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Purpose: Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase II clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post–cyclin-dependent kinase (CDK) 4/6 inhibitor progression. Patients and Methods: Pre-/postmenopausal females ≥18 years were randomized 1:1 to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status. Results: At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR [venetoclax plus fulvestrant: 11.8% (n = 6/51; 95% confidence interval (CI), 4.44–23.87); fulvestrant: 13.7% (7/51; 5.70–26.26); risk difference –1.96% (95% CI, –16.86 to 12.94)]. Median PFS was 2.69 months (95% CI, 1.94–3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84–3.55) with fulvestrant (stratified HR, 0.94; 95% CI, 0.61–1.45; P = 0.7853). Overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (IHC 3+), a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status. Conclusions: Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy–resistant, CDK4/6 inhibitor–refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting.

Supplementary Data from VERONICA: Randomized Phase II Study of Fulvestrant and Venetoclax in ER-Positive Metastatic Breast Cancer Post-CDK4/6 Inhibitors – Efficacy, Safety, and Biomarker Results

Purpose:Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase II clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post–cyclin-dependent kinase (CDK) 4/6 inhibitor progression.Patients and Methods:Pre-/postmenopausal females ≥18 years were randomized 1:1 to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status.Results:At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR [venetoclax plus fulvestrant: 11.8% (n = 6/51; 95% confidence interval (CI), 4.44–23.87); fulvestrant: 13.7% (7/51; 5.70–26.26); risk difference –1.96% (95% CI, –16.86 to 12.94)]. Median PFS was 2.69 months (95% CI, 1.94–3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84–3.55) with fulvestrant (stratified HR, 0.94; 95% CI, 0.61–1.45; P = 0.7853). Overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (IHC 3+), a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status.Conclusions:Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy–resistant, CDK4/6 inhibitor–refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting.

Supplementary Table from VERONICA: Randomized Phase II Study of Fulvestrant and Venetoclax in ER-Positive Metastatic Breast Cancer Post-CDK4/6 Inhibitors – Efficacy, Safety, and Biomarker Results

Background: The incidence of brain metastases (BrM) has steadily increased over time as women with metastatic breast cancer (MBC) live longer and survive to experience spread of cancer to the central nervous system (CNS). Women with triple negative and HER2+ MBC, which represent 30-40% of the MBC population, are at particularly high risk of BrM. At present, MBC patients are not screened for BrM; rather, they undergo imaging of the brain only after symptoms suggestive of CNS involvement develop. Unfortunately, by the time that patients experience potentially debilitating symptoms of BrM, they often have a significant burden of disease with limited treatment options and a poor prognosis. We hypothesize that early detection of BrM via magnetic resonance imaging (MRI)-based screening may allow for early intervention and, ultimately, improved outcomes for MBC patients. Methods: A multi-centre, open-label prospective phase II study, randomizing 50 women with triple negative or HER2+ MBC to either MRI-based BrM screening or symptom-directed surveillance. Randomization is stratified for tumor subtype. Intervention arm: Contrast-enhanced MRI of the brain at baseline, 4-, 8- and 12-months with concurrent chemical exchange saturation transfer (CEST) imaging, a new metabolic MRI sequence that may detect BrM even earlier than standard MRI. Control arm: Symptom-directed surveillance (brain imaging only if patients develop symptoms suggestive of BrM). All participants complete questionnaires at baseline, 6- and 15-months to assess overall (EORTC QLQ BN20) and neurologic-specific (FACT-BR tools) quality of life (QoL) as well as cancer-related anxiety (NCI PRO-CTCAE). A blood sample is collected for ctDNA analysis at baseline in all patients at diagnosis of BrM, if applicable. Key inclusion criteria: 1) Age ≥18; 2) Triple negative MBC, with metastatic disease diagnosed ≤12 weeks prior to study entry OR HER2+ MBC with no restrictions regarding timeline of diagnosis; 3) No symptoms of BrM or known asymptomatic BrM at study entry. Key exclusion criteria: 1) ECOG>2; 2) Inability to complete an MRI (e.g., claustrophobia). Analyses: The primary goal of this study is to determine the feasibility of a randomized trial of BrM screening versus symptom-directed surveillance in the proposed patient population. The pilot study will be considered “not feasible” if 50% of patients allocated to the control arm are screened for BrM with CT or MRI. Overall survival will be assessed as a secondary endpoint. We will also investigate how screening for BrM influences the detection rate of BrM and explore how subsequent intervention affects both overall and neurologic-specific QoL. Our data will enable a power calculation to determine a sample size for a future, larger trial. 28 of 50 planned patients have enrolled in the study to-date. Citation Format: Katarzyna J Jerzak, Arjun Sahgal, Gregory Pond, Priscilla K Brastianos, Orit Freedman, Gregory Stanisz, Ellen Warner. MRI screening versus symptom-directed surveillance for brain metastases among patients with triple negative or HER2+ metastatic breast cancer: A pilot study (nct03881605) [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 OT1-07-01.

PURPOSE Neoadjuvant chemotherapy (NAC) is used to treat locally advanced breast cancer (LABC) and high-risk early breast cancer (BC). Pathological complete response (pCR) has prognostic value depending on BC subtype. Rates of pCR, however, can be variable. Predictive modeling is desirable to help identify patients early who may have suboptimal NAC response. Here, we test and compare the predictive performances of machine learning (ML) prediction models to a standard statistical model, using clinical and pathological data. METHODS Clinical and pathological variables were collected in 431 patients, including tumor size, patient demographics, histological characteristics, molecular status, and staging information. A standard multivariable logistic regression (MLR) was developed and compared with five ML models: k-nearest neighbor classifier, random forest (RF) classifier, naive Bayes algorithm, support vector machine, and multilayer perceptron model. Model performances were measured using a receiver operating characteristic (ROC) analysis and statistically compared. RESULTS MLR predictors of NAC response included: estrogen receptor (ER) status, human epidermal growth factor-2 (HER2) status, tumor size, and Nottingham grade. The strongest MLR predictors of pCR included HER2+ versus HER2− BC (odds ratio [OR], 0.13; 95% CI, 0.07 to 0.23; P < .001) and Nottingham grade G3 versus G1-2 (G1-2: OR, 0.36; 95% CI, 0.20 to 0.65; P < .001). The area under the curve (AUC) for the MLR was AUC = 0.64. Among the various ML models, an RF classifier performed best, with an AUC = 0.88, sensitivity of 70.7%, and specificity of 84.6%, and included the following variables: menopausal status, ER status, HER2 status, Nottingham grade, tumor size, nodal status, and presence of inflammatory BC. CONCLUSION Modeling performances varied between standard versus ML classification methods. RF ML classifiers demonstrated the best predictive performance among all models.

Background Breast cancer is the most common cancer among women worldwide and the second leading cause of brain metastases (BrM). We assessed the treatment patterns and outcomes of women treated for breast cancer BrM at our institution in the modern era of stereotactic radiosurgery (SRS). Materials and Methods We conducted a retrospective analysis of women (≥18 years of age) with metastatic breast cancer who were treated with surgery, whole brain radiotherapy (WBRT), or SRS to the brain at the Sunnybrook Odette Cancer Centre, Toronto, Canada, between 2008 and 2018. Patients with a history of other malignancies and those with an uncertain date of diagnosis of BrM were excluded. Descriptive statistics were generated and survival analyses were performed with subgroup analyses by breast cancer subtype. Results Among 683 eligible patients, 153 (22.4%) had triple-negative breast cancer, 188 (27.5%) had HER2+, 246 (36.0%) had hormone receptor (HR)+/HER2−, and 61 (13.3%) had breast cancer of an unknown subtype. The majority of patients received first-line WBRT (n = 459, 67.2%) or SRS (n = 126, 18.4%). The median brain-specific progression-free survival and median overall survival (OS) were 4.1 months (interquartile range [IQR] 1.0–9.6 months) and 5.1 months (IQR 2.0–11.7 months) in the overall patent population, respectively. Age >60 years, presence of neurological symptoms at BrM diagnosis, first-line WBRT, and HER2− subtype were independently prognostic for shorter OS. Conclusion Despite the use of SRS, outcomes among patients with breast cancer BrM remain poor. Strategies for early detection of BrM and central nervous system–active systemic therapies warrant further investigation. Implications for Practice Although triple-negative breast cancer and HER2+ breast cancer have a predilection for metastasis to the central nervous system (CNS), patients with hormone receptor–positive/HER2− breast cancer represent a high proportion of patients with breast cancer brain metastases (BrM). Hence, clinical trials should include patients with BrM and evaluate CNS-specific activity of novel systemic therapies when feasible, irrespective of breast cancer subtype. In addition, given that symptomatic BrM are associated with shorter survival, this study suggests that screening programs for the early detection and treatment of breast cancer BrM warrant further investigation in an era of minimally toxic stereotactic radiosurgery.

