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Background This study was conducted in order to develop a model for predicting response to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer (LABC) using pretreatment quantitative ultrasound (QUS) radiomics. Methods This was a multicenter study involving four sites across North America, and appropriate approval was obtained from the individual ethics committees. Eighty‐two patients with LABC were included for final analysis. Primary tumors were scanned using a clinical ultrasound system before NAC was started. The tumors were contoured, and radiofrequency data were acquired and processed from whole tumor regions of interest. QUS spectral parameters were derived from the normalized power spectrum, and texture analysis was performed based on six QUS features using a gray level co‐occurrence matrix. Patients were divided into responder or nonresponder classes based on their clinical‐pathological response. Classification analysis was performed using machine learning algorithms, which were trained to optimize classification accuracy. Cross‐validation was performed using a leave‐one‐out cross‐validation method. Results Based on the clinical outcomes of NAC treatment, there were 48 responders and 34 nonresponders. A K‐nearest neighbors (K‐NN) approach resulted in the best classifier performance, with a sensitivity of 91%, a specificity of 83%, and an accuracy of 87%. Conclusion QUS‐based radiomics can predict response to NAC based on pretreatment features with acceptable accuracy., This multi‐institutional study investigated the role of radiomics from quantitative ultrasound (QUS) in predicting the final response to neoadjuvant chemotherapy (NAC) for 82 patients with locally advanced breast cancer (LABC). We had shown the QUS‐radiomics model can predict the response to treatment with an accuracy of 87% from spectroscopic features obtained before the start of NAC.

Background: Radiomics involving quantitative analysis of imaging has shown promises in oncology to serve as non-invasive biomarkers. We investigated whether pre-treatment T2-weighted magnetic resonance imaging (MRI) can be used to predict response to neoadjuvant chemotherapy (NAC) in breast cancer. Materials and Methods: MRI scans were obtained for 102 patients with locally advanced breast cancer (LABC). All patients were treated with standard regimens of NAC as decided by the treating oncologist, followed by surgery and adjuvant treatment according to standard institutional practice. The primary tumor was segmented, and 11 texture features were extracted using the grey-level co-occurrence matrices analysis of the T2W-images from tumor cores and margins. Response assessment was done using clinical-pathological responses with patients classified into binary groups: responders and non-responders. Machine learning classifiers were used to develop a radiomics model, and a leave-one-out cross-validation technique was used to assess the performance. Results: 7 features were significantly (p < 0.05) different between the two response groups. The best classification accuracy was obtained using a k-nearest neighbor (kNN) model with sensitivity, specificity, accuracy, and area under curve of 63, 93, 87, and 0.78, respectively. Conclusions: Pre-treatment T2-weighted MRI texture features can predict NAC response with reasonable accuracy.

Background Neratinib has efficacy in central nervous system (CNS) metastases from HER2‐positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus capecitabine (L + C). Materials and Methods NALA was a randomized, active‐controlled trial in patients who received two or more previous HER2‐directed regimens for HER2‐positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to N + C (neratinib 240 mg per day, capecitabine 750 mg/m2 twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m2 twice daily) orally. Independently adjudicated progression‐free survival (PFS), overall survival (OS), and CNS endpoints were considered. Results Of 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (N + C, n = 51; L + C, n = 50); 81 had received prior CNS‐directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41–1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59–1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for N + C versus 36.0% for L + C, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (n = 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed. Conclusion These analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2‐positive MBC. Implications for Practice In a subgroup of patients with central nervous system (CNS) metastases from HER2‐positive breast cancer after two or more previous HER2‐directed regimens, the combination of neratinib plus capecitabine was associated with improved progression‐free survival and CNS outcomes compared with lapatinib plus capecitabine. These findings build on previous phase II and III studies describing efficacy of neratinib in the prevention and treatment of CNS metastases, and support a role for neratinib as a systemic treatment option in the management of patients with HER2‐positive brain metastases following antibody‐based HER2‐directed therapies., This article reports outcomes among HER2‐positive breast cancer patients with central nervous system metastases at baseline from the phase III NALA trial of neratinib plus capecitabine versus lapatinib plus capecitabine.

Background: Neratinib (NERLYNX®), an irreversible pan-HER tyrosine kinase inhibitor, is used for the extended adjuvant treatment of patients with early-stage HER2-positive (HER2+) breast cancer following adjuvant trastuzumab-based therapy and for patients with HER2+ metastatic breast cancer in the 3rd-line setting. Diarrhea, particularly in the first 1-2 months, is the main tolerability concern with neratinib and is common in the absence of proactive management. In the ExteNET trial, where no mandatory prophylaxis was used, the rate of grade 3 diarrhea was 40%, 34% of patients experienced at least 1 dose hold, and 17% of patients discontinued due to diarrhea. The CONTROL trial previously showed that pre-emptive antidiarrheal prophylaxis (loperamide alone or in combination with budesonide or colestipol) or dose escalation (DE) reduced the rate, severity, and duration of neratinib-associated grade ≥3 diarrhea compared with ExteNET. Currently, antidiarrheal prophylaxis is initiated with the first dose of neratinib and used during the first 2 cycles of treatment (US PI). Updated findings from two DE cohorts in CONTROL are reported. Methods: CONTROL is an international, multi-cohort, open-label, phase 2 study. Patients ≥18 years with stage I-IIIc HER2+ breast cancer were treated with neratinib (240 mg/day for 1 year) after trastuzumab-based adjuvant therapy. Patients were enrolled sequentially into separate cohorts including 2 dose-escalation cohorts: DE1 (neratinib 120 mg/day on days 1-7, 160 mg/day on days 8-14, then 240 mg/day to day 365) + loperamide as needed (PRN); and DE2 (neratinib 160 mg/day on days 1-14, 200 mg/day on days 15-28, then 240 mg/day to day 365) + loperamide PRN. Adverse events were graded per NCI-CTCAE v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. Data cut-off: May 1, 2020. Results: Complete data for DE1 (60 patients) and interim data for the ongoing DE2 (60 patients) are presented. All patients in DE1 were off study and 40 (66.7%) of patients remained on treatment in the ongoing DE2. The median treatment duration for DE1 was 12.0 months (IQR 11.1-12.0) and for DE2 was 3.7 months (IQR 1.6-9.1). Overall, 48% and 57% of DE1 and DE2 patients, respectively, had prior pertuzumab; 0% and 3%, respectively, had prior T-DM1. The majority of patients in both DE1 and DE2 dose-escalated to 240 mg on planned schedule. The incidence of grade ≥3 diarrhea was 13.3% in DE1 and 20.0% in DE2. The median cumulative duration of grade ≥3 diarrhea over the entire 12-month treatment period was 3 days (range 1-6 days) for DE1 and 2 days (range 1-7 days) for DE2. In both DE1 and DE2, 7 patients (11.7%) had at least one dose hold while on study (none during escalation phase in DE1 and 4 during escalation phase in DE2). In both DE1 and DE2, 2 (3.3%) patients discontinued neratinib because of diarrhea (1 during escalation phase in each cohort). Updated data for the DE2 cohort will be presented. Conclusions: Adoption of neratinib DE reduced the incidence, severity, and duration of neratinib-associated diarrhea in CONTROL compared with ExteNET. DE1 was associated with low rates of dose holds and diarrhea-related discontinuations compared with all previously mandated prophylaxis strategies investigated in CONTROL and with ExteNET. Together these results show improved tolerability of neratinib with DE and suggest that DE combined with loperamide PRN may allow patients to stay on neratinib for the recommended period of time. Neratinib dose escalation scheme 1 (n=60)Neratinib dose escalation scheme 2 (n=60)On neratinib treatment, %066.7Median duration of treatment, months12.03.7Diarrhea, %Grade 140.041.7Grade 245.033.3Grade 313.320.0Grade 400Discontinuation rate due to diarrhea, %3.33.3At least one dose hold due to diarrhea, %11.711.7 Citation Format: Manuel Ruiz-Borrego, Arlene Chan, Gavin Marx, Adam Brufsky, A Jo Chien, Michael Thirlwell, Maureen Trudeau, Ron Bose, José A García-Sáenz, Daniel Egle, Daniel Hunt, Utpal Khambholja, Leanne McCulloch, Naisargee Shah, Debu Tripathy, Carlos H Barcenas, the CONTROL Investigators. Bringing diarrhea under CONTROL: Dose escalation reduces neratinib-associated diarrhea and improves tolerability in HER2-positive early-stage 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 PS13-20.

