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Background: Triple-negative breast cancer (TNBC) is the subtype of breast cancer with the worst prognosis and is the subtype most often associated with germline mutations of BRCA1 as well as other genes. Alpha-lactalbumin (aLA) is a milk protein expressed in lactating breasts but not at other times or in other normal tissues. Expression of aLA is found in approximately 70% of TNBC (Cancers PMID: 27322324) so is an attractive immunologic target for TNBC based on the “retired protein hypothesis” (Semin Immunol PMID: 31926646). Pre-clinical studies have shown that vaccination with aLA inhibits the growth of established breast tumors and provides potent protection from development of autochthonous tumors in transgenic murine models of breast cancer and against 4T1 transplantable breast cancer in BALB/c mice (Nat Med PMID: 20512124). Specific Aims: We are conducting a Phase I trial of vaccination with an aLA vaccine in patients with early stage TNBC to demonstrate the safety of this approach and to document the ability to produce a relevant immunologic response to aLA. Trial Design: Patients are being entered into a Phase I trial of alpha-lactalbumin with GMP-grade zymosan adjuvant in Montanide ISA 51 VG vehicle. Subjects receive a total of 3 vaccinations administered once every 2 weeks. Toxic events of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or greater are considered dose-limiting. Dose levels being tested in the current protocol are alpha-lactalbumin/zymosan 0.01/0.01, 0.1/0.01, 0.5/0.01, 0.5/0.03, and 0.5 mg/0.06 mg. Patients are being monitored for toxicity until 84 days after the first vaccination or resolution of toxicity, whichever is later. Blood is being drawn prior to therapy and 14, 28, and 56 days after the first vaccination to assess cellular response using enzyme-linked immunosorbent spot (ELISpot) assays of interferon-gamma and interleukin-17 production in response to aLA. Humoral response to aLA vaccination is being assessed by enzyme-linked immunosorbent assay (ELISA). Eligibility Criteria: Patients with ER-negative, PR-negative, HER2-negative breast cancer of pathologic stage II-III or who had residual disease after standard pre-operative systemic therapy. Participants must be within 3 years of initiation of treatment and have no evidence of recurrence. Dose Selection: Doses are being escalated using a 3+3 trial design to determine the maximum tolerated dose, the lowest immunologic dose and the optimal immunologic dose Present Accrual and Target Accrual: Dependent on toxicity, 18-30 patients will be treated. Future Plans and Contact Information: After identification of the maximum tolerated dose and expansion of the dose levels associated with effective tumor immunity we plan to enroll 2 additional cohorts of patients: 1) patients who have completed pre-operative chemo-immunotherapy and are receiving pembrolizumab as standard of care therapy, and 2) patients without cancer planning to undergo prophylactic bilateral mastectomy. Interested parties may contact Dr. Budd at buddg@ccf.org. Funding Source: Department of Defense (W81XWH-17-1-0592 and W81XWH-17-1-0593) Citation Format: George Budd, Justin M. Johnson, Emily Rhoades, Halle Moore, Megan L. Kruse, Erin Roesch, Jame Abraham, Brenna Elliott, Elena Haury, Vincent K. Tuohy. Phase I trial of an alpha-lactalbumin vaccine in patients with operable triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-10-02.

Treatment advances have improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer (eBC) but certain patients remain at high risk of recurrence. Neoadjuvant therapy (NAT) has comparable outcomes to adjuvant therapy with the advantage of surgical down-staging, response assessment, informing prognosis, and tailoring adjuvant treatment. Thus, the standard of care for the majority of HER2-positive eBC has become a combination of chemotherapy and HER2-targeted agents given in the neoadjuvant setting.Mounting evidence suggests that pathologic complete response after NAT translates to a favorable long-term prognosis. The efficacy and tolerability of post-NAT are key, particularly for patients with residual disease. This is demonstrated, for example, by the use of trastuzumab emtansine in the appropriate clinical setting and various new drugs under investigation. This review summarizes the current clinical management and exciting future directions to optimize outcomes in HER2-positive eBC.Targeted therapies such as trastuzumab deruxtecan, tucatinib, and immunotherapy have demonstrated impressive responses in metastatic breast cancer, including CNS disease. Incorporating these agents in the post-neoadjuvant space may improve the prognosis of HER2-positive eBC. Future research should prioritize the identification of biomarkers that personalize treatments to achieve maximum benefit and less toxicity.

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. These NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of ductal carcinoma in situ and the workup and locoregional management of early stage invasive breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visitNCCN.org.

Background: CDK 4/6 inhibitors (CDKI) with Endocrine therapy (ET) is mainstay treatment for hormone receptor-positive (HR+) Her2- metastatic breast cancer (MBC). Despite excellent efficacy, most patients develop resistance to CDKI limiting its utility. CDK4/6 are thought to act by upregulating VEGF causing tortuous angiogenesis and promoting cancer progression. Recent studies have shown aggressive tumors possess a higher density and tortuous vasculature. In this study, we evaluated if vascular radiomic features computationally extracted from liver CT scans pre- and post CDKI treatment could predict patient survival and treatment response. Method: From a registry of 350 patients on treatment with CDKI at institution 1(S1), 51 pts with HR+, Her2-, MBC patients with evidence of liver mets and disease progression (PFS) data were identified. 30 pts discontinued treatment due to progression or death, with a median time to progression of 195 days. Pre-treatment and first post-treatment CT exams were analyzed from 25 and 34 patients, respectively. Median time between scans was 128 days. To validate the prognostic value of our signature, a cohort of 29 patients with available OS data was identified from institution 2 (S2). A publicly available pre-trained deep learning model was applied to isolate liver metastases and vessels. Next, fast marching algorithm was applied to reduce vessels to their centerlines and divide the vasculature into constituent branches. 7 quantitative metrics were computed measuring vascularity of metastases and 3-D shape of hepatic vessels. First, the number (f1) and percentage (f2) of hepatic vessels arising from the tumor were computed. Vessel tortuosity - measuring the degree of twisting across a vessel - was computed separately for each branch. The mean (f3), standard deviation (f4), maximum (f5), skewness (f6), and kurtosis (f7) tortuosity values were calculated to summarize these measurements at patient level. The features were individually assessed at pre- and post-treatment for association with PFS at S1 in univariable Cox proportional hazards models. Features found to be associated in S1 were evaluated for association with OS in S2. Results: On the initial post-treatment scan, features of both tumor vascularization (f6 - HR=1.115 [1.039-1.196]; f7 - HR=10.646 [2.539-44.641]), as well as two features of vessel tortuosity (f3 - HR=0.011 [0.001-0.199]; f4 - HR=0.545 [0.313-0.949]) were significantly associated with PFS. Both tortuosity features were also significantly associated with OS in S2 (f3 - HR=0.085 [0.009-0.780]; f4 - HR=0.331 [0.130-0.842]). In addition the percentage (f7 - HR=6.445 [2.001-20.753]]),of vessels feeding the lesions was also significant in S2 while the number (f6 - HR=1.070 [0.966-1.184]), of vessels was not. No vessel metrics from the pre-treatment baseline exam were significantly associated with OS. Conclusions: Radiomic analysis of tumor vascularity and vessel tortuosity on CT scans post-CDK treatment was associated with patient survival and treatment response. Table 1.Association of vessel features with PFS in Institution 1(S1)and OS in Institution 2(S2)S1- Pretreatment CT (n=25)S1 - Post-Treatment CT (n=34)S2 - Post-treatment CT - Validation (n=29)f1Tortuosity - Mean0.9912702470.852294696–f2Tortuosity - St. Dev0.7563942230.273115373–f3Tortuosity - Max0.1387051870.0022517550.02931473f4Tortuosity - Skewness0.254463710.0318270370.02022882f5Tortuosity - Kurtosis0.3058266760.108967601–f6Number of vessels feeding lesions0.419096650.0025747910.19306052f7Percentage of vessels feeding lesions0.0517942660.0012205950.00179103 Citation Format: Vidya Sankar Viswanathan, Nathaniel Braman, Priyanka Reddy, Siddharth Kunte, Jame Abraham, Alberto J Montero, Anant Madabhushi. Post-treatment vascularity and vessel shape are associated with survival and response to CDK4/6 inhibitors in hormone receptor-positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-27.