Background To evaluate the potential intracranial efficacy of immunotherapy among patients with breast cancer brain metastases (BrM), we analyzed the immunohistochemical expression of programmed death-ligand 1 (PD-L1), a predictive biomarker of response to immunotherapy. Methods In this single-center retrospective cohort study, consecutive patients with breast cancer BrM (immunotherapy naïve) who underwent surgery for BrM at Sunnybrook Health Sciences Center between July 1999 and June 2013 were identified. PD-L1 expression by immunohistochemistry (IHC) was assessed on BrM samples in triplicate; PD-L1 positive status was defined as PD-L1 expression ≥1% on tumor-infiltrating cells as a percentage of tumor area using the Ventana SP142 antibody. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2) status was determined using 2018 ASCO/CAP guidelines. Results The median patient age at the time of BrM diagnosis was 52 (range 32–85). PD-L1 expression using the SP42 antibody was identified in 9 out of 59 (15.3%) breast cancer BrM. The frequency of PD-L1 positive BrM by subtype is as follows: TNBC (n = 3/12, 25.0%), HER2+/HR- (n = 3/14, 21.4%), HR+/HER2- (n = 2/18, 11.1%), and HER2+/HR+ (n = 1/14, 7.1%). 24-month brain-specific progression-free survival was 66.7% (95% CI 37.9%–100%) among patients with PD-L1 positive BrM versus 42% (95% CI 26.6%–67.3%) among those with PD-L1 negative BrM (log-rank P-value .142). Conclusions One in 7 patients in our cohort had PD-L1 positive BrM; this proportion was highest (25%) among those with TNBC. Intracranial efficacy of immunotherapy warrants further study, particularly among patients with treatment-naïve metastatic TNBC, for whom extracranial efficacy has already been established.

We aimed to evaluate the expression of the “targetable” androgen receptor (AR) in breast cancer brain metastases (BrM). An established, retrospective 57-patient cohort with metastatic breast cancer who underwent surgery for BrM at the Sunnybrook Odette Cancer Centre between 1999–2013 was studied. AR expression in BrM samples was assessed in triplicate using immunohistochemistry (IHC). AR positive status was defined as nuclear AR expression ≥ 10% by IHC using the SP107 antibody. The median age of patients was 52 years (range 32–85 years). 28 (49%) of BrM were HER2+, 17 (30%) were hormone receptor positive (HR+)/HER2−, and 12 (21%) were triple negative breast cancers (TNBCs). 56% (n = 32/57) of BrM were AR positive, and median AR expression was 20% (CI 1.6–38.3%). AR expression was different across breast cancer subtypes; AR was most frequently expressed in HER2+ (n = 21/28), followed by HR+/HER2− (n = 9/17), and lowest in TNBC (n = 2/12) BrM (p = 0.003). Patients with AR positive versus AR negative BrM had similar overall survival (12.5 vs. 7.9 months, p = 0.6), brain-specific progression-free survival (8.0 vs. 5.1 months, p = 0.95), and time from breast cancer diagnosis to BrM diagnosis (51 vs. 29 months, p = 0.16). AR is expressed in the majority of breast cancer BrM and represents a potential therapeutic target.

To compare clinical-pathologic characteristics and outcomes of pregnancy-associated, post-partum (PP) and nulliparous (NP) breast cancer (BC) patients and explore mediators of the poor prognosis associated with post-partum BC. A prospective database of 233 women ≤ 40 years of age diagnosed with BC between February 2008 and January 2015 was analysed. Clinical–pathologic characteristics and outcomes among pregnant, PP and NP patients were compared using chi-square or Kruskal–Wallis tests. The Kaplan–Meier method was used to estimate disease-free survival (DFS), distant DFS and overall survival (OS). Survival curves were compared using the log-rank test. Univariable Cox proportional hazards regression models were used to evaluate factors that were potentially prognostic for the clinical outcomes of interest; a multivariable Cox model was constructed using a forward stepwise selection process. Androgen receptor (AR), GATA3, PDL1 status and the presence/absence of tumour-infiltrating lymphocytes (TILs) were assessed when possible. Pre-treatment neutrophil and lymphocyte counts were abstracted retrospectively. Statistical significance was defined as a p value ≤ 0.05. Women ≤ 2 years PP had a numerically higher incidence of lymph node-positive and high-grade disease and were significantly more likely to have estrogen receptor-negative BC compared to NP controls. With a median follow-up of 7.2 years, increasingly poor outcomes were observed among NP (longest OS), > 2 years PP, ≤ 2 years PP and pregnant (shortest OS) patients, but these differences were not statistically significant. The ≤ 2 years PP group had significantly lower AR expression, a strong trend toward higher PDL1 expression and a higher expression of stromal TILs compared to NP women. PPBC patients had numerically lower DFS and OS compared to NP controls. Higher PDL1 and stromal TILs in PPBC suggest that adjuvant immunotherapy may be effective in the post-partum BC subgroup.

In this study, we investigate factors associated with radionecrosis (RN) in HER2 + (human epidermal growth factor receptor 2) patients with brain metastases (BrM) treated with stereotactic radiosurgery (SRS).Patients with HER2 + breast cancer BrM treated with SRS (2010-2020) were identified from an institutional database. The incidence of RN was determined per treated BrM according to serial imaging and/or histology. Factors associated with RN such as age, RT dose, BrM volume, and initiation of Trastuzumab Emtansine (T-DM1) were investigated with univariate and multivariable analyses (MVA).67 HER2 + patients with 223 BrM were identified. 21 patients (31.3%) were treated with T-DM1 post-SRS, including 14 patients (20.9%) who received T-DM1 within 12 months of SRS. The median follow-up was 15.6 (interquartile range (IQR) 5.4-35.3) months. The overall probability of RN post-SRS was 21.6% (95% confidence interval (CI) 2.7-10.7), and the 1 and 2 year risk was 6.7% (95% CI 2.7-10.7) and 15.2% (95% CI 9.2-21.3). MVA identified T-DM1 treatment post-SRS (hazard ratio (HR) 2.5, 95% CI 1.2-5.3, p = 0.02) and equivalent dose in 2 Gy fractions (EQD2) 90 GyT-DM1 exposure post-SRS was associated with a higher risk of RN among patients with HER2 + BrM.

