secondary outcomes included participation in a clinical trial and reported motivators and barriers to clinical trial participation. RESULTS: A total of 3113 respondents with no reported history of cancer were included. Overall, 8.1% of respondents reported being invited to participate in a clinical trial. Amongst those invited to participate, 47.7% reported participating in a clinical trial. Respondents reported that clinical trial participation was motivated "somewhat" or "a lot" by "wanting to get better" (80.5%), "helping other people" (61.4%), "physician encouragement" (60.6%), "getting a chance to try new care" (60.2%), "family friend encouragement" (54.2%), or "getting paid" (50.0%). Overall, 82.5% of all respondents "don't know anything" or have "a little knowledge" about clinical trials. Reported barriers to clinical trial participation including getting transportation, childcare or paid time off work (48.4%) and standard of care not covered by insurance (62.0%) influenced the decision to participate "somewhat" or "a lot." CONCLUSION: Amongst a nationally representative sample, non-oncology clinical trial invitation is low, but participation amongst those invited is nearly 50%. This highlights the need for clinician engagement in clinical trials. Identifying modifiable social determinants of non-oncologic clinical trial participation may help promote improved engagement.

Sociodemographic and Clinical Predictors of Neoadjuvant Chemotherapy in cT1-T2/N0 HER2-Amplified Breast Cancer.

BACKGROUND: The optimal treatment strategy for small node-negative human epidermal growth factor receptor 2-positive (HER2+) breast cancer remains controversial. Neoadjuvant chemotherapy may risk overtreatment, whereas surgery first fails to identify patients with residual disease in need of escalated adjuvant systemic therapy. We investigated patient characteristics associated with receipt of neoadjuvant chemotherapy. METHODS: Adult women with cT1-T2/N0, HER2+ breast cancer between 2013 and 2017 in the National Cancer Database who underwent surgery within 8 months of diagnosis were included. Patients were classified as receiving neoadjuvant chemotherapy versus a surgery-first approach. We assessed the sociodemographic and clinical predictors of neoadjuvant chemotherapy versus surgery first and associations between neoadjuvant chemotherapy and breast cancer treatments using multivariable regression models. RESULTS: We identified 56,784 women, of whom 12,758 (22%) received neoadjuvant chemotherapy, 29,139 (53%) received adjuvant chemotherapy, 12,907 (24%) received no chemotherapy, and 1980 were missing chemotherapy information. After adjustment, cT2 stage was the strongest predictor of neoadjuvant chemotherapy compared with surgery first. Younger age and later diagnosis year were positively associated with receipt of neoadjuvant chemotherapy. In contrast, hormone receptor positivity, Black race, rural county, and government-funded or no health insurance were inversely associated with neoadjuvant chemotherapy. In multivariable analyses, patients who received neoadjuvant chemotherapy were more likely to have a mastectomy (vs. lumpectomy) and sentinel lymph node biopsy or no nodal surgery (vs. axillary lymph node dissection). Patients who received neoadjuvant chemotherapy were more likely to receive multi-agent (vs. single-agent) chemotherapy than those who received adjuvant chemotherapy. CONCLUSIONS: Substantial differences in the utilization of neoadjuvant chemotherapy exist in women with HER2+ breast cancer, which reflect both clinical parameters and disparities. Optimal treatment strategies should be implemented equitably across sociodemographic groups.

Bridging Endocrine Therapy for HR+/HER2- Resectable Breast Cancer: Is it Safe?