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.

Background: The development of central nervous system (CNS) metastases presents a considerable challenge in metastatic breast cancer (MBC) due to the limited availability of evidence-based treatments. Up to 50% of patients with HER2-positive (HER2+) MBC develop CNS metastases during the course of their disease. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated activity against CNS metastases in HER2+ MBC in two phase 2 studies (NEfERT-T, TBCRC 022) and one phase 3 study (NALA); significant benefits for predefined CNS endpoints were reported in NEfERT-T and confirmed in NALA. Here we present an exploratory analysis of patients from NALA with CNS involvement at enrollment. Methods: NALA was an international, randomized, open-label, active-controlled, phase 3 study in patients with HER2+ MBC who had received ≥2 lines of HER2-directed therapy in the metastatic setting (ClinicalTrials.gov: NCT01808573). Patients with asymptomatic metastatic brain disease managed with stable doses of corticosteroids for ≥14 days prior to randomization were eligible, whereas patients with symptomatic or unstable brain metastases were excluded. Patients were randomized (1:1 ratio) to neratinib (N; 240 mg qd po) + capecitabine (C; 750 mg/m2 bid po) or lapatinib (L; 1250 mg qd po) + C (1000 mg/m2 bid po). Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Intervention for symptomatic metastatic CNS disease was a secondary endpoint. CNS disease at baseline was defined as patients with treated or untreated disease in the ‘brain’ assessed by investigator at enrollment. CNS imaging was not mandatory at screening. Results: Of the 621 patients enrolled in NALA, 101 (16%) had documented baseline CNS disease and 520 (74%) had no CNS disease at baseline. Patients with CNS disease had a lower performance status and were more likely to have hormone receptor-negative disease than those with no CNS disease; no major imbalances of baseline characteristics were noted between treatment arms. Overall, 78 (77%) patients had previously received CNS radiation [whole brain, n=59 (58%); stereotactic, n=17 (17%); unknown, n=2 (2%)], and 5 (5%) patients had undergone CNS surgery. Median treatment duration was 5.7 (IQR 2.8-8.5) months for N, and 3.5 (IQR 2.1-6.9) months for L. PFS, OS, and cumulative incidence of interventions for symptomatic CNS disease are summarized in the table. No new safety signals were detected. Conclusions: Regardless of the status of CNS metastases at baseline, patients appeared to have better outcomes in the N+C arm compared with the L+C arm. Table. Efficacy outcomes in patients with and without CNS disease at baselineIntention-to-treat (n=621)CNS metastases at baseline – Yes (n=101)CNS metastases at baseline – No (n=520)N+C (n=307)L+C (n=314)N+C (n=51)L+C (n=50)N+C (n=256)L+C (n=264)PFSaHazard ratio (95% CI)0.76 (0.63–0.93)0.66 (0.41–1.05)0.76 (0.62–0.94)P-value0.00590.07410.0099Restricted mean PFSb, months8.86.67.85.59.06.9Difference, months2.22.32.1OSHazard ratio (95% CI)0.88 (0.72–1.07)0.90 (0.59–1.38)0.85 (0.68–1.06)P-value0.20860.63520.1517Restricted mean OSb, months24.022.216.415.425.623.6Difference, months1.71.02.0Incidence of CNS interventionOverall cumulative incidencec, %22.7629.1940.1347.7919.1624.65P-value0.0430.4300.067aCentrally confirmed; bRestriction prespecified as 24 months for PFS, and 48 months for OS; c % requiring intervention for CNS disease (competing risk model) Citation Format: Cristina Saura, Larisa Ryvo, Sara Hurvitz, William Gradishar, Beverly Moy, Suzette Delaloge, Sung-Bae Kim, Mafalda Oliveira, Maureen Trudeau, Ming-Shen Dai, Barbara Haley, Ron Bose, Luciana Landeiro, Judith Bebchuk, Aimee Frazier, Kiana Keyvanjah, Richard Bryce, Adam Brufsky. Impact of neratinib on outcomes in HER2-positive metastatic breast cancer patients with central nervous system disease at baseline: Findings from the phase 3 NALA trial [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 PD13-09.