Background: For patients with ABC being treated with CDK4/6is palliative (RT may still be necessary to metastatic sites that are symptomatic or at risk for complications. Although preclinical data suggests synergy between CDK4/6is and RT, clinical data regarding the safety of this combination are conflicting, with some reports of increased toxicity in the radiation field. Our aim was to review the practice regarding holding CDK4/6is during RT and subsequent clinical outcomes at the cancer centre with the largest volume of ABC patients in Canada. Methods: Chart review was completed for 313 ER positive and Her2 ABC pts treated with CDK4/6is at the Sunnybrook Health Sciences Centre from 2016 to 2020. All patients who received RT during the course of treatment with CDK4/6is were included in this analysis. Greater than expected toxicity events were defined as higher than grade 1 non-hematological toxicity as per Common Terminology Criteria for Adverse Events during RT or in the 30 days post RT. Descriptive statistics were used for demographics and treatment outcomes. Results: Fifty patients received RT to 74 different sites during treatment with CDK4/6is (46 palbociclib and 4 ribociclib). Median age was 56 (41-88) years. Most frequent RT sites were: bone (n=51), brain (n=7), lung (n=4), breast (n=4) and liver (n=3). CDK4/6is were held during RT of 55 sites (37 patients), starting a median of 7 (0-43) days prior to first fraction of RT and restarted a median of 7 (0-71) days after completing the RT. A CDK4/6i was administered concomitantly with RT to 19 sites (15 patients). No greater than expected toxicity was observed in patients for whom the CDK4/6i was held during RT. Among patients who received concomitant treatment, we observed 4 non-hematological adverse events (21%) in organs included in the field of radiation. In combination with palbociclib we observed grade 3 colitis after 30 Gy to hip/pelvis bones, grade 2 esophagitis after 30 Gy to C1-C4 vertebrae and grade 2 enteritis after 30 Gy to the upper femur. In combination with ribociclib one patient developed grade 3 hepatitis after 20Gy to T10-L2 vertebrae. Conclusions: This retrospective observational study of 50 patients with advanced ER positive Her2 negative BC treated with CDK4/6is who received palliative RT demonstrated a high rate of radiation toxicity (21%) in those patients for whom the CDK4/6i was given concurrently. Quality improvement work in this area, including practice guidelines, is warranted. Citation Format: Neda Stjepanovic, Alia Thawer, Dilshad Nathoo, Danilo Giffoni, Maria Romero, Anthony Lott, Andrea Eisen, Rossanna Pezo, Katarzyna Jerzak, Maureen Trudeau, Sonal Gandhi, Ellen Warner. Radiation therapy (RT) induced toxicity in advanced breast cancer (ABC) patients treated with CDK4/6 inhibitors (CDK4/6is) [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 PS11-20.

Background: For Hormonal Receptor positive/HER2 negative (HR+/HER2-) metastatic Breast Cancer (mBC) the optimal treatment post-progression on a CDK4/6 inhibitor is still not defined. We aim to identify real-world patterns of systemic treatment choice following palbociclib use at a large tertiary cancer centre and to determine the outcomes for this patient population. Methods: We identified HR+/HER2- mBC patients treated with palbociclib between January 2016 and June 2020 using the institutional computerized prescriber order entry (CPOE) system. Patients with a 2nd primary other than breast, male, or with HER 2 overexpression were excluded. Electronic medical records were retrospectively reviewed to determine clinical, pathological characteristics, and treatment patterns. Our primary outcome was Time to Treatment Failure (TTF) for the subsequent treatment, using the Kaplan Meier survival method. Results: A total of 136 patients were included. At first diagnosis the median age was 52 years; 52% were premenopausal, the most prevalent primary tumor features were ductal histology (79%), and lymph node positive disease (54%). Regarding initial treatment 77% underwent surgery, 52% had adjuvant radiation therapy, 61% had chemotherapy (CT) and 67% had endocrine therapy (ET). The most frequent metastatic sites were bone 70%, liver 36%, and lung 33%. 63 tumors were rebiopsied, in 21 (33.3%) biomarkers had changed. Palbociclib was indicated as 1 Line in 45% of patients, 2 Line 26%, and ≥ 3 Line 27%. The most tolerated dose was 75 mg (44% v 33% tolerating 125 mg). The most prescribed endocrine backbones were AI (66%) and fulvestrant (30%). mTTF was 29.9 mo. (95%CI 12.68-47.11) for 1L, 33.2 mo. (95%CI 22.45-44.08) for 2L, 7.03 mo. (95%CI 2.29-11.76) for ≥ 3L. After a median follow-up of 18.7 mo, 74 patients (54%) had discontinued palbociclib due to progression (46%), toxicity (5%), or death (4%). Sites of progression were liver 37%, bone 29%, pleura 11%, lung 10% and peritoneum 6.5%. 63 patients had subsequent systemic therapy, with mTTF of 5.6 mo. 46 patients (34%) received chemotherapy, 29 patients had capecitabine, mTTF was 4.8 mo. 13 patients (9%) received endocrine therapy, 9 patients had fulvestrant +/- others, mTTF was 8.9 mo. For 5 patients (4%) the subsequent treatment was CDKi-based, 4 patients continued with palbociclib plus another endocrine backbone, mTTF was 16.5 mo. Only 1 patient (.7%) received everolimus-based subsequent treatment, with a TTF 5.6 mo. Conclusion: In this real-world analysis, we found that palbociclib was most tolerated at 75 mg and most prescribed with an AI. After progression on CDKi, the tendency was to prescribe a chemotherapy-based subsequent line, mainly capecitabine. Citation Format: Maria Luisa Romero Lagunes, Faisal Sickandar, Alia Thawer, Neda Stjepanovic, Katarzyna Jerzak, Maureen Trudeau, Andrea Eisen, Sonal Gandhi, Ellen Warner, Danilo Giffoni M. M. Mata, Abdullah MA Al-Humiqani, Anthony Lott, Rossanna C Pezo. Single-centre retrospective study of treatment choices and outcomes of metastatic breast cancer post-progression on the CDK4/6 inhibitor palbobiclib [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 PS10-54.

Background: Pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) is associated with improved survival outcomes among women with HER2 positive (HER2+) breast cancer. We aimed to analyze the clinical, pathological and molecular factors associated with pCR in our series of HER2+ breast cancer patients. Methods: Between 2009 and 2019, breast cancer patients receiving NAC at our centre were enrolled in a prospective database. For this study we selected women with HER2+ unilateral breast cancer stages II or III who received anthracycline-taxane NAC regimens (with trastuzumab given concurrently with the taxane) and subsequently underwent breast and axillary surgery with curative intent. Medical charts of these 161 women were retrospectively reviewed to determine what clinical, pathological and molecular characteristics were associated with pCR using bivariate and multivariate analysis. Results: Of the 161 HER2+ women median age at diagnosis was 49 years (range 25-78) with 90 (56%) women under age 50. Total of 104 (65%) tumors were stage II, 108 (67%) expressed estrogen and/or progesterone receptors, 139 (86%) had HER2 3+ expression by immunohistochemistry (IHC) and 22 (14%) had HER2 IHC 2+ expression with amplified HER2 on fluorescence in situ hybridization (FISH) test. The NAC regimens were: Doxorubicin-Cyclophosphamide-Paclitaxel for 83 (52%) and Fluorouracil-Epirubicin-Cyclophosphamide-Docetaxel for 78 (48%) women. A total of 73 patients [45%; 44/108 HR+ (41%) and 29/53 HR- (55%)] achieved pCR (p=0.94). pCR rate among HER2 IHC 3+ tumors was 69/139 (50%), while for HER2 IHC 2+ tumors was 4/22 (18%). On bivariate analysis HER2 IHC 3+, absence of estrogen receptors and absence of progesterone receptors were predictive of pCR, while age, menopausal status, histologic subtype, tumor grade and NAC regimen were not. In the multivariate model only HER2 IHC 3+ expression remained a significant predictor of pCR (OR =4.443, 95% CI 1.376 - 14.344). Conclusion: Our analysis suggests that for HER2+ breast cancers treated with NAC with anthracycline-taxane and trastuzumab, HER2 IHC 3+ expression is associated with a higher rate of pCR compared to HER2 IHC 2+ expression with FISH amplification. Further analysis in a larger cohort is warranted. Citation Format: Neda Stjepanovic, Katarzyna Jerzak, Maureen Trudeau, Andrea Eisen, Sonal Gandhi, Ellen Warner, Danilo Giffoni MM Mata, Anthony Lott, Maria Romero, Sharon Lemon-Wong, Althea VanMassop, Xingshan Cao, William Tran, Rossanna Pezo. Analysis of factors associated with pathological complete response (pCR) in patients with HER2+ breast cancer receiving neoadjuvant chemotherapy [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 PS10-33.