Supplementary Data from Novel Radiomic Measurements of Tumor-Associated Vasculature Morphology on Clinical Imaging as a Biomarker of Treatment Response in Multiple Cancers

Purpose:The tumor-associated vasculature (TAV) differs from healthy blood vessels by its convolutedness, leakiness, and chaotic architecture, and these attributes facilitate the creation of a treatment-resistant tumor microenvironment. Measurable differences in these attributes might also help stratify patients by likely benefit of systemic therapy (e.g., chemotherapy). In this work, we present a new category of computational image-based biomarkers called quantitative tumor-associated vasculature (QuanTAV) features, and demonstrate their ability to predict response and survival across multiple cancer types, imaging modalities, and treatment regimens involving chemotherapy.Experimental Design:We isolated tumor vasculature and extracted mathematical measurements of twistedness and organization from routine pretreatment radiology (CT or contrast-enhanced MRI) of a total of 558 patients, who received one of four first-line chemotherapy-based therapeutic intervention strategies for breast (n = 371) or non–small cell lung cancer (NSCLC, n = 187).Results:Across four chemotherapy-based treatment strategies, classifiers of QuanTAV measurements significantly (P < 0.05) predicted response in held out testing cohorts alone (AUC = 0.63–0.71) and increased AUC by 0.06–0.12 when added to models of significant clinical variables alone. Similarly, we derived QuanTAV risk scores that were prognostic of recurrence-free survival in treatment cohorts who received surgery following chemotherapy for breast cancer [P = 0.0022; HR = 1.25; 95% confidence interval (CI), 1.08–1.44; concordance index (C-index) = 0.66] and chemoradiation for NSCLC (P = 0.039; HR = 1.28; 95% CI, 1.01–1.62; C-index = 0.66). From vessel-based risk scores, we further derived categorical QuanTAV high/low risk groups that were independently prognostic among all treatment groups, including patients with NSCLC who received chemotherapy only (P = 0.034; HR = 2.29; 95% CI, 1.07–4.94; C-index = 0.62). QuanTAV response and risk scores were independent of clinicopathologic risk factors and matched or exceeded models of clinical variables including posttreatment response.Conclusions:Across these domains, we observed an association of vascular morphology on CT and MRI—as captured by metrics of vessel curvature, torsion, and organizational heterogeneity—and treatment outcome. Our findings suggest the potential of shape and structure of the TAV in developing prognostic and predictive biomarkers for multiple cancers and different treatment strategies.

Supplementary Materials and Methods, Supplementary Figures S1-S4, and Supplementary Tables S1-S9

Purpose: The purpose of this study is to predict breast cancer recurrence and metastases and to identify gene signatures indicative of clinicopathologic characteristics using gene expression patterns derived from cDNA microarray.Experimental Design: Expression profiles of 7,650 genes were investigated on an unselected group of 99 node-negative and node-positive breast cancer patients to identify prognostic gene signature of recurrence and metastases. The identified gene signature was validated on independent 78 patients with primary invasive carcinoma (T1/T2 and N0) and on 58 patients with locally advanced breast cancer (T3/T4 and/or N2). The gene predictors were identified using a combination of random forests and linear discriminant analysis function.Results: This study identified a new 28-gene signature that achieved highly accurate disease-free survival and overall survival (both at P < 0.001, time-dependent receiver operating characteristic analysis) in individual breast cancer patients. Patients categorized into high-risk, intermediate-risk, and low-risk groups had distinct disease-free survival (P < 0.005, Kaplan-Meier analysis, log-rank test) in three patient cohorts. A strong association (P < 0.05) was identified between risk groups and tumor size, tumor grade, estrogen receptor and progesterone receptor status, and HER2/neu overexpression in the studied cohorts. We also identified 14-gene predictors of nodal status and 9-gene predictors of tumor grade.Conclusions: This study has established a population-based approach to predicting breast cancer outcomes at the individual level exclusively based on gene expression patterns. The 28-gene recurrence signature has been validated as quantifying the probability of recurrence and metastases in patients with heterogeneous histology and disease stage.

Purpose: P-glycoprotein (Pgp) antagonists have had unpredictable pharmacokinetic interactions requiring reductions of chemotherapy. We report a phase I study using tariquidar (XR9576), a potent Pgp antagonist, in combination with vinorelbine.Experimental Design: Patients first received tariquidar alone to assess effects on the accumulation of 99mTc-sestamibi in tumor and normal organs and rhodamine efflux from CD56+ mononuclear cells. In the first cycle, vinorelbine pharmacokinetics was monitored after the day 1 and 8 doses without or with tariquidar. In subsequent cycles, vinorelbine was administered with tariquidar. Tariquidar pharmacokinetics was studied alone and with vinorelbine.Results: Twenty-six patients were enrolled. Vinorelbine 20 mg/m2 on day 1 and 8 was identified as the maximum tolerated dose (neutropenia). Nonhematologic grade 3/4 toxicities in 77 cycles included the following: abdominal pain (4 cycles), anorexia (2), constipation (2), fatigue (3), myalgia (2), pain (4) and dehydration, depression, diarrhea, ileus, nausea, and vomiting, (all once). A 150-mg dose of tariquidar: (1) reduced liver 99mTc-sestamibi clearance consistent with inhibition of liver Pgp; (2) increased 99mTc-sestamibi retention in a majority of tumor masses visible by 99mTc-sestamibi; and (3) blocked Pgp-mediated rhodamine efflux from CD56+ cells over the 48 hours examined. Tariquidar had no effects on vinorelbine pharmacokinetics. Vinorelbine had no effect on tariquidar pharmacokinetics. One patient with breast cancer had a minor response, and one with renal carcinoma had a partial remission.Conclusions: Tariquidar is a potent Pgp antagonist, without significant side effects and much less pharmacokinetic interaction than previous Pgp antagonists. Tariquidar offers the potential to increase drug exposure in drug-resistant cancers.