Purpose We develop a multi-centric response predictive model using QUS spectral parametric imaging and novel texture-derivate methods for determining tumour responses to neoadjuvant chemotherapy (NAC) prior to therapy initiation. Materials and methods QUS Spectroscopy provided parametric images of mid-band-fit (MBF), spectral-slope (SS), spectral-intercept (SI), average-scatterer-diameter (ASD), and average-acoustic-concentration (AAC) in 78 patients with locally advanced breast cancer (LABC) undergoing NAC. Ultrasound radiofrequency data were collected from Sunnybrook Health Sciences Center (SHSC), University of Texas MD Anderson Cancer Center (MD-ACC), and St. Michaels Hospital (SMH) using two different systems. Texture analysis was used to quantify heterogeneities of QUS parametric images. Further, a second-pass texture analysis was applied to obtain texture-derivate features. QUS, texture- and texture-derivate parameters were determined from both tumour core and a 5-mm tumour margin and were used in comparison to histopathological analysis for developing a response predictive model to classify responders versus non-responders. Model performance was assessed using leave-one-out cross-validation. Three standard classification algorithms including a linear discriminant analysis (LDA), k-nearest-neighbors (KNN), and support vector machines-radial basis function (SVM-RBF) were evaluated. Results A combination of tumour core and margin classification resulted in a peak response prediction performance of 88% sensitivity, 78% specificity, 84% accuracy, 0.86 AUC, 84% PPV, and 83% NPV, achieved using the SVM-RBF classification algorithm. Other parameters and classifiers performed less well running from 66% to 80% accuracy. Conclusions A QUS-based framework and novel texture-derivative method enabled accurate prediction of responses to NAC. Multi-centric response predictive model provides indications of the robustness of the approach to variations due to different ultrasound systems and acquisition parameters.

Purpose: To determine whether the androgen receptor (AR) inhibitor, enzalutamide, improves effectiveness of endocrine therapy (ET) in hormone receptor–positive (HR+) breast cancer. Patients and Methods: In this phase II trial, patients with HR+/HER2 normal advanced/metastatic breast cancer were randomized 1:1 to exemestane 25 mg with placebo or exemestane 50 mg with enzalutamide 160 mg daily (NCT02007512). Two parallel cohorts enrolled patients with 0 (cohort 1) or 1 (cohort 2) prior ET for advanced disease. Progression-free survival (PFS) was the primary endpoint in the intent-to-treat (ITT) population of each cohort. Biomarkers were evaluated in an exploratory analysis. Results: Overall, 247 patients were randomized (cohort 1, n = 127 and cohort 2, n = 120). PFS was not improved in either cohort of the ITT population [HR, 0.82 (95% confidence interval (CI), 0.54–1.26); P = 0.3631 for cohort 1 and HR, 1.02 (95% CI, 0.66–1.59); P = 0.9212 for cohort 2]. In cohort 1, high levels of AR mRNA were associated with greater benefit of enzalutamide (Pinteraction = 0.0048). This effect was particularly apparent in patients with both high levels of AR mRNA and low levels of ESR1 mRNA [HR, 0.24 (95% CI, 0.10–0.60); P = 0.0011]. The most common any grade adverse events in the enzalutamide arms were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2. Conclusions: Enzalutamide with exemestane was well tolerated. While PFS was not improved by the addition of enzalutamide to exemestane in an unselected population, ET-naïve patients with high AR mRNA levels, particularly in combination with low ESR1 mRNA levels, may benefit from enzalutamide with exemestane.

Background To investigate quantitative ultrasound (QUS) based higher-order texture derivatives in predicting the response to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer (LABC). Materials and methods 100 Patients with LABC were scanned before starting NAC. Five QUS parametric image-types were generated from radio-frequency data over the tumor volume. From each QUS parametric-image, 4 grey level co-occurrence matrix-based texture images were derived (20 QUS-Tex1), which were further processed to create texture derivatives (80 QUS-Tex1-Tex2). Patients were classified into responders and non-responders based on clinical/pathological responses to treatment. Three machine learning algorithms based on linear discriminant (FLD), k-nearest-neighbors (KNN), and support vector machine (SVM) were used for developing radiomic models of response prediction. Results A KNN-model provided the best results with sensitivity, specificity, accuracy, and area under curve (AUC) of 87%, 81%, 82%, and 0.86, respectively. The most helpful features in separating the two response groups were QUS-Tex1-Tex2 features. The 5-year recurrence-free survival (RFS) calculated for KNN predicted responders and non-responders using QUS-Tex1-Tex2 model were comparable to RFS for the actual response groups. Conclusions We report the first study demonstrating QUS texture-derivative methods in predicting NAC responses in LABC, which leads to better results compared to using texture features alone.

The Edmonton Symptom Assessment Scale (ESAS) is a validated tool used in patients with varied cancer diagnoses to measure patient symptoms. The present manuscript will review the literature assessing the ability of the ESAS to predict patient-related outcomes in breast cancer patients. A literature search was conducted of Cochrane Central Register of Controlled Trials databases, Ovid MEDLINE, and Embase for English articles that investigated the use of predictive modelling with the ESAS in the breast cancer population. Study type, publication year, sample size, patient demographics, predicted outcomes, and strongest predictive factors/symptoms were summarized for each study. A total of nine articles were included in this review. Five articles used the ESAS in predictive models to determine patient time to death. ESAS was also used to predict emergency department visits, determine symptoms associated with decreased quality of life, and generate a Health Utility Score. Lack of appetite was the most common ESAS symptom, as it was reported in five studies to be associated with decreased survival. In four of the nine articles, an additional survey investigating physical functioning was used in combination with ESAS to strengthen the predictive models. Included studies support the use of ESAS in predictive models, particularly for predicting survival. Using the ESAS as a predictive tool allows for more accurate time to death predictions, potentially improving symptom management and preventing overtreatment of palliative patients near the end of life.

ObjectivesThe pan-Canadian Oncology Drug Review (pCODR) evaluates new cancer drugs for public funding recommendations. While pCODR's deliberative framework evaluates overall clinical benefit and includes considerations for exceptional circumstances, rarity of indication is not explicitly addressed. Given the high unmet need that typically accompanies these indications, we explored the impact of rarity on oncology HTA recommendations and funding decisions.MethodsWe examined pCODR submissions with final recommendations from 2012 to 2017. Incidence rates were calculated using pCODR recommendation reports and statistics from the Canadian Cancer Society. Indications were classified as rare if the incidence rate was lower than 1/100,000 diagnoses, a definition referenced by the Canadian Agency for Drugs and Technologies in Health. Each pCODR final report was examined for the funding recommendation/justification, level of supporting evidence (presence of a randomized control trial [RCT]), and time to funding (if applicable).ResultsOf the ninety-six pCODR reviews examined, 16.6 percent were classified as rare indications per above criteria. While the frequency of positive funding recommendations were similar between rare and nonrare indication (78.6 vs. 75 percent), rare indications were less likely to be presented with evidence from RCT (50 vs. 90 percent). The average time to funding did not differ significantly across provinces.ConclusionRare indications appear to be associated with weaker clinical evidence. There appears to be no association between rarity, positive funding recommendations, and time to funding. Further work will evaluate factors associated with positive recommendations and the real-world utilization of funded treatments for rare indications.