Observational studies have suggested that HER2 inhibition with trastuzumab may be associated with an increased incidence of intracranial metastatic disease (IMD) due to its ability to prolong survival. We hypothesized that prolonged survival associated with dual-agent HER2 inhibition may be associated with an even higher incidence of IMD. This study pooled estimates of IMD incidence and survival among patients with HER2-positive breast cancer receiving dual- versus single-agent HER2 targeted therapy, as well as trastuzumab versus chemotherapy, observation, or another HER2-targeted agent. We searched PubMed, EMBASE, and CENTRAL from inception to 25 March 2020. We included randomized controlled trials that reported IMD incidence for patients with HER2-positive breast cancer receiving trastuzumab as the experimental or control arm irrespective of disease stage. Among 465 records identified, 19 randomized controlled trials (32,572 patients) were included. Meta-analysis of four studies showed that dual HER2-targeted therapy was associated with improved overall survival (HR 0.76; 95% CI, 0.66–0.87) and progression-free survival (HR 0.77; 95% CI, 0.68–0.87) compared to single HER2-targeted therapy, but the risk of IMD was similar (RR 1.03; 95% CI, 0.83–1.27). Our study challenges the hypothesis that prolonged survival afforded by improved extracranial disease control is associated with increased IMD incidence.

This systematic review examines the proportion of patients with leptomeningeal disease included in phase 3 randomized clinical trials for patients with metastatic breast cancer, lung cancer, and melanoma.

ImportanceIntracranial metastatic disease (IMD) is a severe complication of cancer with profound prognostic implications. Patients with IMD in the setting of limited or stable extracranial disease (IMD-SE) may represent a unique and understudied subset of patients with IMD with superior prognosis.ObjectiveTo evaluate overall survival (OS), progression-free survival (PFS), and intracranial PFS (iPFS) in patients with IMD-SE secondary to any primary cancer.Data SourcesRecords were identified from MEDLINE, EMBASE, CENTRAL, and gray literature sources from inception to June 21, 2021.Study SelectionStudies in English reporting OS, PFS, or iPFS in patients with IMD-SE (defined as IMD and ≤2 extracranial metastatic sites) and no prior second-line chemotherapy or brain-directed therapy were selected.Data Extraction and SynthesisAuthor, year of publication, type of study, type of primary cancer, and outcome measures were extracted. Random-effects meta-analyses were performed to estimate effect sizes, and subgroup meta-analysis and metaregression were conducted to measure between-study differences in February 2022.Main Outcomes and MeasuresThe primary end point was OS described as hazard ratios (HRs) and medians for comparative and single-group studies, respectively. Secondary end points were PFS and iPFS.ResultsOverall, 68 studies (5325 patients) were included. IMD-SE was associated with longer OS (HR, 0.52; 95% CI, 0.39-0.70) and iPFS (HR, 0.63; 95% CI, 0.52-0.76) compared with IMD in the setting of progressive extracranial disease. The weighted median OS estimate for patients with IMD-SE was 17.9 months (95% CI, 16.4-22.0 months), and for patients with IMD-PE it was 8.0 months (95% CI, 7.2-12.8 months). Pooled median OS for all patients with IMD-SE was 20.9 months (95% CI, 16.35-25.98 months); for the subgroup with breast cancer it was 20.2 months (95% CI, 10.43-38.20 months), and for non–small cell lung cancer it was 27.5 months (95% CI, 18.27-49.66 months). Between-study heterogeneity for OS and iPFS were moderate (I2 = 56.5%) and low (I2 = 0%), respectively.Conclusions and RelevanceIn this systematic review and meta-analysis of patients with IMD-SE, limited systemic disease was associated with improved OS and iPFS. Future prospective trials should aim to collect granular information on the extent of extracranial disease to identify drivers of mortality and optimal treatment strategies in patients with brain metastases.

Background: The 49% decrease in breast cancer mortality since 1986 has increased the number of breast cancer survivors requiring survivorship care. The purpose of this analysis was to estimate the 2022 prevalence of breast cancer survivors diagnosed within the past 15 years among Canadian women. Methods: We extracted the projected female breast cancer cases from 2007 to 2021 and rates of net survival (competing noncancer causes of death removed) from the Canadian Cancer Society’s statistical reports. Overall survival was extracted from published Ontario data. Using known survival rates for 1, 5, 10, and 15 years, we interpolated remaining years and applied the corresponding net and overall survival rates to the projected cases for each year from 2007 to 2021 to determine survivors in 2022. Prevalence for predefined age groups was also calculated. As an example of excess healthcare costs attributable to breast cancer, we calculated the excess costs of heart failure hospitalizations. Results: From 2007 to 2021, there were 370,756 breast cancer cases. Using net survival, 318,429 (85.9%) of these patients were projected to survive breast cancer by 2022, a prevalence of 2.1% of Canadian women. Using overall survival, prevalence was 1.8%. Prevalence increased with age group, from 0.01% of those aged 20 to 24 years to 12.7% of those aged ≥90 years, and from 1.0% among the working and/or child-raising (age 20–64 years) to 5.4% among elderly populations (age ≥65 years). Among these survivors, 24.9% of projected heart failure hospitalizations would be in excess of those among matched control subjects, with projected excess costs of $16.5 million CAD. Given the excess healthcare costs, potential for reduced contributions to the workforce, and reduced quality of life associated with long-term impairments and risk of excess non–breast cancer death, enhanced breast cancer survivorship care is warranted. Conclusions: With an overall prevalence of 2% among Canadian women, breast cancer survivors represent an increasing segment of the working-age and elderly populations.

Purpose We sought to expand the currently limited, Canadian, population-based data on the characteristics, treatment pathways, and health care costs according to stage in patients with human epidermal growth factor receptor-2 positive (HER2+) breast cancer (BC). Methods We extracted data from the publicly funded health care system in Ontario. Baseline characteristics, treatment patterns, and health care costs were descriptively compared by cancer stage (I–III vs. IV) for adult women diagnosed with invasive HER2+ BC between 2012 and 2016. Resource use was multiplied by unit costs for publicly funded health care services to calculate costs. Results Overall, 4535 patients with stage I–III and 354 with stage IV HER2+ BC were identified. Most patients with stage I–III disease were treated with surgery (4372, 96.4%), with the majority having a lumpectomy, and 3521 (77.6%) received radiation. Neoadjuvant (NAT) and adjuvant (AT) systemic treatment rates were 20.1% (n = 920) and 88.8% (n = 3065), respectively. Systemic treatment was received by 311 patients (87.9%) with metastatic HER2+ BC, 264 of whom (84.9%) received trastuzumab. Annual health care costs per patient were nearly 3 times higher for stage IV vs. stage I–III HER2+ BC. Conclusion Per-patient annual costs were substantially higher for women with metastatic HER2+ BC, despite less frequent exposure to surgery and radiation compared to those with early stage disease. Increasing NAT rates in early stage disease represent a critical opportunity to prevent recurrence and reduce the costs associated with treating metastatic HER2+ BC.