Supplementary Data from A Phase I Study of the P-Glycoprotein Antagonist Tariquidar in Combination with Vinorelbine

Purpose: There are case reports of patients with both primary breast cancer (BC) and renal cell carcinoma (RCC). We explore the association between these two malignancies using SEER population data and our institutional records.Methods: We studied the association between BC and RCC in the 2000-2016 Surveillance, Epidemiology and End Results (SEER) database. We then reviewed our hospital records of patients with both BC and RCC and collected information including personal and family history of cancers, genetic testing, and patient outcomes.Results: Of the 813,477 females diagnosed with BC in the SEER database, 1,914 later developed RCC. The risk of developing RCC was significantly increased within the first six months, 7-12 months, and 1-5 years following BC diagnosis with standardized incidence ratios (SIRs) of 5.08 (95% CI, 4.62- 5.57), 2.09 (95% CI, 1.8-2.42), and 1.15 (95% CI, 1.06-1.24), respectively. Of 56,200 females with RCC, 1,087 later developed BC. The risk of developing BC following RCC was elevated within the first six months (SIR of 1.45 [95% CI, 1.20-1.73]). For our hospital patients, 437 had both BC and RCC. 427 (97.71%) were female, and 358 (81.92%) were white, and breast cancer was diagnosed before RCC in 246 (61.5%) patients. There were 15 germline mutations in those with genetic testing. Conclusion:Our findings suggest that BC patients are at higher risk of developing RCC and vice versa. BC tended to precede RCC, and patients frequently had personal histories of other malignancies and a family history of cancer, particularly BC.

Background The combination of Cyclin-dependent kinase 4/6 inhibitors (CDKi) and endocrine therapy (ET) is the standard of care for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Currently, there are no robust biomarkers that can predict response to CDKi, and so far, it is not clear which patients benefit from this therapy. Because MBC patients with liver metastases have a poorer prognosis and are consequently often treated with chemotherapy rather than endocrine therapy, developing predictive biomarkers that could identify patients likely to respond to CDKi is clinically important. We hypothesized that changes (“delta”) in the radiomic texture patterns on CT scans both within and outside metastatic liver lesions before and after CDKi therapy are associated with overall survival (OS) and can accurately assess early response to CDKi therapy. Methods From a retrospective patient registry, 73 HR + MBC patients with known liver metastases who received palbociclib (palbo) plus ET were identified from two different academic sites. One site was used as a training set (n = 32), while the other as a validation set (n = 41). Patients with objective response/stable disease per RECIST v1.1 were defined as ‘responders’, and those with progressive disease within 6 months were labelled ‘non-responders’. Radiomic texture and shape features measuring subtle differences in lesion heterogeneity and size on a pixel level were extracted from pre-treatment and post-treatment CT scans within the lesions measured for RECIST assessment, and the difference (delta) radiomic features were computed. Delta radiomic features were selected by least absolute shrinkage and selection operator with the Cox regression model within the training set and top selected features along with their corresponding coefficients were used for radiomic risk score (RRS) construction. The RRS was further evaluated for association with OS within the validation set. Patients were stratified into low and high-risk groups based on an ideal threshold of RRS identified in the training set and the association of RRS with OS was assessed with a log-rank test, Hazard ratio (HR (95% CI), and Harrell’s concordance index (C-index). In addition, a linear discriminant analysis (LDA) classifier was trained with identified features to predict RECIST-derived response in the validation set. Results RRS was found to be significantly associated with OS in training (HR: 2.9; 95% CI, 1.6–5.5; P = 0.0006; C-index = 0.82) and validation sets (HR: 2.4; 95% CI, 1.06–5.6; P = 0.035; C-index = 0.77). Median OS times in high and low-risk groups were 12.58 and 23.17 months, respectively (P = 5.7e-04). Compared to RECIST response in the training and validation set, delta radiomic features were able to assess early response with a ROC curve AUC of 0.74 and 0.72, respectively. Conclusions Delta radiomics analysis can reasonably predict response and survival in HR+/HER2- MBC patients treated with CDKi in combination with endocrine therapy.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

Background: CDK 4/6 inhibitors are currently standard of care for patients CDK 4/6 inhibitors but currently lack validated predictive markers. We evaluated whether changes in intra-lesional heterogeneity, extracted computationally from routine computed tomography (CT) of MBC could predict survival following treatment with CDK 4/6 inhibitors. Methods: 33 patients with ER+ breast cancer metastasized to the liver who received palbociclib in combination with anti-estrogen therapy were identified from a registry. For each patient, CT exams were acquired prior to treatment and following initiation of treatment (median time between scans of 106 +/- 48.6 days). Liver metastases were manually delineated on all scans with consultation of radiology reports. On each scan, gray level co-occurrence matrix (GLCM) entropy, a computational measure of intra-lesional heterogeneity, was calculated and averaged across all metastatic lesions and its change over treatment was computed. For comparison, response was also assessed via RECIST v1.1: 65% of patients had objective response/stable disease, while 35% had progressive disease on scan following initiation of treatment. Imaging metrics were assessed individually and in a multivariate comparison including clinical features for association with overall survival (OS) via a cox proportional hazards model. Results: Change in intra-lesion heterogeneity was associated with OS with a hazard ratio [HR] of 2.82 (p=0.019). An increase in entropy between the pre- and treatment scan was associated with poorer viability on treatment including CDK inhibitors, indicating that a favorable response can be distinguished by a decrease in intra-lesion heterogeneity. RECIST response was also associated with OS (HR=0.24, p Conclusions: The change in lesion heterogeneity on clinical imaging following the initiation of treatment was found to offer independent value in distinguishing patients with favorable survival following CDK 4/6 inhibitor treatment. Multivariate association of imaging features and clinical variables with overall survivalHazard ratio (HR)p-valueChange in Heterogeneity4.670.019RECIST response0.160.003PR status1.010.99HER2 status1.130.92Age1.040.26Pathology0.770.39Line of Treatment1.360.12 Citation Format: Nathaniel Braman, Siddharth Kunte, Kaustav Bera, Jame Abraham, Albert Montero, Anant Madabhushi. Change in intra-lesion heterogeneity on CT predicts long-term survival following treatment with CDK4/6 inhibitors in hormone receptor-positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-42.

Background. Given the significant clinical activity of the anti-PD1 inhibitor pembrolizumab as either a single agent or in combination with cytotoxic chemotherapy in the treatment of patients with metastatic triple-negative breast cancer (mTNBC), as well as the favorable cytotoxic and immunomodulatory properties of carboplatin and nab-paclitaxel, we identified a strong rationale to treat patients with mTNBC with the combination of carboplatin (C), nab-paclitaxel (N) and pembrolizumab (P) (CNP). Material and Methods. We undertook a prospective, single-arm pilot study of 30 patients with mTNBC treated at two institutions. Inclusion criteria included: radiographically measurable mTNBC, ECOG performance status of 0-1, Conclusions. CNP demonstrated significant activity in patients with mTNBC. Studies are underway to identify pathologic and genomic correlates of clinical response to CNP. Citation Format: Joseph Baar, Jame Abraham, G. Thomas Budd, Paula Silverman, Alberto Montero, Halle Moore, Pingfu Fu, Vinay Varadan, Kara Ladaika, Lauren Hricik. Pilot study of carboplatin, nab-paclitaxel and pembrolizumab for metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-16.