BACKGROUND: The COVID-19 pandemic has required new treatment paradigms to limit exposures and optimize hospital resources, including the use of neoadjuvant endocrine therapy (NAET) as bridging therapy for HR+/HER2-invasive tumors and DCIS. While this approach has been used in locally advanced disease, it is unclear how it may affect outcomes in resectable HR+/HER2- tumors. METHODS: Women ≥18 years diagnosed with in situ (Tis) or non-metastatic HR+/HER2- breast cancer from March-May 2019 and 2020 were included. Fisher's exact test and two-sample t test were used to compare baseline characteristics and surgical outcomes between strata. Sub-analysis was performed between patients who received primary surgery vs a bridging NAET approach. RESULTS: Despite similar clinical characteristics, patients in 2019 were more likely to have a surgery-first approach (75% vs 42%, P-value = .0007), receive surgery sooner (22 vs 29 days, P-value < .001), and within 60 days from diagnosis date (100% vs 85%, P-value = .0301). Neoadjuvant endocrine therapy was a more prevalent approach in 2020 (48% vs 7%, P-value < .0001). Rates of clinical to pathologic up-staging remained consistent across primary surgery vs bridging NAET subgroups (P-value = .9253). DISCUSSION: Pandemic-driven treatment protocols provide a unique opportunity to assess the utility of bridging endocrine therapy for resectable HR+/HER2- tumors. Differences in clinical and pathologic staging were similar across groups and did not appear to be affected by receipt of NAET. Our limited cohort demonstrates this strategic therapeutic avenue can optimize health care utilization and may be a reasonable approach when delaying surgery is preferred.

Are we choosing wisely? Drivers of preoperative MRI use in breast cancer patients.

INTRODUCTION: Factors contributing to the use of preoperative MRI remain poorly understood. METHODS: Data from a randomized controlled trial of stage 0-3 breast cancer patients undergoing breast conserving surgery between 2016 and 2018 were analyzed. RESULTS: Of the 396 patients in this trial, 32.6% had a preoperative MRI. Patient age, race, ethnicity, tumor histology, and use of neoadjuvant therapy were significant predictors of MRI use. On multivariate analysis, younger patients with invasive lobular tumors were more likely to have a preoperative MRI. Rates also varied significantly by individual surgeon (p < 0.001); in particular, female surgeons (39.9% vs. 24.0% for male surgeons, p = 0.001) and those in community practice (58.9% vs. 14.2% for academic, p < 0.001) were more likely to order preoperative MRI. Rates declined over the two years of the study, particularly among female surgeons. CONCLUSIONS: Preoperative MRI varies with patient age and tumor histology; however, there remains variability by individual surgeon.

Factors Affecting Time to Surgery in Breast Cancer Patients.

BACKGROUND: We sought to determine factors affecting time to surgery (TTS) to identify potential modifiable factors to improve timeliness of care. METHODS: Patients with clinical stage 0-3 breast cancer undergoing partial mastectomy in 2 clinical trials, conducted in ten centers across the US, were analyzed. No preoperative workup was mandated by the study; those receiving neoadjuvant therapy were excluded. RESULTS: The median TTS among the 583 patients in this cohort was 34 days (range: 1-289). Patient age, race, tumor palpability, and genomic subtype did not influence timeliness of care defined as TTS ≤30 days. Hispanic patients less likely to have a TTS ≤30 days (P = .001). There was significant variation in TTS by surgeon (P < .001); those practicing in an academic center more likely to have TTS ≤30 days than those in a community setting (55.1% vs 19.3%, P < .001). Patients who had a preoperative ultrasound had a similar TTS to those who did not (TTS ≤30 days 41.9% vs 51.9%, respectively, P = .109), but those who had a preoperative MRI had a significantly increased TTS (TTS ≤30 days 25.0% vs 50.9%, P < .001). On multivariate analysis, patient ethnicity was no longer significantly associated with TTS ≤30 (P = .150). Rather, use of MRI (OR: .438; 95% CI: .287-.668, P < .001) and community practice type (OR: .324; 95% CI: .194-.541, P < .001) remained independent predictors of lower likelihood of TTS ≤30 days. CONCLUSIONS: Preoperative MRI significantly increases time to surgery; surgeons should consider this in deciding on its use.

Dosimetric and Clinical Factors Associated With Breast Reconstruction Complications in Patients Receiving Postmastectomy Radiation.