PURPOSE: Iron is essential to energy metabolism, cell proliferation and DNA synthesis, and sufficient iron availability may be required for tumor growth. The hormone hepcidin is a systemic regulator of iron concentration in plasma. Intra-tumor RNA expression of hepcidin has been linked to shorter metastasis-free survival in women with early breast cancer, but the prognostic implications of this inflammatory marker and iron-regulating plasma peptide in the blood are unknown. METHODS: Using an ELISA assay, hepcidin was measured in the banked blood of 518 women who were recruited from 1989 to 1996 for a prospective cohort study of diet and lifestyle factors in breast cancer. Blood samples were obtained 4–12 weeks post-operatively, prior to treatment with chemotherapy or tamoxifen. RESULTS: Hepcidin was not associated with time to distant breast cancer recurrence (primary outcome) nor time to death from any cause. However, a pre-planned interaction test of body mass index (BMI) was statistically significant (p < 0.01). Among obese women (BMI > 30 kg/m(2)), higher hepcidin was associated with a shorter time to distant breast cancer recurrence in both uni- and multivariable analyses (adjusted HR 1.84; 95% CI 1.04–3.25). For overall survival, a similar pattern was seen in the univariable model but the effect was diminished in a multivariable analysis. Plasma hepcidin was not associated with high-sensitivity C-reactive protein, but it was significantly associated (r ≥ 0.32) with iron indices, including total iron (p < 0.01), transferrin (p < 0.01) and soluble transferrin receptor (p < 0.01). CONCLUSIONS: Hepcidin may be associated with poor breast cancer outcome in obese women, however, replication is required. The biologic basis for this prognostic association requires further research.

Background There have been few publications exploring the characteristics, treatment pathways, and health‐care costs by stage in patients with a triple‐negative breast cancer (TNBC) phenotype. Methods Data from a publicly funded health‐care system in Ontario were assessed. Baseline characteristics, treatment patterns, and health‐care costs were descriptively compared by cancer stage (I‐III vs IV) for adult women diagnosed with invasive TNBC between 2012 and 2016. Resource use was multiplied by unit costs for publicly funded health‐care services to calculate health system‐related costs. Results A total of 3271 cases were identified, 3081 with stage I‐III and 190 with stage IV TNBC. Baseline characteristics were aligned with previous reports. Surgery was the most common treatment among patients with stage I‐III disease (n = 2979, 96.7%); 557 (18.7%) received neoadjuvant therapy (NAT) and 1974 (66.3%) received adjuvant therapy (AT), the latter at a median of 44 days postsurgery, and 2446 (79.4%) in the stage I‐III cohort received radiation. Treatment for metastatic TNBC included surgery in 48 (25.3%), systemic therapy in 138 (72.6%), and radiotherapy in 112 (58.9%) patients. Top drug regimens included anthracyclines/taxanes. Annual per‐patient health care costs were four times higher for stage IV vs. stage I‐III TNBC. Conclusion Per‐patient costs were higher in metastatic TNBC, despite a less frequent use of all treatment modalities compared to early TNBC. Treatment patterns were aligned with the options available at the time; however, neoadjuvant treatment rates were low., Characteristics and treatment patterns of Ontario patients diagnosed with TNBC are similar to that of other contemporary reports; however, it appears that uptake of neoadjuvant therapy could be improved. Cost of metastatic disease is high and novel treatments should be adopted and evaluated for their impact.

Background: Since the discovery of HER2-targeted treatments for HER2+ breast cancer (BC), women with this historically poor-prognosis subtype have benefitted from dramatic improvements in outcome. As treatment algorithms and staging become more personalized, there is increasing value in understanding real-world clinical characteristics of patients, as well as treatment patterns, resource use and outcomes. To our knowledge, no such data currently exist by BC subtype and stage in one single cohort. Methods: We retrospectively collected data for women aged 18-105 years, residing in Ontario, utilizing the public healthcare system, and diagnosed with invasive BC from Apr 1, 2012 to Mar 31, 2016. Data were extracted from datasets housed by the Institute for Clinical Evaluative Sciences. Women with HER2+ pathology were identified and baseline characteristics, treatment patterns, and healthcare resource use were descriptively compared between stage I-III and stage IV sub-cohorts. Outcomes assessed included 5-year overall survival (OS) rates by stage. Patients alive/lost to follow-up at the end of the study period (Mar 31, 2017) were censored. Unit costs (2017 CAD $) for publicly funded healthcare services were multiplied by resources used in order to calculate total and annual health-system related costs. Results: In total, 4,889 women were identified as having HER2+ BC; 4535 with stage I-III and 354 with stage IV disease at diagnosis. Patients with stage IV HER2+ BC more frequently had larger or unknown tumour size and lower hormone receptor positivity rates than those with stage I-III tumours. With a median follow-up of 34.1, 33.7, 32.2 and 21.4 mos, 5-year OS rates were 96.5, 87.5, 79.9 and 36.6% for stage I, II, III, and IV, respectively. Surgery was the most common treatment modality in stage I-III (n=4372, 96.4%) and least common in stage IV (n=82, 23.2%). Among patients treated with upfront surgery for early stage disease (n=3451, 78.9%), 3135 (90.8%) received adjuvant systemic therapy (AT) with a median time from surgery to treatment of 42 days (IQR: 26,56). The remaining 921 stage I-III patients (20.1%) received neo-AT starting a median of 28 days (IQR: 21,39) after diagnosis, with 912 (99.0%) also receiving AT. In total, 3521 (77.6%) of patients with stage I-III BC received radiation. Among patients with metastatic HER2+ BC, 314 (88.7%) received systemic therapy and 213 (60.2%) were treated with radiotherapy. Annual mean healthcare cost per person was $54,852.39 for stage I-III and $159,347.97 for stage IV HER2+ BC. In the stage I-III sub-cohort, pharmaceuticals and cancer clinic visits accounted for ~70% of measured resource costs, whereas pharmaceuticals and inpatient hospital services were the main cost contributors for patients with stage IV disease. Conclusions: Characteristics and clinical outcomes were as expected for our Ontario-based population of women with HER2+ BC. Patients appeared to be treated within reasonable timeframes and in alignment with the strategies recommended by Cancer Care Ontario at the time of the study. Improvements in survival of stage IV HER2+ BC coincide with increased resource utilization, largely driven by systemic therapy and inpatient hospitalization. While there are fewer patients with stage IV HER2+ BC, the annual mean cost per person is nearly three-fold higher than in those with early stage disease, and demonstrates a need for interventions that decrease hospitalizations and/or pharmaceutical treatment costs. Citation Format: Christine Brezden-Masley, Kelly Elizabeth Fathers, Megan Coombes, Cloris Xue, Behin Pourmirza, Katarzyna J. Jerzak. A population-based study examining the epidemiology, treatment patterns and resource utilization by stage in Ontario patients with HER2+ breast cancer [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 P2-08-23.