Background: Everolimus in combination with exemestane (EVE+EXE) was initially FDA approved to treat metastatic hormone receptor-positive breast cancer (mHRBC) in patients previously treated with nonsteroidal aromatase inhibitors based on the BOLERO-2 trial. However, none of the patients in the BOLERO-2 trial received prior CDK4/6 inhibitors, which have become standard of care for mHRBC. There is limited data to support the use and clinical benefit of EVE+EXE in mHRBC patients previously treated with CDK4/6 inhibitors. Methods: We reviewed patients ≥18 years old with mHRBC treated with EVE+EXE at our institution from January 1, 2012, to April 1, 2020. Patients were excluded if they received EVE+EXE ≤30 days. Data collected included patient and tumor characteristics, prior therapies in the metastatic setting, adverse drug events, and clinical outcomes. The primary objective was to compare progression free survival (PFS) for EVE+EXE between patients with and without prior exposure to CDK4/6 inhibitors. Secondary outcomes included overall survival (OS) and safety. Group comparisons were performed by two-sample t test or Wilcoxon rank sum test for continuous variables and Pearson’s chi-square test or Fisher’s exact test for categorical variables. Log-rank test was used to compare the PFS and OS between groups. Results: One-hundred ninety two patients were included in the study; 79 patients had received prior CDK4/6 inhibitor based therapies, while 113 patients did not. Baseline patient characteristics such as histology, menopause status, de novo metastatic disease, presence of lung or liver metastases, and bone only disease were similar between groups. There was a median of 2 lines of treatment in the metastatic setting prior to receiving EVE+EXE in both groups. Fewer patients received prior chemotherapy in the metastatic setting in those who received prior CDK4/6 inhibitors (32.9% vs 49.6%, p=0.032). In patients who received a prior CDK4/6 inhibitor, median PFS was 3.9 months (95% CI: 3.5 to 4.8) compared to 5.5 months (95% CI: 4.0 to 6.3) in those who did not receive a prior CDK4/6 inhibitor (HR for progression, 1.46; 95% CI: 1.08 to 1.97, p=0.013). Overall survival between groups was not significantly different. A total of 32 (16.7%) patients discontinued EVE+EXE due to intolerance or adverse drug events. Conclusion: Patients who received a prior CDK4/6 inhibitor had a lower median PFS benefit from EVE+EXE compared to those who did not. Citation Format: Hanjie Mo, Catherine E Renna, Halle CF Moore, Jame Abraham, Megan L Kruse, Alberto J Montero, Susan B LeGrand, G Thomas Budd. Efficacy of everolimus and exemestane for the treatment of metastatic hormone receptor-positive breast cancer in patients previously treated with CDK4/6 inhibitors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-18.

e19407 Background: The purpose of this study was to evaluate the impact of a continuous improvement process aimed at reducing time to treatment on minimizing the number of days spent to complete pre-treatment visits and the associated costs for patients with non-metastatic breast cancer. Methods: System-wide initiatives were implemented in 2015 to minimize time to treatment initiation (TTI), by incorporating lean process strategies and enhanced coordination. Patient and treatment information was obtained through an IRB-approved registry for the years 2015 and 2018. Average number of days spent to complete visits, TTI, and associated patient costs including driving expenses, parking, food, childcare, and lost wages were calculated and compared between the years 2015 and 2018. Results: In 2015, the median TTI was 43.5 days and the average number of separate days spent to attend multidisciplinary visits prior to first treatment was 1.86. These were reduced to 29 days and 1.52 visits, respectively, in 2018 (p < 0.0001 for both). When evaluating treatment visits by surgical procedure, the average number of visits was reduced regardless of surgical procedure. The average number of visits was highest for patients undergoing mastectomy with reconstruction (2.34 in 2015, reduced to 1.65 in 2018, p < 0.0001). A single visit to complete treatment planning was associated with patient costs of $249 as compared with multiple trips costing $491 for 2 visits and up to $1,226 for 5 visits. Conclusions: In breast cancer patients, implementing a continuous improvement process to reduce time to treatment was associated with fewer visits required prior to treatment initiation, resulting in lower patient costs.

IMPORTANCE: Obesity increases the incidence and mortality from some types of cancer, but it remains uncertain whether intentional weight loss can decrease this risk. OBJECTIVE: To investigate whether bariatric surgery is associated with lower cancer risk and mortality in patients with obesity. DESIGN, SETTING, AND PARTICIPANTS: In the SPLENDID (Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death) matched cohort study, adult patients with a body mass index of 35 or greater who underwent bariatric surgery at a US health system between 2004 and 2017 were included. Patients who underwent bariatric surgery were matched 1:5 to patients who did not undergo surgery for their obesity, resulting in a total of 30 318 patients. Follow-up ended in February 2021. EXPOSURES: Bariatric surgery (n = 5053), including Roux-en-Y gastric bypass and sleeve gastrectomy, vs nonsurgical care (n = 25 265). MAIN OUTCOMES AND MEASURES: Multivariable Cox regression analysis estimated time to incident obesity-associated cancer (a composite of 13 cancer types as the primary end point) and cancer-related mortality. RESULTS: The study included 30 318 patients (median age, 46 years; median body mass index, 45; 77% female; and 73% White) with a median follow-up of 6.1 years (IQR, 3.8-8.9 years). The mean between-group difference in body weight at 10 years was 24.8 kg (95% CI, 24.6-25.1 kg) or a 19.2% (95% CI, 19.1%-19.4%) greater weight loss in the bariatric surgery group. During follow-up, 96 patients in the bariatric surgery group and 780 patients in the nonsurgical control group had an incident obesity-associated cancer (incidence rate of 3.0 events vs 4.6 events, respectively, per 1000 person-years). The cumulative incidence of the primary end point at 10 years was 2.9% (95% CI, 2.2%-3.6%) in the bariatric surgery group and 4.9% (95% CI, 4.5%-5.3%) in the nonsurgical control group (absolute risk difference, 2.0% [95% CI, 1.2%-2.7%]; adjusted hazard ratio, 0.68 [95% CI, 0.53-0.87], P = .002). Cancer-related mortality occurred in 21 patients in the bariatric surgery group and 205 patients in the nonsurgical control group (incidence rate of 0.6 events vs 1.2 events, respectively, per 1000 person-years). The cumulative incidence of cancer-related mortality at 10 years was 0.8% (95% CI, 0.4%-1.2%) in the bariatric surgery group and 1.4% (95% CI, 1.1%-1.6%) in the nonsurgical control group (absolute risk difference, 0.6% [95% CI, 0.1%-1.0%]; adjusted hazard ratio, 0.52 [95% CI, 0.31-0.88], P = .01). CONCLUSIONS AND RELEVANCE: Among adults with obesity, bariatric surgery compared with no surgery was associated with a significantly lower incidence of obesity-associated cancer and cancer-related mortality.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20% of all breast cancers. Before the development of HER2-directed monoclonal antibodies, HER2-positive breast cancer was associated with a rather poor prognosis. With the advent of monoclonal HER2-targeting antibodies (trastuzumab and pertuzumab) and antibody-drug conjugates (trastuzumab emtansine [T-DM1] and trastuzumab deruxtecan), clinical outcomes for HER2-positive breast cancer have dramatically changed, and a greater proportion of patients in the nonmetastatic setting are cured. However, in the metastatic setting, resistance to anti-HER2 treatments still remains a major therapeutic challenge, underscoring the importance of developing novel HER2-directed therapies. Over the last year, there has been a dramatic shift in the current treatment paradigms for HER2-positive metastatic breast cancer, with recent U.S. Food and Drug Administration approvals of trastuzumab deruxtecan (DS-8201), neratinib, and tucatinib in combination with trastuzumab and capecitabine. The authors summarize recent phase 3 data with novel HER2-targeted therapies as well as phase 1 and 2 data with other novel HER2-targeting agents.