Little data exist for comparing cardiac safety and survival outcomes of trastuzumab/pertuzumab or ado-T emtansine (TDM1) in metastatic breast cancer (MBC) patients enrolled in randomized clinical trial (RCT) vs the real-world. This was a retrospective population-based cohort of all patients with MBC treated with trastuzumab/pertuzumab or TDM1 (2012–2017) in Ontario, Canada. Outcomes were incident heart failure (HF) and overall survival (OS). RCT data were obtained from digitizing survival curves and compared with cohort data using Kaplan–Meier analysis. Age-based comparison of outcomes was conducted for patients ≥ 65 years old vs younger than 65. The two cohorts composed of 833 and 397 patients treated with trastuzumab/pertuzumab and TDM1, of whom 5.5% and 7.6% had baseline HF, respectively. Incident HF following trastuzumab/pertuzumab or TDM1 was low (trastuzumab/pertuzumab 1.8 events/100 person years; TDM1 0.02 events/100 person years). The median OS was 39.2 and 56.4 months in the trastuzumab/pertuzumab population-based cohort and CLEOPATRA, respectively. The median OS was 15.4 and 30.9 months in the TDM1 population-based cohort and EMILIA, respectively. Cohort OS was significantly worse than RCT OS (trastuzumab/pertuzumab HR 1.67, 95% CI 1.37–2.03, p

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.

Introduction The introduction of immunotherapy (IO) in the treatment of patients with cancer has significantly improved clinical outcomes. Population level information on actual IO utilization is limited. Methods We conducted a retrospective cohort study using provincial health administrative data from Ontario, Canada to: (1) assess the extent of IO use from 2011 (pre-IO funding) to 2019; and (2) identify factors associated with IO use in patients with advanced cancers for which IO is reimbursed including melanoma, bladder, lung, head and neck, and kidney tumors. The datasets were linked using a unique encoded identifier. A Fine and Gray regression model with death as a competing risk was used to identify factors associated with IO use. Results Among 59 510 patients assessed, 8771 (14.7%) received IO between 2011 and 2019. Use of IO increased annually from 2011 (3.3%) to 2019 (39.2%) and was highest in melanoma (52%) and lowest in head and neck cancer (6.6%). In adjusted analysis, factors associated with lower IO use included older age (hazard ratio (HR) 0.91 (95% CI, 0.89-0.93)), female sex (HR 0.85 (95% CI, 0.81-0.89)), lower-income quintile, hospital admission (HR 0.78 (95% CI, 0.75-0.82)), high Charlson score and de novo stage 4 cancer. IO use was heterogeneous across cancer centers and regions. Conclusion IO utilization for advanced cancers rose substantially since initial approval albeit use is associated with patient characteristics and system-level factors even in a universal healthcare setting. To optimize IO utilization in routine practice, survival estimates and potential inequity in access should be further investigated and addressed.

The blood-brain barrier (BBB) is an important factor limiting the effectiveness of central nervous system (CNS) therapeutics. MR-guided focused ultrasound (MRgFUS) is a noninvasive, spatially precise technology that enhances drug delivery across a temporarily permeable BBB. However, despite promising preclinical data, successful drug delivery has yet to be proven in human patients. In this study, we provide primary evidence of enhanced brain penetration of trastuzumab with MRgFUS in patients with Her2-positive breast cancer and brain metastases (NCT03714243). Four patients with progressive intracranial disease and stable systemic disease were enrolled in a single-arm open-labeled study. Twenty treatments combining transcranial MRgFUS with concomitant standard-of-care intravenous trastuzumab-based therapies were administered as outpatient procedures. The primary outcome was safety, and there were no treatment-related serious adverse events. The efficacy of trastuzumab delivery was demonstrated using

Patients aged 70 years and older may be suboptimally treated with cancer therapy because of the lack of clinical trial data in this population. The Comprehensive Geriatric Assessment can be time consuming, and access to geriatricians is limited. This study aims to determine whether gait speed (GS) analysis is equivalent to the widely accepted Vulnerable Elders Survey 13 (VES-13) in identifying vulnerable or frail patients in need of a Comprehensive Geriatric Assessment.A pilot prospective cohort study was carried out at a tertiary cancer centre in Toronto, Canada, in a radiation oncology breast follow-up clinic. GS analysis and VES-13 were completed by each patient at the same clinic visit. GS of1 meter/second (m/s) and VES-13 score ≥3 were considered abnormal. Sensitivity, specificity, positive and negative predictive values, and Kappa characteristic were calculated for GS compared with VES-13.Twenty-nine participants aged 70 years and older with any stage of breast cancer were included. The GS was 67% sensitive and 95% specific for abnormal VES-13 scores. The GS had an 86% positive predictive value and 86% negative predictive value for abnormal scores on VES-13. Overall, the GS showed a substantial strength of agreement with the VES-13 (kappa 0.66, P.0001).The GS analysis compared very well with VES-13 scores, and this may be a reasonable alternative to VES-13 screening. This pilot data warrant further study in a larger group of patients.

Background For women with lymph node (LN)–positive, estrogen receptor–positive, and her2 (human epidermal growth factor receptor 2)–negative breast cancer (BCa), current guidelines recommend treatment with both hormonal therapy and chemotherapy. The 21-gene Recurrence Score (RS) assay might be helpful in selecting patients with bca who can be spared chemotherapy when they have 1–3 positive lns and a lower risk of recurrence. In the present study, we performed a cost–utility analysis comparing use of the 21-gene rs assay with current practice from the perspective of a Canadian health care payer. Methods A Markov model was developed to determine costs and quality-adjusted life-years (QALYS) over a patient’s lifetime. Patient outcomes in both study groups were examined based on published clinical trials. Costs were derived primarily from published Canadian sources. Costs and outcomes were discounted at 1.5% annually, and costs are reported in 2016 Canadian dollars. A probabilistic analysis was used, and the model parameters were varied in a sensitivity analysis. Results The results indicate that use of the 21-gene rs assay was less costly ($432 less) and more effective (0.22 qalys) than current practice. The probabilistic analysis revealed that 70% of the 10,000 simulated incremental cost-effectiveness ratios were in the southeast quadrant. The results were sensitive to the probability of a low rs and to the probability of receiving chemotherapy in the low-risk rs category and in current practice. Conclusions Use of the 21-gene rs assay could be a cost-effective strategy for Ontario patients with estrogen receptor–positive, HER2-negative early bca and 1–3 positive LNS.