Background: The survival of women with HER2+ metastatic breast cancer (MBC) has improved with the introduction of the anti-HER2 antibody trastuzumab, but responses vary greatly among individuals. A predictive signature of response (and lack thereof) to trastuzumab may help personalize therapy for women with HER2+ MBC and enable the discovery of new “druggable” targets. Methods: In this retrospective cohort study, 256 patients with HER2+ MBC at the Sunnybrook Odette Cancer Centre were identified sequentially from January 1999 to December 2013 using the Cancer Care Ontario Registry. In total, 53 patients (21%) had archived metastatic tissue available for analysis, 29 (55%) of whom had samples obtained 30 months after starting trastuzumab). Results were compared between these two groups of patients using a Fisher’s exact test (dichotomous groups) and Wilcoxon rank sum tests (continuous scores). Univariable Cox regression models were evaluated using all patients, to evaluate if risk scores were prognostic of overall survival (OS). Statistical significance was set at the p=0.05 level and all tests were two-sided. Results: The median patient age was 60 years (interquartile range 53-65 years), 24% (n=7) had de-novo MBC and the majority of patients (52%) had ER or PR positive tumors. Among 29 included patients, the median OS was 23.4 months (95%CI 10.3-34.3 months); 10 patients died within 12 months and 10 patients survived >30 months after starting trastuzumab-based therapy. A median of 155 days (range 4-812) elapsed between metastatic biopsy and initiation of trastuzumab. The distribution of the Prosigna ROR Score, Basal Cor, HER2 Cor, Luminal A Cor, Luminal B Cor, Mammaprint Subtype/Risk Group, Oncotype Risk Score/Risk Group, IHC4 mRNA Risk Group and GGI Risk Score/Risk Group did not differ between the short- and long-term survivors. However, the Mammaprint Predictor Score was significantly higher [mean 0.34 (std 5.50) versus -4.95 (std 5.24), p=0.033] and the IHC4 Risk Score was significantly lower among long-term as compared to short-term survivors [mean 99.3 (std 67.1) versus 160.3 (std 40.9), p=0.044]. The association between molecular gene signatures and OS are described in Table 1. Conclusion: Several gene signatures were associated with OS in this exploratory analysis of women with HER2+ MBC who received trastuzumab-based therapy. The Mammaprint Predictor and the IHC4 Risk Scores differed among short- versus long-term survivors, warranting validation in an independent dataset. Table 1. Univariable Survival Results (n=29)ComparatorHR (95% CI)p-valueProsigna ROR Score/ 10 units1.23 (0.92, 1.65)0.17ProsignaHER2 vs Other1.25 (0.50, 3.13)0.64Basal Cor/ unit3.61 (1.10, 11.78)0.034Her2 Cor/ unit0.99 (0.15, 6.40)0.99Luminal A Cor/ unit0.22 (0.05, 0.95)0.042Luminal B Cor/ unit0.26 (0.06, 1.06)0.060Mammaprint Predictor Score/ unit1.10 (1.02, 1.19)0.015Mammaprint SubtypeHER2 vs Other0.85 (0.37, 2.00)0.72Mammaprint RiskHigh vs Low4.20 (1.37, 12.86)0.012Oncotype Risk Score/ 10 units1.27 (0.95, 1.70)0.11Oncotype Risk GroupHigh vs Intermediate4.83 (0.60, 39.07)0.14IHC4 Risk Score/ 10 units1.09 (1.00, 1.18)0.046IHC4 mRNA Risk GroupHigh vs Intermediate4.83 (0.60, 39.07)0.14GGI Risk Score/ 10 units1.63 (1.02, 2.61)0.043GGI Risk GroupHigh vs Low5.14 (1.13, 23.51)0.035 Citation Format: Katarzyna Joanna Jerzak, Danielle N Desautels, Phillip S Blanchette, Jane Bayani, Sharon Nofech-Mozes, Martin J Yaffe, Gregory Pond, Kathleen I Pritchard, John MS Bartlett. Identifying novel molecular markers of response to trastuzumab in metastatic breast cancer [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 P4-10-29.

Background: There is limited current data on the incidence, clinical characteristics, treatment patterns, and resource utilization in breast cancer patients with a triple negative (TNBC) clinical phenotype (ER-/PR-/HER2-). Moreover, no prior publications have detailed the differences in resource use according to TNBC stage in a publicly funded healthcare setting. Methods: We retrospectively collected data for women aged 18-105 years, residing in Ontario, utilizing the public healthcare system, and diagnosed with invasive BC from Apr 1, 2012 to Mar 31, 2016. Data were extracted from datasets housed by the Institute for Clinical Evaluative Sciences. Women with triple negative pathology were identified and baseline clinical characteristics, treatment patterns, and healthcare resource utilization were descriptively compared between stage I-III and stage IV sub-cohorts. Outcomes assessed included 5-year overall survival (OS) rate by stage. Patients alive/lost to follow-up at the end of the study period (Mar 31, 2017) were censored. Unit costs (2017 CAD $) for publicly funded healthcare services were multiplied by resources used in order to calculate the total and annual health system-related costs. Results: In total, 3,271 women were identified as having TNBC; 3,081 with stage I-III and 190 with stage IV disease at diagnosis. Patients with metastatic TNBC tended to be older (63.9 ± 15.7 years) compared to those with stage I-III disease (58.8 ± 14.4 years). With a median follow-up of 34.5, 32.7, 26.2 and 8.9 mos, 5-year OS rates were 93.3%, 78.9%, 47.2% and 7.4% for stage I, II, III, and IV, respectively. Surgery was the most common treatment modality among patients with stage I-III (n=2,979, 96.7%) and least common in those with stage IV (n=16, 8.4%) disease. Among patients treated with upfront surgery for early stage disease (n=2,419, 81.2%), 1,890 (78.1%) received adjuvant systemic therapy (AT) with a median time from surgery to treatment of 45 days (IQR: 35,62). The remaining 560 patients (18.8%) with stage I-III disease received neo-AT starting a median of 28 days (IQR: 21,39) after diagnosis, with 221 (39.5%) also receiving AT. In total, 2,341 (76.0%) of patients with stage I-III BC received radiation. Among patients with metastatic TNBC, 138 (72.6%) received systemic therapy and 109 (57.4%) were treated with radiotherapy. Annual mean healthcare cost per person was $35,063.96 for stage I-III and $140,160.23 for stage IV TNBC. In both early and metastatic TNBC, cancer clinic visits, in-patient hospitalization, and professional fees were the main contributors to healthcare costs whereas pharmaceutical, home care, day surgery and continuing care contributed Conclusions: Characteristics and clinical outcomes were as expected for our Ontario-based population of women with TNBC. Our data highlights room for improvement related to wait times for surgery and initiation of systemic therapy in patients with early stage TNBC; an important endeavour considering the aggressiveness of this disease. Despite receiving fewer treatment interventions (surgery, pharmacologic and/or radiation), patients with stage IV TNBC incurred more healthcare costs per person than those with earlier stage disease. These data illustrate the treatment patterns and resource utilization for women with TNBC in Ontario and highlight opportunities to improve their outcomes. Citation Format: Christine Brezden-Masley, Kelly Elizabeth Fathers, Megan Coombes, Cloris Xue, Behin Pourmirza, Katarzyna J. Jerzak. A population-based study examining the epidemiology, treatment patterns and resource utilization by stage in Ontario patients with triple negative breast cancer [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 P2-08-08.

Background: Women with locally advanced triple negative breast cancer (LA-TNBC) have a high risk of disease recurrence and are monitored clinically and with annual mammograms. High risk women, such as BRCA1/2 carriers, are additionally monitored for second primary breast cancers (BC) with annual MRIs and may opt for risk reducing mastectomy (RRM) as a prophylactic measure. Our aim was to explore the clinical outcomes of patients (pts) with average BC risk and high BC risk (known BRCA1/2 carriers) who undergo RRM at the time of LA-TNBC diagnosis. Methods: We included 78 consecutive LA-TNBC pts, stages IIB and III, with resectable unilateral disease, treated at the Sunnybrook Health Sciences Centre from 2009 to 2018. Pts who did not undergo systemic chemotherapy and surgical treatment were excluded, as well as pts with a history of prior BC. Medical records were reviewed for clinical outcomes, pathology and germline BRCA1/2 testing results. Log rank test was used to determine the time to recurrence (TTR) and overall survival (OS) differences among women who underwent RRM and those who did not. Results: Median age at diagnosis of LA-TNBC was 49 years (range 27-82) and 14 (18%) pts were BRCA1/2 carriers. All pts underwent neoadjuvant chemotherapy with 27 (35%) presenting complete pathological response. Fifteen pts underwent RRM, out of which seven were BRCA1/2 carriers. Mean follow up time was 34 (2-86) months, during which 25 pts (32%) were diagnosed with distant disease recurrence and none with second primary BC. Median TTR was 10 months (range 1-48) and median OS was 18 months (range 2-86). RRM was not associated with TTR (p=0.45) and OS (p=0.98). Presence of germline BRCA1/2 also did not correlate with TTR (p=0.16) and OS (p=0.21). Conclusions: In our cohort of pts with LA-TNBC, the prognosis was driven by the risk of recurrence rather than the risk of second primary BCs. RRM was not associated with improved clinical outcomes, regardless the BRCA1/2 status and larger studies are required to support this procedure at the time of diagnosis of LA-TNBC. Citation Format: Neda Stjepanovic, Danilo Giffoni, Sonal Gandhi, Katarzyna Jerzak, Sharon Lemon, Karen Ott, Rossanna Pezo, Kathleen Pritchard, Samuel Tabbarah, Maureen Trudeau, Ellen Warner, William Tran, Andrea Eisen. Risk reducing mastectomy in average and high risk patients with locally advanced triple negative breast cancer [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 P5-08-08.