Background: Avelumab, a human IgG1 anti–PD-L1 monoclonal antibody, has shown antitumor activity and a manageable safety profile in several tumor types. Talazoparib, an orally available PARP inhibitor, is approved for the treatment of patients with deleterious or suspected deleterious germline BRCA1/2-mutated HER2− locally advanced (LA) or metastatic (M) breast cancer (BC). Preclinical data suggest that PARP inhibitors may have synergistic activity when administered in combination with immune checkpoint inhibitors. We report results from patients with LA/MBC enrolled in the phase 1b/2, multicohort JAVELIN PARP Medley study (NCT03330405). Methods: In phase 1b (cohort 1), patients with advanced solid tumors who had received ≥1 prior standard of care chemotherapy (CT) regimen were treated with avelumab 800 mg IV every 2 weeks (Q2W) in combination with talazoparib 1.0 mg orally once daily (QD) (dose de-escalation to 0.75 or 0.5 mg permitted following toxicity). In 2 phase 2 cohorts, eligible patients had either LA/M triple-negative BC (TNBC, cohort 2A) or LA/M hormone receptor positive (HR+), HER2−, DNA damage repair defect-positive BC (cohort 2B). Patients in cohort 2A had received 0 to 2 prior CT regimens (no progression on prior platinum-based CT) and patients in cohort 2B had received prior standard of care hormone therapy in either the adjuvant and/or LA/M setting followed by 0 to 2 prior CT regimens (no progression on prior platinum-based CT). The primary endpoint for phase 1b was first-cycle dose-limiting toxicities (DLTs) and for phase 2 was objective response (investigator assessed per RECIST v1.1). Adverse events (AEs) were characterized using National Cancer Institute Common Terminology Criteria for AEs v4.03. Results: By the data cutoff on December 24, 2018, 34 patients had been treated in cohorts 1 and 2. Twelve patients with advanced solid tumors were treated in cohort 1 (including 2 patients with TNBC); 3 patients (25.0%) had a first-cycle DLT: grade 3 neutropenia, (n=1) and grade 3 thrombocytopenia, (n=2). Best overall response (BOR) was partial response (PR) in 1 patient, stable disease (SD) in 3, progressive disease (PD) in 6, and non-complete response/non-PD in 1 patient with metastatic castration-resistant prostate cancer and non-measurable disease at baseline; 1 patient was not evaluable for response. Both patients with TNBC had a BOR of SD and remained on treatment for ≥9 months. Objective response rate in this pre-treated and heterogenous population was 8.3% (95% CI, 0.2, 38.5). Based on the phase 1b data, the recommended phase 2 dose was avelumab 800 mg Q2W and talazoparib 1 mg QD. By data cutoff, 22 patients had been treated in cohorts 2A (n=19) and 2B (n=3); median age was 56 and 50 years, respectively. In cohort 2A, 12 patients were evaluable for disease assessment; BOR was PR in 1, SD in 6, and PD in 5. All 3 patients in cohort 2B were non-evaluable for response at data cutoff. Treatment-related AEs (TRAEs) of any grade occurred in 11 patients (91.7%) in cohort 1, and 18 (94.7%) patients in cohort 2A. In cohort 2A, the most common TRAEs were anemia (57.9%), nausea (26.3%), fatigue (21.1%) and thrombocytopenia (21.1%); 9 patients (47.4%) had grade ≥3 TRAEs. There were no treatment-related deaths. Safety data from cohort 2B are not reported owing to low patient numbers. Observed pharmacokinetic (PK) data for avelumab 800 mg Q2W were similar to simulated data derived from a population PK model developed using 10 mg/kg dosing. Conclusions: Avelumab 800 mg Q2W administered in combination with talazoparib 1 mg QD in patients with advanced solid tumors, showed preliminary antitumor activity and a manageable safety profile, which was comparable to the safety profiles of the single agents. The study is ongoing; updated safety and efficacy data, and biomarker data will be presented. Citation Format: Timothy A Yap, Panagiotis Konstantinopoulos, Melinda L. Telli, Smita Saraykar, J Thaddeus Beck, Matthew D. Galsky, Jame Abraham, David R. Wise, Mustafa Khasraw, Gabor Rubovszky, Mikhail Dvorkin, Anil A Joy, Mateusz Opyrchal, Daria Stypinski, Colombe Chappey, Ross Stewart, Rossano Cesari, Anita Scheuber, Aditya Bardia. JAVELIN PARP Medley, a phase 1b/2 study of avelumab plus talazoparib: Results from advanced breast cancer cohorts [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-03.

Background: Invasive lobular breast cancer (ILC) is the second most common histological type of invasive breast cancer and accounts for 10-15% of all breast cancer cases. It is commonly strongly hormone receptor positive and, in general, is considered to be less chemo-sensitive compared with invasive ductal carcinoma (IDC). The aim of this study was to compare survival outcomes among ILC patients treated with adjuvant endocrine therapy (ET) compared with chemoendocrine therapy (CET). We also sought to assess utilization of Oncotype Dx testing and distribution of Recurrence Score results among ILC patients treated at our institution. Methods: We conducted an IRB approved retrospective study at Cleveland Clinic Taussig Cancer Institute of patients with non-metastatic ILC. Patient diagnosed with ILC and treated from January 2004 through December 2017 were identified from our tumor registry. Patient characteristics including demographics, pathologic features, hormone replacement therapy (HRT) use, Oncotype Dx recurrence score, treatment details and recurrence data were obtained through medical chart review. Recurrence-free and overall survival (OS) were compared between ET and CET using Kaplan-Meier method and Cox proportional hazard model with consideration of differences on age and prognostic factors. The outcomes between age and pathological stage propensity score matched treatment groups were also compared. Results: A total of 638 patients (Mean age 61.9±11.7, 99.1% estrogen receptor positive, 82.6% progesterone receptor positive) were identified. 406 (63.6%) patients received ET and 232 (36.4%) patients received CET. Compared to ET, patients who received CET were significantly younger (Mean 56.3 vs 65.0 years) and more likely to be premenopausal (40.1% vs 14.6%), however they had significant worse prognostic features including pathological stage (stage III: 38.9% vs 2.1%), grade (≥ II: 69.0% vs 55.9%) and Oncotype Dx score (≥18: 72.4% vs 36.2%). Patients were followed for median (IQR) time of 4 (2.0, 6.4) years for survival outcomes. Although recurrence-free survival (local or distant) was worse in CET (5-year recurrence-free: 81.9% vs 96.5%), age and clinical prognostic features adjusted recurrence risk was similar as ET (Adjusted HR and 95% CI: 0.83, 0.36-1.92) and risk of death was also similar (Adjusted HR and 95% CI: 0.68, 0.31-1.50). Only 222 patients had Oncotype Dx score (35%), with 59% falling in the low risk range, 39% intermediate risk range and 2% high risk range. The Oncotype Dx recurrence score was not associated with recurrence or death. The recurrence-free (5-year: 97.4% vs 90.4%, p=0.37) and OS (At 5-year OS: 94.3% vs 89.4%, p=0.08) were also similar between age and pathological stage matched CET and ET groups. Conclusion: Use of chemoendocrine therapy did not result in improved survival outcomes for patients with ILC compared to those treated with endocrine monotherapy in the adjuvant setting. The majority of ILC patients did not have Oncotype Dx testing sent however when it was ordered, most cases resulted in the low-intermediate risk range, suggesting limited benefit of chemotherapy as reflected by survival outcome results observed. Citation Format: Mathew Thomas, Hong Li, Jame Abraham, Halle CF Moore, G Thomas Budd, Alberto J Montero, Megan L Kruse. Comparison of survival outcomes between treatment with endocrine therapy and chemoendocrine therapy in patients with invasive lobular carcinoma [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-14-13.