Background The soaring costs of anti‐cancer drugs pose a threat to the sustainability of cancer care. The pricing strategy chosen by manufacturers can impact the costs of oral anti‐cancer drugs during dose modifications, but this issue remains under‐recognized in the literature. In general, with the flat pricing strategy, there is a single fixed price for each tablet regardless of dosage strength, whereas with linear pricing, the price of each tablet increases with its dose. We hypothesize that flat pricing will have increased drug costs compared to linear pricing during dose reductions since the cost remains fixed despite decreased dose requirements. This practice may have significant financial implications considering the high costs, extensive utilization, and frequent occurence of dose reductions with anti‐cancer drugs. Methods Oral anti‐cancer drugs reviewed by the pan‐Canadian Oncology Drug Review program between 2011 and 2018 were identified. The cost per mg and cost per 28‐day cycle were calculated for dose levels −2 to +2. The percent change in cost per mg and cost per cycle during dose modifications from the standard dose were calculated. We conducted Mann‐Whitney U and Fisher‐exact tests to compare the association between drug costs during dose reductions and pricing strategy. Results In this study, 30 oral anti‐cancer drugs for use in 41 indications were analyzed; 44% of drugs used linear pricing and 56% used flat pricing. Dose reductions increased the mean cost per mg for drugs with linear pricing by 14.7% (range: 0%‐50%) at dose level −1 and 17.2% (range: 0%‐50%) at dose level −2 and flat pricing by 60.8% (range: 19%‐100%) at dose level −1 and 99.1% (range: 0%‐300%) at dose level −2. The cost per mg was significantly increased in drugs using flat pricing compared to linear pricing when dose reduction to either level ‐1 (P = 0.010) or level ‐2 (P = 0.006) occurred. The mean cost per cycle was decreased for drugs using linear pricing by 20.9% (range: −40% to 0%) at dose level −1 and 48.7% (range: −60% to −25%) at dose level −2 and flat pricing by 0.8% (range −6% to 0%) at dose level −1 and 11.0% (range: −50% to 100%) at dose level −2. The cost per cycle was significantly decreased in drugs with linear pricing compared to flat pricing when the standard dose is reduced to either dose level ‐1 (P = 0.005) or dose level ‐2 (P = 0.026). Conclusions Overall, flat pricing had significantly greater costs compared to linear pricing during dose reductions of anti‐cancer drugs. While there is a general expectation that the cost of drugs should decrease with dose reduction, drugs with flat pricing were generally found to have increased cost per mg and no change in the cost per cycle. The resultant increased spending on drug acquisition (despite purchasing lower doses) lead to financial wastage, which has significant implications on cost‐effectiveness considerations and budgets. Future economic evaluations should take into consideration the hidden costs associated with dose reductions of flat priced drugs.

Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor. ExteNET, a randomized placebo-controlled phase III study, showed that neratinib given for 12 months after trastuzumab-based adjuvant therapy significantly improved 2-year (HR 0.67; 95% CI 0.50–0.91; p=0.0091) and 5-year (HR 0.73; 95% CI 0.57-0.92; p=0.008) iDFS in pts with early-stage HER2+ breast cancer. Anti-diarrheal prophylaxis was not mandated by protocol; grade 3/4 diarrhea occurred in 40% of pts with a median cumulative duration of 5 days. The phase II CONTROL study was initiated to investigate the effectiveness of various prophylactic regimens in the prevention of neratinib-associated diarrhea. Loperamide (L) alone or in combination with add-on agents targeting underlying inflammation [i.e. budesonide (BUD)] or bile acid malabsorption [i.e. colestipol (COL)] were tested. We report longitudinal HRQoL findings from both ExteNET and CONTROL. Methods: Pts with early-stage HER2+ breast cancer who had received trastuzumab-based adjuvant therapy were eligible for both studies. In ExteNET, pts received neratinib or placebo for 12 months. In CONTROL, pts received neratinib for 13 x 28-day cycles combined with L, L + BUD or L + COL for 1 or 2 cycles (see table for schedules). HRQoL was assessed using Functional Assessment of Cancer Therapy–Breast (FACT-B), v4.0, at baseline, months 1, 3, 6, 9, 12 (ExteNET) or baseline, cycles 2, 4, 7, 10, 13 (CONTROL). Changes in scores from baseline were considered to be clinically meaningful if greater than the lowest estimate for an 'important difference' (ID) reported in the literature. Evaluable pts were required to have HRQoL assessments at baseline and at least 1 post-baseline. ClinicalTrials.gov: NCT00878709 (ExteNET); NCT02400476 (CONTROL). Results: HRQoL findings are summarized in the table. Hospitalization rates due to diarrhea: 1.5% (neratinib + L), 0% (other cohorts) in CONTROL; and 1.4% (neratinib), 0.1% (placebo) in ExteNET. Mean change from baselineStudyCohort/GroupM1M3M6M9M12 FACT-B TOTAL (ID range: 7–8 points)CONTROLN + La,b (N=40)–3.8–4.5–1.5–2.5–3.3 N + L + BUDa,b,c (N=62)–6.0–4.9–1.6–3.6–4.5 N + L + COLa,b,d (N=125)–3.8–2.0–4.0–4.6–3.6 N + L prn + COLa,d (N=85)–1.8–1.54.0e––ExteNETN + L prna (N=1124)–4.6–3.4–3.5–3.3–3.7 P (N=1188)–1.7–3.5–2.9–2.9–2.8 FACT-B PWB (ID range: 2–3 points)CONTROLN + La,b (N=40)–4.0–2.3–1.9–2.4–2.3 N + L + BUDa,b,c (N=62)–3.2–2.1–1.4–1.7–1.7 N + L + COLa,b,d (N=125)–2.8–2.0–2.4–2.5–2.4 N + L prn + COLa,d (N=85)–2.8–1.80.0e––ExteNETN + L prna (N=1124)–2.9–1.9–1.7–1.6–1.5 P (N=1188)–0.6–0.8–0.7–0.6–0.4C, cycle; L, loperamide; M, month; N, neratinib; prn, as needed; PWB, physical well-being. CONTROL cut-off: 1 May 2018. aN 240 mg qd for 13 x 28d cycles or 12 months; bL 4 mg, then 4 mg tid d1-14, then 4 mg bid d15-28 or d15-56, then prn; cBUD 9 mg qd d1-28; dCOL 2 g qd d1-28; en=1. Conclusions: Adjuvant neratinib with or without anti-diarrheal prophylaxis was associated with small decreases in HRQoL. With the exception of the FACT-B PWB subscale, HRQoL changes did not reach clinically meaningful thresholds. Follow-up in CONTROL is ongoing. Citation Format: Delaloge S, Hurvitz S, Chan N, Bose R, Jankowitz RC, Thirlwell M, Láng I, ten Tije A, Trudeau M, Osborne CR, Shen Z-Z, Lalla D, Xu F, Hunt D, Olek E, Tripathy D, Rugo HS, Chien J, Chan A, Barcenas CH. The impact of neratinib with or without anti-diarrheal prophylaxis on health-related quality of life in HER2+ early-stage breast cancer: Analyses from the ExteNET and CONTROL trials [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 P2-13-03.