Progress in computing power and advances in medical imaging over recent decades have culminated in new opportunities for artificial intelligence (AI), computer vision, and using radiomics to facilitate clinical decision-making. These opportunities are growing in medical specialties, such as radiology, pathology, and oncology. As medical imaging and pathology are becoming increasingly digitized, it is recently recognized that harnessing data from digital images can yield parameters that reflect the underlying biology and physiology of various malignancies. This greater understanding of the behaviour of cancer can potentially improve on therapeutic strategies. In addition, the use of AI is particularly appealing in oncology to facilitate the detection of malignancies, to predict the likelihood of tumor response to treatments, and to prognosticate the patients' risk of cancer-related mortality. AI will be critical for identifying candidate biomarkers from digital imaging and developing robust and reliable predictive models. These models will be used to personalize oncologic treatment strategies, and identify confounding variables that are related to the complex biology of tumors and diversity of patient-related factors (ie, mining “big data”). This commentary describes the growing body of work focussed on AI for precision oncology. Advances in AI-driven computer vision and machine learning are opening new pathways that can potentially impact patient outcomes through response-guided adaptive treatments and targeted therapies based on radiomic and pathomic analysis.

Metastatic HER2-positive (HER2+) and triple-negative breast cancer (TNBC) confer a 30% or higher risk of developing brain metastases (BrM), but BrM is typically an exclusion criteria for clinical trials, which limits the generalizability of trial results to these patients. We therefore analysed trends in the enrollment of patients with BrM, as well as the use of outcomes specific to the central nervous system (CNS), in phase III clinical trials evaluating systemic therapy for patients with advanced HER2+ and/or TNBC. Notably, 10 of the 34 trials (29%, 95% confidence interval = 15.1%-47.5%) evaluated CNS-specific outcomes and trials that completely excluded patients with BrM were significantly less likely to meet their primary endpoint (n = 6/17, 35%) than those that permitted conditional enrollment (n = 13/15, 87%) (P = .005), suggesting that enrollment of patients with BrM is not detrimental to trial success.

Background: Evaluating histologic grade for breast cancer diagnosis is standard and associated with prognostic outcomes. Current challenges include the time required for manual microscopic evaluation and interobserver variability. This study proposes a computer-aided diagnostic (CAD) pipeline for grading tumors using artificial intelligence. Methods: There were 138 patients included in this retrospective study. Breast core biopsy slides were prepared using standard laboratory techniques, digitized, and pre-processed for analysis. Deep convolutional neural networks (CNNs) were developed to identify the regions of interest containing malignant cells and to segment tumor nuclei. Imaging-based features associated with spatial parameters were extracted from the segmented regions of interest (ROIs). Clinical datasets and pathologic biomarkers (estrogen receptor, progesterone receptor, and human epidermal growth factor 2) were collected from all study subjects. Pathologic, clinical, and imaging-based features were input into machine learning (ML) models to classify histologic grade, and model performances were tested against ground-truth labels at the patient-level. Classification performances were evaluated using receiver-operating characteristic (ROC) analysis. Results: Multiparametric feature sets, containing both clinical and imaging-based features, demonstrated high classification performance. Using imaging-derived markers alone, the classification performance demonstrated an area under the curve (AUC) of 0.745, while modeling these features with other pathologic biomarkers yielded an AUC of 0.836. Conclusion: These results demonstrate an association between tumor nuclear spatial features and tumor grade. If further validated, these systems may be implemented into pathology CADs and can assist pathologists to expeditiously grade tumors at the time of diagnosis and to help guide clinical decisions.

Postpartum breast cancer (PPBC) - which according to new data, can extend to 5-10 years after the birth - are estimated to represent 35-55% of all cases of breast cancer in women younger than 45 years. Increasing clinical evidence indicates that PPBC represents a high-risk form of breast cancer in young women with an approximately 2-fold increased risk for metastasis and death. Yet, the exact mechanisms that underlay this poor prognosis are incompletely understood and, hence, it is unknown why postpartum breast cancer has an enhanced risk for metastasis or how it should be effectively targeted for improved survival. This article is an accompanying resource of the original article entitled "Breast cancer diagnosed in the post-weaning period is indicative for a poor outcome" and present epidemiological data that compare standard prognostic parameters, first site of metastatic disease and survival and metastatic rates in young women with primary invasive breast cancer diagnosed within two years postpartum (PP-BC), in young women diagnosed during pregnancy (Pr-BC) and nulliparous women (NP-BC). Via an international collaboration of 13 centres participating in the International Network on Cancer, Infertility and Pregnancy (INCIP), retrospective data of 1180 patients with primary invasive breast cancer, aged 25-40 years and diagnosed between January 1995 and December 2017 were collected. In particular, tumour-, patient, and therapy-related characteristics were collected. Furthermore, patient files were reviewed thoroughly to assess, for each parity, if and for how long breastfeeding was given. For PP-BC patients, breastfeeding history was used to differentiate breast cancers identified during lactation (PP-BCDL) from those diagnosed post-weaning (PP-BCPW). Primary exposures were prior childbirth or no childbirth, time between most recent childbirth and breast cancer diagnosis, time between cessation of lactation and breast cancer diagnosis and time between breast cancer diagnosis and metastasis or death. Distribution of standard prognostic parameters and first site of distant metastasis among study groups was determined applying fisher's exact, chi-squared, One-Way ANOVA or Kruskal-Wallis tests or logistic regression models, where applicable. The risks for metastasis and death were assessed using Cox proportional hazards models. A subgroup analysis was performed in PP-BCPW patients that never lactated (PP-BCPW/NL), lactated ≤3 months (PP-BCPW/Lshort) or lactated >3 months (PP-BCPW/Llong). ispartof: DATA IN BRIEF vol:38 ispartof: location:Netherlands status: published

BACKGROUND: In young women, a breast cancer diagnosis after childbirth increases the risk for metastasis and death. Studies in rodents suggest that post-weaning mammary gland involution contributes to the poor prognosis of postpartum breast cancers. However, this association has not been investigated in humans, mainly because of missing information on the patient's lactation status at diagnosis. PATIENTS AND METHODS: Clinicopathological data of 1180 young women with primary invasive breast cancer, diagnosed within 2 years postpartum (PP-BC), during pregnancy (Pr-BC), or nulliparous (NP-BC), were collected. For PP-BC patients, breastfeeding history was retrieved to differentiate breast cancers identified during lactation (PP-BCDL) from those diagnosed post-weaning (PP-BCPW). Differences in prognostic parameters, first site of distant metastasis, and risks for metastasis and death were determined between patient groups. RESULTS: Cox proportional hazard models pointed to a twofold increased the risk of metastasis and death in PP-BCPW patients compared with PP-BCDL (hazard ratio [HR] 2.1 [PDRS = 0.021] and 2.9 [POS = 0.004]), Pr-BC (HR 2.1 [PDRS