Background: Although the advent of targeted therapy has substantially improved outcomes for HER2+ breast cancer patients, many will still fail to achieve pathological complete response (pCR) following neoadjuvant chemotherapy (NAC). In order to reduce overtreatment among patients resistant to standard HER2-targeted NAC and identify candidates for alternative therapeutic interventions, there is a need for validated markers of anti-HER2 agent benefit. The computational analysis of pretreatment imaging has shown recent promise in identifying responsive breast cancers. However, previous applications have explored response prediction among cohorts of mixed subtype and therapeutic approach, thus limiting its relevance in informing specific therapeutic strategy. Methods: This study comprised retrospective contrast-enhanced MRI data from a total of 159 patients who received anti-HER2 therapy at 5 institutions. A deep learning (DL) model was trained and tuned using 100 HER2+ breast cancer patients who received neoadjuvant taxane (T), carboplatin (C), trastuzumab (H), and pertuzumab (P) at Institution A, of which 49 achieved pCR (ypT0/is). A convolutional neural network was designed to analyze pre- and post-contrast MRI images acquired before NAC and compute a patient's probability of achieving pCR. Institution A data was split randomly into a 85 patient training cohort, used to directly train the model, and a 15 patient internal validation cohort, used to monitor and improve training progress. Two external, held-out testing datasets were used to evaluate capability to predict response in HER2+: Testing Cohort 1, consisting of 28 patients (16 pCR, 12 non-pCR) treated with TCHP at Institution B, and Testing Cohort 2, consisting of 29 patients (10 pCR, 19 non-pCR) who received TCH at one of 3 other institutions as part of the BrUOG 211B trial. A multivariable clinical model (MCM) incorporating age, ER/PR status, stage, and size was evaluated separately and in combination with the neural network. Performance was assessed by area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. Results: The neural network was able to strongly predict response to HER2-targeted NAC in the internal validation (AUC=.93) and testing cohorts (AUC=.84 and AUC=.77). This model offered superior performance compared to a MCM, which performed poorly across institutions. Strikingly, the higher accuracy of DL included correctly identifying responders within the ER+/PR+ subgroup of patients and non-responders within the ER-/PR- subgroup. Combining DL predictions with the clinical model improved performance to AUC of 0.89 in testing cohort 1, but did not improve AUC in cohort 2. Conclusions: DL analysis of breast DCE-MRI could be used to better identify benefit of HER2-targeted therapeutic approaches prior to administration. As the first exploration of automated response prediction from imaging with respect to a targeted NAC approach, this work uniquely has the potential to help guide therapeutic decision-making. Our approach was effective in predicting response to multiple HER2-targeted NAC regimens, with better performance in the cohort who received TCHP (as in the training cohort). The strong performance of this model across 5 institutions is a promising indicator of its robustness and ability to tailor therapy even within clinically-distinct HER2+ patient subpopulations. Deep learning (DL) and multivariable clinical model (MCM) pCR prediction by cohortCohortModelAUC (%)Sensitivity (%)Specificity (%)Accuracy (%)Validation (n=15, 53% pCR)DL93888687MCM66637173Testing 1 (n=28, 57% pCR)DL85889289MCM54388350DL+MCM89819286Testing 2 (n=29, 34% pCR)DL77708479MCM53208966DL+MCM76808483 Citation Format: Nathaniel Braman, Mohammed El Adoui, Manasa Vulchi, Paulette Turk, Maryam Etesami, Pingfu Fu, Stylianos Drisis, Vinay Varadan, Donna Plecha, Mohammed Benjelloun, Jame Abraham, Anant Madabhushi. Validation of neural network approach for the prediction of HER2-targeted neoadjuvant chemotherapy response from pretreatment MRI: A multi-site study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-13.

Background: Angiogenesis is crucial to a tumor's growth and an important factor in therapeutic outcome. Although quantitative analysis of tumors on dynamic contrast enhanced (DCE) MRI can provide indirect characterization of a tumor's vascularization, direct computational analysis of the tumor-associated vessel network remains a promising, but under-explored potential marker of therapeutic response. For instance, surrounding vasculature with a convoluted 3-dimensional shape and poor blood flow may indicate a more aggressive tumor and poorly facilitate delivery of therapeutic agents. In this work, we present a computational approach for the prediction of neoadjuvant chemotherapy response using quantitative imaging features describing the morphology and function of tumor associated vasculature on pretreatment MRI. Methods: 243 patients who received DCE-MRI scans prior to neo-adjuvant chemotherapy (NAC) at institution A [n=83], B [n=76], or one of nine other institutions as part of the ISPY1 Trial [n=84] were divided randomly into training (n=123) and testing (n=120) sets. 148 patients were HER2- and received neoadjuvant AC-T, while the 95 HER2+ patients were treated with TCHP (ISPY predates anti-HER2 therapy and HER2+ ISPY patients were excluded). 79 patients achieved pathological complete response [pCR, ypT0/is] following NAC. MRI exams were collected with a 1.5 or 3 Tesla scanner in the axial or sagittal plane. A baseline scan and 2-5 scans after injection of a gadolinium-based contrast agent with a median temporal resolution of 2.5 minutes were acquired. A portion of the tumor was manually delineated, then semi-automatically expanded to 3D. Vasculature was isolated from subtraction images with a specialized filtering approach to detect vessel-shaped objects. Features describing the 3D shape and architecture of the tumor-associated vessel network (e.g. curvature, torsion, and local orientation) and functional semi-quantitative pharmacokinetic (PK) measurements of temporal contrast enhancement changes (e.g. signal enhancement ratio, time to peak enhancement, and rates of uptake and washout) were calculated. Performance was assessed by area under the receiver operating characteristic curve (AUC), as well as the accuracy, sensitivity, and specificity at the operating point corresponding to the Youden Index. The most discriminating features were determined based on frequency of selection by the random forest classifier. Results: Within the training set, PK parameters of the vessels (AUC=.66) outperformed relative to the PK of tumor (AUC=.63) and the PK of peritumoral regions (AUC=.64); however, a combination of the three yielded best performance (AUC=.75). Vessel shape features alone achieved AUC=.67 in the training set. When multi-region PK features and tumor shape features were combined and applied to the 120-patient independent testing set, the random forest classifier achieved an AUC of 0.70 and identified 81% of patients who would achieve pCR. Non-pCR was best characterized by increased vessel curvature and PK parameters indicating poor perfusion, such as greater time to peak enhancement, slower uptake rate, and quicker washout. Conclusions: Our findings suggest that properties of the tumor-associated vessel network, such as its shape and enhancement profile, might provide value in identifying patients who will respond to NAC before administration of treatment. Accuracy (%)Sensitivity (%)Specificity (%)Full testing set (n=120)678160HER2+ (n=44)709548HER2- (n=76)646365HER2-, HR+ (n=51)678364Triple Negative (n=25)605067 Citation Format: Nathaniel Braman, Prateek Prasanna, Kaustav Bera, Mehdi Alilou, Manasa Vulchi, Maryam Etesami, Paulette Turk, Jame Abraham, Donna Plecha, Anant Madabhushi. Radiomic measurements of tumor-associated vasculature morphology and function on pretreatment dynamic MRI identifies responders to neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-06.