Background: This study was conducted in order to explore the use of quantitative ultrasound (QUS) based higher-order texture derivatives in predicting recurrence for patients with locally advanced breast cancer (LABC) early during neoadjuvant chemotherapy (NAC). Methods: Eighty-three patients with LABC were scanned with 7 MHz ultrasound before starting NAC (week 0) and during treatment (week 4). Spectral parametric maps were generated corresponding to tumor volume. Twenty-four textural features (QUS-Tex1) were determined from parametric maps acquired using grey-level co-occurrence matrices (GLCM) for each patient, which were further processed to generate 64 texture derivatives (QUS-Tex1-Tex2), leading to a total of 95 features from each time points. Analysis was carried out on week 4 data and compared to baseline (week 0) data. ∆Week 4 data was obtained from the difference in QUS parameters, texture features (QUS-Tex1), and texture derivatives (QUS-Tex1-Tex2) of week 4 data and week 0 data. Patients were divided into two groups based on their clinical status: recurrence and no-recurrence. Machine learning algorithms using k-nearest neighbor (k-NN) and support vector machines (SVM) were used to generate radiomic models. Results: With a median follow up of 69 months (range 7-118 months), 28 patients had disease recurrence. The k-NN classifier was the best performing algorithm at week 4 with sensitivity, specificity, accuracy, and area under curve (AUC) of 87%, 75%, 81%, and 0.83, respectively. The inclusion of texture derivatives (QUS-Tex1-Tex2) in week 4 QUS data analysis led to the improvement of the classifier performances. The AUC increased significantly from 0.70 (without texture derivatives) to 0.83 (with texture derivatives). The most relevant features in separating the two groups were higher-order texture derivatives obtained from scatterer diameter and acoustic concentration-related parametric images. Conclusion: This is the first study highlighting the utility of QUS radiomics in the prediction of recurrence during the treatment of LABC. It reflects that the ongoing treatment-related changes can predict clinical outcomes with higher accuracy as compared to pretreatment features alone. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT00437879 .Registry name: Clinicaltrials.gov.Date of registration: 20th February 2007URL: https://clinicaltrials.gov/ct2/show/study/NCT00437879

Importance Cyclin-dependent kinases 4/6 (CDK4/6) inhibitors had been recently introduced in clinical practice approved for use in hormone receptor (HR) positive/ human epidermal growth factor receptor 2 (HER2) negative advanced or metastatic breast cancer. We report the first incidence of radiation recall reaction with the use of abemaciclib. Observations A 46-year old woman was diagnosed with oligometastatic HR+/HER2- breast cancer (L1 vertebra and right 8th rib). Following mastectomy and sentinel lymph node biopsy, she started letrozole with ovarian suppression. She received loco-regional radiotherapy (RT) to the chest wall and regional lymph nodes to a dose of 50 Gy in 25 fractions using a four-field technique. She was treated with stereotactic body radiotherapy (SBRT) to L1 and rib lesion to a dose of 28 Gy and 24 Gy in 2 fractions, respectively. She had developed grade 2 radiation dermatitis during RT. Subsequently, she was started on palbociclib, which was later switched to abemaciclib 100 mg twice daily due to neutropenia. Three months after switching (14 months after RT), she developed erythema and hyperpigmentation over areas of prior radiation dermatitis. The reaction was grade 2 radiation recall dermatitis (RRD) over the upper back and grade 1 reaction involving axilla, chest wall, and other sites receiving SBRT. The reactions stabilized over the next 3 months with some improvement with the use of emollients and topical steroids. Conclusion and Relevance This is the first incidence of RRD with the use of a CDK4/6 inhibitor upon switching to abemaciclib (receiving reduced dose) from palbociclib. The RRD possibly had a dose-dependent effect with grade 2 reactions developing over areas receiving higher skin dose.

538 Background: Adjuvant chemotherapy in breast cancer (BC) substantially improves overall survival (OS) and the risk of recurrence. The short and long-term side effects of anthracycline, and its modest benefits in the adjuvant setting, led to controversy about its role in comparison with TC. We aim to compare the OS of TC with anthracycline-based regimens in Ontario, the most populous province in Canada. Methods: We conducted a retrospective population-based cohort study using the Institute for Clinical Evaluative Sciences (ICES) database, involving females with stage I-III BC HER2-negative. Patients were treated with adjuvant chemotherapy between January 2009 to December 2017. The anthracycline regimens for comparison were as follows, FEC-D: Fluorouracil, Epirubicin, Cyclophosphamide, followed by Docetaxel; and ACT: Doxorubicin, Cyclophosphamide, followed by Docetaxel or Paclitaxel. Exclusion criteria included missing baseline characteristics, a prior history of malignancy or chemotherapy starting more than 120 days from breast surgery. The end of follow-up was March 31st, 2018. Adjusted analyses to compare OS by positive axillary lymph nodes (LN) and chemotherapy regimens were conducted with Cox proportional hazards models. Results: Of a total 10634 female patients with BC, 60% were ≥ 50 years-old, with 19.6% stage I, 61.1% stage II, and 19.3% stage III and 7130 (67%) women were classified as ER+ and 2379 (22.4%) as ER-. Among 5764 (54.2%) patients with positive LN, 4300 (40.4%) had LN 1-3 and 1464 (13.8%) had LN ≥ 4. There were 4945 (46.5%) high-grade cases. There were 2487 (23.5%) patients treated with TC, 2981 (28%) with ACT, and 5166 (48.5%) with FEC-D. With a median follow-up of 5.5 years, the OS comparison for the entire study population showed hazard ratio (HR) of TC vs ACT was 1.47 (95% CI 1.14 – 1.90), p = 0.0027 and TC vs FEC-D HR was 1.48 (95% CI 1.18 – 1.86), p = 0.0007. For ER+ patients treated with TC, the OS comparison of LN 1-3 and LN ≥ 4 vs. LN 0 showed HR 1.34 (95% CI 0.81 – 2.21), p = 0.26, and HR 4.29 (95% CI 2.09 – 8.79), p < 0.0001, respectively. For ER+ LN 0 patients, the OS HR of TC vs. ACT was 1.15 (95% CI 0.58 – 2.35), p = 0.67, and TC vs. FEC-D HR was 1.38 (95% CI 0.81 – 2.33), p = 0.23. For ER- patients treated with TC, the OS comparison of LN 1-3 and LN ≥ 4 vs. LN 0 showed HR 1.12 (95% CI 0.42 – 3.01), p = 0.82 and HR 4.41 (95% CI 1.33 – 14.59), p = 0.015, respectively. For ER- LN 0 patients, the OS HR for TC vs. ACT was 2.04 (95% CI 1.09 – 3.81), p = 0.025, and TC vs. FEC-D HR was 2.05 (95% CI 1.08 – 3.90), p = 0.028. Conclusions: Patients treated with adjuvant TC who had four or more axillary LN had significantly lower OS when compared to patients with LN 0. For women with ER- disease, TC demonstrated a significant unfavourable survival outcome when compared to anthracycline-based treatments.