Approximately 1 in 7 patients with metastatic breast cancer (MBC) will receive radiotherapy for brain metastases (BRM). Significant differences in cumulative incidence of BRM by breast cancer subtype may inform future BRM screening protocols.To describe cumulative incidence of BRM among patients with de novo MBC.In this population-based cohort study, population health administrative databases in Ontario, Canada, held at the ICES were used to identify patients diagnosed with de novo MBC between 2009 and 2018. Given that a code for BRM does not exist within ICES, we analyzed the incidence of radiotherapy for BRM. The median (IQR) follow-up was 19.3 (6.2-39.5) months. A total of 100 747 patients with a new diagnosis of breast cancer between January 2009 and December 2018 were identified. Of these patients, 17 955 were excluded because they had previous or subsequent malignant neoplasms, 583 were excluded because they were younger than 18 years, 974 were excluded because there was an invalid Ontario Health Insurance Plan number or a date of death on or before the index date. Among 81 235 remaining patients, 3916 were identified as having de novo MBC.Treatment with radiotherapy for breast cancer BRM.Cumulative incidence of radiotherapy for BRM accounting for the competing risk of death, and time from MBC diagnosis to brain radiotherapy. Kaplan-Meier analyses were performed for time-to-event end points. Logistic regression was used to account for confounding variables.Among 3916 patients with MBC, 1215 (31.0%) had HR-positive/ERBB2 (formerly HER2)-negative cancer, 310 (7.9%) had ERBB2-positive/HR-positive cancer, 200 (5.1%) had ERBB2-positive/HR-negative cancer, 258 (6.6%) had TNBC, and the remaining 1933 patients (49.4%) had an unknown breast cancer subtype. The median (IQR) age at diagnosis was 63 (52-75). A total of 549 (14.0%) underwent stereotactic radiosurgery or whole brain radiotherapy for breast cancer BRM. Cumulative incidence of BRM was higher among patients with ERBB2-positive/HR-negative breast cancer (34.7%), ERBB2-positive/HR-positive breast cancer (28.1%), and triple-negative breast cancer (21.9%) compared to those with HR-positive/ERBB2-negative breast cancer (12.1%). The median (IQR) time from MBC diagnosis to brain radiotherapy ranged from 7.5 (2.3-17.4) months for patients with TNBC to 19.8 (12.2-35.1) months for those with ERBB2-positive/HR-positive breast cancer.Incidence and time to development of BRM vary significantly by breast cancer subtype. A better understanding of the biology of intracranial metastatic disease may help inform potential screening programs or preventative interventions.

This cohort study determines the proportion of phase 3 clinical trials for patients with metastatic breast cancer, lung cancer, and melanoma that included patients with brain metastases and/or evaluated central nervous system–specific end points.

Importance: Metastatic breast cancer with central nervous system (CNS) metastases carries a poor prognosis. Recently, CDK4/6 inhibitors have demonstrated a progression free survival (PFS) and overall survival benefit when combined with standard endocrine therapy in advanced hormone receptor (HR)+/HER2- breast cancer. Pre-clinical data suggests possible activity of CDK4/6 inhibitors in the brain, but their CNS-specific benefit has not been explored in clinical practice. Methods: We reviewed clinical trials investigating the efficacy of CDK4/6 inhibitors for advanced or metastatic HR+/HER2- breast cancer. We also reviewed pre-clinical studies that demonstrated the ability of CDK4/6 inhibitors to cross the blood-brain barrier (BBB) and halt the growth of brain metastases in animal models. Findings: An ongoing phase II trial (NCT02308020) was designed to investigate the safety and tolerability of abemaciclib for treatment of patients with CNS metastases, with preliminary data showing partial response in some patients. Review of key randomized phase III trials revealed a scarcity of data pertaining to the development of new CNS metastases. Pre-clinical models demonstrate that CDK4/6 inhibitors are able to cross the BBB and can delay the growth of brain metastases. Conclusions: Despite encouraging pre-clinical evidence, there is a lack of clinical data to inform CNS-specific response rates to CDK4/6 inhibitors among patients with metastatic breast cancer. Given that the treatment of patients with breast cancer brain metastases represents an area of unmet medical need, enrollment of patients with CNS metastases in ongoing clinical trials should be encouraged; innovative trials that examine response of CNS metastases to CDK4/6 inhibitors are also of interest.

One of the most prevalent potential therapeutic targets for women with endometrioid endometrial cancer (EC) is the estrogen receptor (ER)/progesterone receptor (PR) pathway. Despite a high proportion of endometrioid ECs being ER and/or PR positive, endocrine therapy is only effective in a minority of women with EC and ultimately patients progress with resistance developing to treatment. A variety of treatment approaches with progestins, selective ER modulators (SERMs) and aromatase inhibitors (AIs) are available. Exploration of these agents is desirable given their favorable toxicity profile. Greater understanding of ER and PR biology may help identify patient populations who will derive benefit and strategies for new therapeutic options. Here we review the clinical efficacy of endocrine therapy in EC, discuss the role of ER and/or PR as prognostic biomarkers, describe disease-specific mechanisms of resistance to endocrine therapy and explore potential strategies to enhance response for the "next generation" of endocrine therapy clinical trials. We also describe the use of endocrine therapy in younger women seeking to pursue fertility sparing options for management of EC.

Research objectives: To conduct a prospective observational study of patient and tumor-related factors in women with high risk hormone receptor (HR)+/HER2- breast cancer (BC) following at least 5 years of adjuvant hormonal therapy, in order to identify risk factors for imminent recurrence. Rationale: Many of the life-threatening BC recurrences in women with HR+HER2- BC take place more than 5 years post-diagnosis, often after completion of adjuvant hormonal therapy. The identification of a biomarker(s) for late BC recurrence could lead to interventional trials to evaluate preventive therapies. We will evaluate whether the presence of blood-based biomarkers [(i) Circulating Tumor Cells (CTCs), (ii) circulating tumor DNA (ctDNA), (iii) tumor markers (CA 15-3, CEA)] and patient factors may predict BC recurrence. Trial design: A prospective cohort of eligible women with previously treated HR+HER2- BC who have not experienced a distant recurrence will be enrolled; patient and circulating factors will be measured annually until distant recurrence or study completion. Host factors (including BMI, lifestyle, medical illness, surgery, trauma and stress, as well as circulating PlGF, VEGF-1 and inflammatory markers) that may contribute to exit of BC cells from dormancy will also be assessed. The primary outcome is distant BC recurrence. Any BC event, including loco-regional recurrence, new breast or other primary cancer will be evaluated as a secondary endpoint. Outcomes will be ascertained by regular self-report (via annual telephone calls) and/or physician report and confirmed by medical record review. Key eligibility criteria: i) Diagnosis of ER and/or PR positive (either or both 10% positive), HER2 negative invasive BC, ii) predicted >1.5-2% annual risk of recurrence (T2, T3 or T4 with any N+;T1 N2+; T2N0 or T1 N1 cancers with high risk genomic scores), iii) receipt of adjuvant endocrine therapy for at least 4 years, with discontinuation planned in the next 12 months or completion of endocrine therapy within the last 5 years, iv) prior adjuvant chemotherapy, targeted therapy and bone targeted therapies are allowed provided they have been completed. Specific aims: 1) Determine if the presence of (i) CTCs, (ii) ctDNA, (iii) CA15-3 and CEA are associated with imminent risk (within 1-2 years) of distant recurrence in the study population. 2) Identify host factors associated with these blood-based biomarkers, as well as clinical outcomes. Statistical methods: A matched case control design (matching for time since completion of adjuvant hormone therapy, baseline T, N and grade) will be used to investigate associations of key study variables with imminent risk of distant recurrence within the next 1-2 years. Measurements of patients who do versus do not recur will be compared over the 1-2 years prior to relapse. Each variable will be allocated one third of a study-wide type one error of 0.05 (2-sided). ROC analyses and multivariable modelling will be used to optimize sensitivity, specificity, PPV and NPV. Available questionnaire data will be summarized at all time-points to generate descriptive survivorship data. Accrual: Starting in August 2018, we plan to recruit 1,000 patients over 2 years at selected Canadian cancer centres. Citation Format: Jerzak KJ, Cescon DW, Chia SK, Bratman S, Ennis M, Stambolic V, Chang M, Dowling R, Goodwin PJ. Exploration of factors associated with imminent risk of late recurrence in hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-12-01.