Background: Triple-negative breast cancer (TNBC) has a poor prognosis and may be associated with germline mutations. α-lactalbumin (aLA) is expressed in lactating breasts but not at other times or in other tissues. Expression of aLA is found in 70% of TNBC (PMID: 27322324) so could be an immunologic target for TNBC based on the “retired protein hypothesis” (PMID: 31926646). In pre-clinical studies vaccination with aLA inhibited growth of established breast tumors and provided protection from development of autochthonous tumors in transgenic murine models of breast cancer and against 4T1 transplantable breast cancer in BALB/c mice (PMID: 20512124). Methods: To determine the safety and immunogenicity of aLA, patients with early stage TNBC are being entered in a Phase I trial of aLA with GMP-grade zymosan adjuvant in Montanide ISA 51 VG vehicle. Subjects receive 3 vaccinations given once every 2 weeks. Events of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥2 are considered dose-limiting toxicities (DLTs). Results: CTCAE toxicity by dose level is summarized below. All DLTs were injection site reactions, with ulceration and need for incisional drainage representing the grade 3 events. ELISpot assays to determine frequencies of T-cells producing IFN-γ and IL-17 in response to recombinant aLA and ELISA assays of antibody response to aLA will be available in December 2022. Conclusion: Dose level 2 appears to be the maximum tolerated dose. Accrual to dose levels 1 and 2 will be expanded to further define toxicity and immunologic effects. Accrual of patients with BRCA1 or PALB2 mutations planning to undergo prophylactic mastectomy is beginning in order to define the toxicity and immunologic effects in this group and to determine whether inflammatory changes from occult lactational foci will be produced. Funding Source: Department of Defense (W81XWH-17-1-0592 and W81XWH-17-1-0593) Worst Toxicity by Dose Level Dose Level aLAC (mcg) dose Zymosan (mcg) dose n Patients n Grade 0 n Grade 1 n Grade 2 n Grade 3 1 10 10 3 3 2 100 10 3 3 3 500 10 3 2 1 Original 2 100 100 1 1 Citation Format: George Thomas Budd, Justin M. Johnson, Emily Rhoades, Halle Moore, Holly Levengood, Megan Kruse, Erin Roesch, Jame Abraham, Brenna Elliott, Elena Haury, Rachel Swartz, Holly Pederson, Zahraa Al Hilli, Vincent Tuohy. Phase I trial of alpha-lactalbumin vaccine in high-risk operable triple-negative 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 3035.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer-focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor-positive, HER2-negative breast cancer.

Patient support and psychosocial services are an important aspect of cancer care. Comprehensive cancer centers need to provide a spectrum of these services to provide high-quality and holistic care to cancer patients. Provision of these services begins from the time of diagnosis, continues through cancer treatment, and then subsequently transitions to survivorship or end-of-life phase. Examples of these services include psychological assessment and management, patient navigation, care coordination, genetic counseling, and complementary medicine. Survivorship care is an important aspect of patients’ experience during their cancer journey and beyond. This chapter discusses key psychosocial and supportive care services that are recommended for cancer centers that strive to provide comprehensive cancer care to their patients.

BACKGROUND Genetics of estrogen synthesis and breast cancer risk has been elusive. The 1245A→C missense-encoding polymorphism in HSD3B1, which is common in White populations, is functionally adrenal permissive and increases synthesis of the aromatase substrate androstenedione. We hypothesized that homozygous inheritance of the adrenal-permissive HSD3B1(1245C) is associated with postmenopausal estrogen receptor–positive (ER-positive) breast cancer. METHODS A prospective study of postmenopausal ER-driven breast cancer was done for determination of HSD3B1 and circulating steroids. Validation was performed in 2 other cohorts. Adrenal-permissive genotype frequency was compared between postmenopausal ER-positive breast cancer, the general population, and postmenopausal ER-negative breast cancer. RESULTS Prospective and validation studies had 157 and 538 patients, respectively, for the primary analysis of genotype frequency by ER status in White female breast cancer patients who were postmenopausal at diagnosis. The adrenal-permissive genotype frequency in postmenopausal White women with estrogen-driven breast cancer in the prospective cohort was 17.5% (21/120) compared with 5.4% (2/37) for ER-negative breast cancer (P = 0.108) and 9.6% (429/4451) in the general population (P = 0.0077). Adrenal-permissive genotype frequency for estrogen-driven postmenopausal breast cancer was validated using Cambridge and The Cancer Genome Atlas data sets: 14.4% (56/389) compared with 6.0% (9/149) for ER-negative breast cancer (P = 0.007) and the general population (P = 0.005). Circulating androstenedione concentration was higher with the adrenal-permissive genotype (P = 0.03). CONCLUSION Adrenal-permissive genotype is associated with estrogen-driven postmenopausal breast cancer. These findings link genetic inheritance of endogenous estrogen exposure to estrogen-driven breast cancer. FUNDING National Cancer Institute, NIH (R01CA236780, R01CA172382, and P30-CA008748); and Prostate Cancer Foundation Challenge Award.

PURPOSE Patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer eventually develop resistance to dual-antibody therapy with trastuzumab plus pertuzumab. Mechanisms of resistance have not been well elucidated. We evaluated the safety, tolerability, and efficacy of ado-trastuzumab emtansine (T-DM1) plus neratinib in patients who progressed on trastuzumab plus pertuzumab. PATIENTS AND METHODS In this 3 + 3 dose-escalation study, patients with metastatic breast cancer who progressed on trastuzumab, pertuzumab, and a taxane were treated with T-DM1 at 3.6 mg/kg intravenously every 3 weeks and dose-escalating neratinib at 120, 160, 200, or 240 mg/d orally. RESULTS Twenty-seven patients were treated across four dose-levels of neratinib. Dose-limiting toxicity in cycle 1 was grade 3 diarrhea in six patients and grade 3 nausea in one; no patient experienced grade 4 diarrhea, and there were no grade 5 toxicities. Other grade 3 to 4 toxicities included nausea (11%), dehydration (11%), electrolyte abnormality (19%), thrombocytopenia (15%), elevated transaminase levels (7%), and fatigue (7%). Twelve (63%) of 19 evaluable patients had an objective response. Responses occurred at all neratinib doses. Plasma cell–free DNA at baseline showed ERBB2 (HER2) amplification in 10 of 27 patients. Deep and more durable responses occurred in patients with cell-free DNA ERBB2 amplification. Two complete responders had high expression of total HER2 and p95HER2 in baseline tissue. CONCLUSION We report the recommended phase II dose of T-DM1 3.6 mg/kg and neratinib 160 mg/d for this combination. Possible resistance mechanisms to HER2 antibodies may be loss of the HER2 receptor and high expression of p95HER2. These data provide the basis for an ongoing phase II study to better define the activity of this regimen.