PURPOSE The aim of this work is to update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer. METHODS An Expert Panel conducted a targeted systematic literature review guided by a signals approach to identify new, potentially practice-changing data that might translate into revised guideline recommendations. RESULTS The Expert Panel reviewed abstracts from the literature review and identified one article for inclusion that reported results of the phase III, open-label KATHERINE trial. In the KATHERINE trial, patients with stage I to III human epidermal growth factor receptor 2 (HER2)–positive breast cancer with residual invasive disease in the breast or axilla after completing neoadjuvant chemotherapy and HER2-targeted therapy were allocated to adjuvant trastuzumab emtansine (T-DM1; n = 743) or to trastuzumab (n = 743). Invasive disease–free survival was significantly higher in the T-DM1 group than in the trastuzumab arm (hazard ratio, 0.50; 95% CI, 0.39 to 0.64; P < .001), and risk of distant recurrence was lower in patients who received T-DM1 than in patients who received trastuzumab (hazard ratio, 0.60; 95% CI, 0.45 to 0.79). Grade 3 or higher adverse events occurred in 190 patients (25.7%) who received T-DM1 and in 111 patients (15.4%) who received trastuzumab. RECOMMENDATIONS Patients with HER2-positive breast cancer with pathologic invasive residual disease at surgery after standard preoperative chemotherapy and HER2-targeted therapy should be offered 14 cycles of adjuvant T-DM1, unless there is disease recurrence or unmanageable toxicity. Clinicians may offer any of the available and approved formulations of trastuzumab, including trastuzumab, trastuzumab and hyaluronidase-oysk, and available biosimilars. Additional information can be found at www.asco.org/breast-cancer-guidelines

PURPOSE NALA (ClinicalTrials.gov identifier: NCT01808573 ) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

Background Whole breast irradiation therapy (WBRT), accelerated partial breast irradiation (APBI), and omission of radiotherapy (ORT) are options for women aged 65 years and older with low-risk breast cancer post lumpectomy. Aim The aim of the study was to develop and pilot a decision aid pamphlet (DA), among women aged 65 years and older with low-risk breast cancer and who were undergoing or had undergone WBRT, to ensure they were fully informed about the different options for radiation treatment following lumpectomy. Methods We piloted the decision aid with 40 participants, women aged 65-86 years with low-risk breast cancer and who had undergone or were undergoing WBRT. The women completed a pre-DA Decisional Conflict Scale (DCS) and post-DA DCS, Knowledge, Preparation for Decision-Making and Acceptability questionnaires. We then used descriptive statistics to compare the DCS scores before and after distributing the decision aid. Results The median age of the 40 participants was 72 years (range, 65-86 years), 38% less than 70, 48% between 70 and 80 and 15% over 80. Ethnicity included 53% Caucasians and the remaining 48% African-Americans, Asians, Europeans, and others. Thirty-three percent completed high school, 25% college/university, and 7.5% elementary education. Seventy-eight percent had T1 and 23% T2 breast cancer. Thirty-three percent completed RT less than one year prior to the study, 30% between one to two years, and 38% greater than two years. The median pre-DA DCS score was 31.2 (31.2-90.6), and the median post-DA DCS score was 23.4 (0-75.0). Six (6/40) patients scored 0 on the DCS post intervention, while 13 (13/40) scored less than 15.6. The median knowledge score was 70%. Preparation for decision-making median score was 90%. Ninety-nine percent stated that the DA was useful for future patients. Conclusion We piloted a DA that aimed to provide the necessary information for women aged 65 years and older with low-risk breast cancer, to understand radiation treatment options post lumpectomy. The results obtained from the study highlighted the utility of the DA in increasing patient comprehension about the different treatment options, reducing decisional conflict in terms of perceptions of uncertainty and preparing patients to engage with their radiation oncologist during the treatment decision-making process. Ultimately, this study promoted the importance of patient-centered care in geriatric oncology by piloting this DA to see its effectiveness while also being responsive to patient’s thoughts regarding the tool, so as to have their values guide its further development.

Purpose To update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer. Methods An Expert Panel conducted targeted systematic literature reviews guided by a signals approach to identify new, potentially practice-changing data that might translate to revised practice recommendations. Results The Expert Panel reviewed phase III trials that evaluated adjuvant capecitabine after completion of standard preoperative anthracycline- and taxane-based combination chemotherapy by patients with early-stage breast cancer HER2-negative breast cancer with residual invasive disease at surgery; the addition of 1 year of adjuvant pertuzumab to combination chemotherapy and trastuzumab for patients with early-stage, HER2-positive breast cancer; and the use of neratinib as extended adjuvant therapy for patients after combination chemotherapy and trastuzumab-based adjuvant therapy with early-stage, HER2-positive breast cancer. Recommendations Patients with early-stage HER2-negative breast cancer with pathologic, invasive residual disease at surgery following standard anthracycline- and taxane-based preoperative therapy may be offered up to six to eight cycles of adjuvant capecitabine. Clinicians may add 1 year of adjuvant pertuzumab to trastuzumab-based combination chemotherapy in patients with high-risk, early-stage, HER2-positive breast cancer. Clinicians may use extended adjuvant therapy with neratinib to follow trastuzumab in patients with early-stage, HER2-positive breast cancer. Neratinib causes substantial diarrhea, and diarrhea prophylaxis must be used. Additional information can be found at www.asco.org/breast-cancer-guidelines .

Purpose Studies suggest that a subset of patients with triple-negative breast cancer (TNBC) have tumors that express the androgen receptor (AR) and may benefit from an AR inhibitor. This phase II study evaluated the antitumor activity and safety of enzalutamide in patients with locally advanced or metastatic AR-positive TNBC. Patients and Methods Tumors were tested for AR with an immunohistochemistry assay optimized for breast cancer; nuclear AR staining > 0% was considered positive. Patients received enzalutamide 160 mg once per day until disease progression. The primary end point was clinical benefit rate (CBR) at 16 weeks. Secondary end points included CBR at 24 weeks, progression-free survival, and safety. End points were analyzed in all enrolled patients (the intent-to-treat [ITT] population) and in patients with one or more postbaseline assessment whose tumor expressed ≥ 10% nuclear AR (the evaluable subgroup). Results Of 118 patients enrolled, 78 were evaluable. CBR at 16 weeks was 25% (95% CI, 17% to 33%) in the ITT population and 33% (95% CI, 23% to 45%) in the evaluable subgroup. Median progression-free survival was 2.9 months (95% CI, 1.9 to 3.7 months) in the ITT population and 3.3 months (95% CI, 1.9 to 4.1 months) in the evaluable subgroup. Median overall survival was 12.7 months (95% CI, 8.5 months to not yet reached) in the ITT population and 17.6 months (95% CI, 11.6 months to not yet reached) in the evaluable subgroup. Fatigue was the only treatment-related grade 3 or higher adverse event with an incidence of > 2%. Conclusion Enzalutamide demonstrated clinical activity and was well tolerated in patients with advanced AR-positive TNBC. Adverse events related to enzalutamide were consistent with its known safety profile. This study supports additional development of enzalutamide in advanced TNBC.