PURPOSE: Approximately 30% of women who receive postmastectomy radiation therapy in the setting of breast reconstruction suffer from reconstruction complications. This study aims to assess clinical and dosimetric factors associated with the risk of reconstruction complications after postmastectomy radiation therapy, with the ultimate goal of identifying a dosimetric constraint that can be used clinically to limit this risk. METHODS AND MATERIALS: We retrospectively identified 41 patients who underwent a modified radical or total mastectomy, followed by immediate or delayed reconstruction (autologous or implant-based) and radiation at a single institution between 2014 and 2020. Reconstruction complications were defined as a flap or implant failure, necrosis, capsular contracture, cellulitis/infection, implant rupture, implant malposition, leakage/rupture, unplanned operation, and hematoma/seroma. Clinical and dosimetric variables associated with complications were assessed with univariate analyses. RESULTS: Twelve patients (29%) suffered reconstruction complications, which led to a flap or implant failure in 5 patients. The median time to complication after reconstruction was 8 months. Thirty-two percent of patients with immediate and 20% with delayed reconstruction suffered a complication, respectively. There were no local failures. Smoking (P = .02), use of bolus (P = .03), and the percentage of the chest wall/reconstructed breast target volume that received ≥107% of the prescribed radiation dose (V107) > 11% (P = .03) were associated with increased complication rates. The complication rates were 42% when V107 > 11% versus 12% when V107 < 11%; 58% in smokers versus 17% in nonsmokers; and 42% with versus 7% without bolus. CONCLUSIONS: Plan heterogeneity appears to be associated with the risk of reconstruction complications. Pending further validation, V107 < 11% may serve as a reasonable guide to limit this risk. Further consideration should be given to the selective use of bolus in this setting and optimization of clinical factors, such as smoking cessation.

Suboptimal therapy following breast conserving surgery in triple-negative and HER2-positive breast cancer patients.

PURPOSE: To assess potential disparities in guideline-concordant care delivery among women with early-stage triple-negative and HER2-positive breast cancer treated with breast conserving therapy. METHODS: Women ≥ 40 years old diagnosed with pT2N0M0 triple-negative or HER2-positive breast cancer treated with primary surgery and axillary staging between 2012 and 2017 were identified using the National Cancer Database (NCDB). The primary outcome was receipt of adjuvant systemic therapy and radiation concordant with current guidelines. Multivariable log-binomial regression was used to assess the prevalence of optimal therapy use across patient and cancer characteristics. Kaplan-Meier curves were used to assess 5-year overall survival. Multivariable Cox proportional hazards regression was used to compare the impact of optimal therapy on 5-year mortality. RESULTS: 11,785 women were included with 7,843 receiving optimal therapy. Receipt of optimal therapy decreased with age even after adjusting for comorbidities and cancer characteristics; other sociodemographic factors were not associated with differences in receipt of optimal therapy. Among patients who did not receive adjuvant systemic therapy, most were not offered the treatment (49%) or refused (40%). Overall 5-year survival was higher among women who received optimal therapy (89% [95% CI 88.0-89.3] vs. 66% [95% CI 62.9-68.5]). Patients who received suboptimal therapy were over twice as likely to die within 5 years of their diagnosis (adjusted HR 2.44, 95% CI 2.12-2.82). CONCLUSION: Age is the primary determinant of the likelihood of a woman to receive optimal adjuvant therapies in high-risk early-stage breast cancer. Patients who did not receive optimal therapy had significantly diminished survival.

FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036.

Inhibition of the HER2/ERBB2 receptor is a keystone to treating HER2-positive malignancies, particularly breast cancer, but a significant fraction of HER2-positive (HER2+) breast cancers recur or fail to respond. Anti-HER2 monoclonal antibodies, like trastuzumab or pertuzumab, and ATP active site inhibitors like lapatinib, commonly lack durability because of adaptive changes in the tumor leading to resistance. HER2+ cell line responses to inhibition with lapatinib were analyzed by RNAseq and ChIPseq to characterize transcriptional and epigenetic changes. Motif analysis of lapatinib-responsive genomic regions implicated the pioneer transcription factor FOXA1 as a mediator of adaptive responses. Lapatinib in combination with FOXA1 depletion led to dysregulation of enhancers, impaired adaptive upregulation of HER3, and decreased proliferation. HER2-directed therapy using clinically relevant drugs (trastuzumab with or without lapatinib or pertuzumab) in a 7-day clinical trial designed to examine early pharmacodynamic response to antibody-based anti-HER2 therapy showed reduced FOXA1 expression was coincident with decreased HER2 and HER3 levels, decreased proliferation gene signatures, and increased immune gene signatures. This highlights the importance of the immune response to anti-HER2 antibodies and suggests that inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting is a potential therapeutic strategy.