Patients were treated at a single institution to a dose of 30 Gy in five fractions delivered every other day using image-guided intensity modulated radiation therapy (IMRT) partial breast irradiation. A total of 34 patients were treated with a median follow-up of 4.6 months. The rate of acute Grade 1 dermatitis was 23.5% (n = 8), and Grade 1 fatigue was 17.6% (n = 6), with no Grade 2 or higher acute toxicities. The rate of chronic Grade 1 dermatitis was 25.0% (n = 6), Grade 1 fat necrosis 4.2% (n=1), with no patients demonstrating other chronic toxicities. Image-guided APBI delivered with IMRT is associated with low rates of acute and chronic toxicity though additional follow-up is warranted.

Patients with breast cancer receiving antiestrogen therapy, specifically aromatase inhibitors, often suffer from vaginal dryness, itching, irritation, dyspareunia, and dysuria, collectively known as genitourinary syndrome of menopause (GSM). GSM can decrease quality of life and is undertreated by oncologists because of fear of cancer recurrence, specifically when considering treatment with vaginal estrogen therapy because of unknown levels of systemic absorption of estradiol. In this article, we review the available literature for treatment of GSM in patients with breast cancer and survivors, including nonhormonal, vaginal hormonal, and systemic hormonal therapy options. First-line treatment includes nonhormonal therapy with vaginal moisturizers, lubricants, and gels. Although initial studies showed significant improvement in symptoms, the US Food and Drug Administration recently issued a warning against CO2 laser therapy for treatment of GSM until additional studies are conducted. In severe or refractory GSM, after discussing risks and benefits of vaginal hormonal therapy, the low-dose 10-μg estradiol-releasing intravaginal tablet or lower-dose 4 μg estrogen vaginal insert and intravaginal dehydroepiandrosterone (prasterone) are options for treatment, because studies show minimal elevation in serum estradiol levels and significant improvement in symptoms. The decision to offer vaginal estrogen therapy must be individualized and made jointly with the patient and her oncologist.

Invasive lobular carcinoma (ILC) is the second most common type of invasive breast cancer after invasive ductal carcinoma (IDC). Invasive lobular carcinoma has unique clinical, pathologic, and radiographic features which suggest that it is a distinct clinical entity; however, it is treated with the same treatment paradigms as IDC. Information regarding the specific treatment of ILC, including response to standard therapy, is sparse. Neoadjuvant treatment considerations are of great importance in this space as ILC is often found at a locally advanced stage. In this review, we summarize the classic features of ILC and the available data regarding efficacy of both endocrine therapy and chemotherapy in curative treatment of breast cancer.

Real-world data are critical to demonstrate the reproducibility of evidence and external generalizability of randomized clinical trials. Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6 that has been shown to improve progression-free survival (PFS) when combined with letrozole or fulvestrant in phase 3 clinical trials. We evaluated real-world outcomes in metastatic breast cancer patients who received palbociclib in combination with endocrine therapy in routine clinical practice. Records of patients with advanced hormone receptor (HR)-positive breast cancer treated with palbociclib at the Cleveland Clinic health system from February, 2015 to December, 2017 were retrospectively reviewed. The primary end point was PFS. In this cohort, 411 women were included. The median age and follow-up times were 53.5 years and 10.2 months, respectively. The median PFS for palbociclib plus letrozole was 15.1 months for patients treated in first line, 10.5 months in second line, and 4.2 months in third line and beyond. For patients who received fulvestrant plus palbociclib, the median PFS in first, second, and third line and beyond were 11.6, 12.3, and 6.4 months, respectively. The most common adverse events were hematologic, with grade 3–4 neutropenia occurring in 58% of patients. Thirty-one (8%) patients permanently discontinued palbociclib due to adverse events. Among patients with HR-positive advanced breast cancer, the estimated PFS in patients treated with fulvestrant and palbociclib was comparable to a previously reported phase 3 trial. However, the median PFS with letrozole and palbociclib was shorter than previously reported data from phase 2 and 3 trials. Palbociclib toxicity was very manageable, with a low drug discontinuation rate.

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor–positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.

BackgroundPseudocirrhosis is characterized by radiological changes in the liver that resemble cirrhosis, but with more rapid onset and progression. Though reported most frequently in patients with metastatic breast cancer, little is known about its prognostic factors and impact on breast cancer outcomes.MethodsIn this observational study, we reviewed abdominal CT and/or MRI scan reports of all patients with invasive breast cancer diagnosed at our center, during a ten-year period, to identify patients with pseudocirrhosis. Exclusion criteria included lack of baseline imaging, pre-existing cirrhosis, hepatitis B or C, other chronic liver diseases, or heavy alcohol use. Routine descriptive statistical measures were used. Survival distributions were estimated using Kaplan-Meier method, and Cox regression was used for multivariate analysis. Two-tailed p < 0.05 was considered significant.ResultsEighty-six patients were included – all were females, median age was 57.5 years, and 90% were Caucasian; 86% of primary tumors were hormone-receptor positive and 17% were HER2 positive. Most patients (98%) had metastatic disease with liver involvement (94%), and were heavily pre-treated – 97% with chemotherapy, 85% with hormonal therapy, and 19% with anti-HER2 agents. Median interval from breast cancer diagnosis to pseudocirrhosis was 75.4 months (IQR 35.2-115.3 months). Thirty-six percentage of patients had ≥1 signs of portal hypertension and 49% had ≥1 signs of hepatocellular failure. Pseudocirrhosis led to permanent discontinuation of chemotherapy, endocrine therapy, and all systemic therapies in 29%, 31%, and 20% patients, respectively. Median overall survival from diagnosis of pseudocirrhosis was 10.0 months (95%CI 5.2-14.8 months). On multivariate analysis, coagulopathy, hyperbilirubinemia, hypoalbuminemia, and cancer progression were independently predictive of mortality.ConclusionsIn this largest series, to date, of breast cancer with pseudocirrhosis, the latter was often complicated by portal hypertension and hepatocellular failure, and markedly impacted breast cancer management. Survival was shorter for patients who developed hepatocellular failure.

Through expert, case-based discussion, Jame Abraham, MD, and Kelley Mayden, MSN, FNP, AOCNP®, presented existing and emerging data for current and investigational therapies for HER2-positive breast cancer and their associated adverse events, in addition to best practices for managing central nervous system metastases.