Introduction: Women over 70 are a growing demographic of breast cancer patients with specific needs requiring individualized care plans. We developed the interdisciplinary Senior Women's Breast Cancer Clinic (SWBCC) to improve access to a comprehensive geriatric assessment (CGA) and allied health services such as social work, occupational therapy, and pharmacy assistance. After initiation of the SWBCC, we conducted a pilot study using the VES-13 (vulnerable elders survey-13) tool to screen all patients over 70 with the goal of focusing referrals for patients who may benefit most from a CGA. The VES-13 was developed for community-dwelling elders and is validated in oncology patients. The objective of this study is to examine the outcomes of VES-13 screening, determine the medical issues identified by the CGA, and describe the development of this clinic. Methods: A retrospective review of the clinic from May 2015 - May 2017 was performed using the electronic medical records and paper screening forms. We separately describe the impact of the VES-13 to manage CGA referrals. A score of 3 or greater is a positive screen, and indicates the patient is at risk for death or decline. Non-parametric descriptive statistics were used for statistical analyses. Results: A total of 25 patients have been seen in the SWBCC for CGA to date. Median age was 83, (range 67-97). A median of two (range 1-4) new medical issues were identified from the CGA for each patient. The most common new diagnoses or issues identified were cognitive impairment (15/25), falls (6/25), neuropathy (4/25), and pain (4/25). The geriatric day program and falls prevention program were common referrals. After the introduction of VES-13 screening, a total of 54 patients were screened. Median age in that group was 78.5 years (range 70-95). The median VES-13 score was 1 (range 0-10). Of the 21 patients screened positive on VES-13, 7 went on to have a CGA. Of the remaining screen-positive patients, 3/21 patients declined SWBCC referral, and the others were not referred at the discretion of the physician. None of the patients with negative VES-13 were referred for CGA. The SWBCC structure was developed to utilize breast cancer-specific resources, whereby geriatricians provide consultation within the oncology space, and the allied health providers were affiliated with the breast centre. Oncology and geriatric administrative staff organized bookings to better coordinate schedules between the two disciplines. The geriatricians supervised trainees for the CGA, and follow-ups took place at SWBCC or in the geriatric outpatient clinic. Clinic coordinators affixed the VES-13 tool to all new patient charts for those aged ≥70. Nursing resources were dedicated to assist patients with VES-13 if needed, and document scores in the electronic medical record. Conclusions: A dedicated clinic for seniors with breast cancer providing geriatric assessment can identify important undiagnosed medical issues that warrant intervention or monitoring during breast cancer treatment. The VES-13 screening tool provides useful information to help manage resources for geriatrics referral. A prospective trial examining the role of CGA in decision-making for adjuvant chemotherapy is underway in this clinic. Citation Format: Menjak IB, Trudeau ME, Mehta R, McCullock F, Bristow B, Wright F, Rice K, Gibson L, Pasetka M, Szumacher EF. Pilot data from the development of the Senior Women's Breast Cancer Clinic at Sunnybrook Odette Cancer Centre [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-10-14.

Purpose This study aimed to evaluate and compare tumor response rates and survival outcomes between single and double hormone receptor (HR) positive (+) [Estrogen Receptor (ER+)/Progesterone Receptor (PR) negative (-) or ER-/PR+ versus ER+/PR+] breast cancer (BC) patients with any HER2 status treated with neoadjuvant chemotherapy at a single institution Methods A retrospective review was conducted using the Sunnybrook “Biomatrix” database to identify eligible patients. A multivariable logistic regression analysis (MLR) was performed to assess the association between HR status (single or double HR+) and pathologic complete response (pCR) rates at surgery. A Kaplan-Meier method was used to estimate Disease Free Survival (DFS) and a log-rank test was used to compare DFS between 3 subgroups of patients: single or double HR+ and HR negative patients Results Three hundred and four BC patients were identified and included in the analysis with a median follow up of 43.3months (Q1-Q3: 28.7-61.1) and a mean age of 49.7 years (Standard deviation 10.9). Forty seven percent (47/101), 31% (11/36) and 14% (24/167) of patients with HR negative, single HR+ and double HR+ disease achieved a pCR respectively (X2 test Conclusion BC patients with single HR+ disease behave differently than double HR+ patients in terms of likelihood of achieving pCR after neoadjuvant chemotherapy and do not differ from HR negative patients. This difference does not translate into a difference in DFS. Prospective studies are needed to validate these findings before considering different treatment strategies for these 2 subgroups of HR+ BC patients. Citation Format: Raphael J, Nofech-Mozes S, Trudeau ME. Clinical outcomes of single versus double hormone receptor positive breast cancer patients treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-34.

Background: The androgen receptor (AR) is expressed in >75% of hormone receptor (HR)+ tumors. AR signaling has been associated with resistance to endocrine therapy (ET). Aromatase inhibitors (AIs) divert estrogen precursors to androgens; in preclinical models enzalutamide (ENZA) blocked both estrogen- and androgen-mediated growth of HR+ cells. In a phase 1 study of ET+ENZA in breast cancer, doubling the dose of exemestane (EXE) to 50 mg was necessary to restore exposure observed with 25 mg.1 Methods: This placebo (PBO)–controlled phase 2 trial randomized patients (pts) with HR+/HER2-normal advanced/metastatic breast cancer (MBC) to either 25 mg EXE+PBO or 50 mg EXE+160 mg ENZA daily (NCT02007512). Two parallel cohorts enrolled pts who had no prior ET (C1) or who had received 1 prior ET for MBC (C2). Randomization was stratified on resistance to prior ET and prior exposure to AI. Tissue samples for biomarker development were mandatory. Brain metastases or a history of seizure was exclusionary. One prior chemotherapy regimen for MBC was permitted. Response was assessed every 8 weeks for 48 weeks, then every 12 weeks. Crossover to ENZA+EXE was allowed at disease progression. A gene signature–based biomarker (Bmkr) indicating AR signaling predictive of response to ENZA was developed using a training set of RNAseq data from 2/3 of randomized pts and validated using a test set of data from the remaining 1/3 of pts. Progression-free survival (PFS) according to RECIST v1.1 was the primary endpoint in the intent-to-treat (ITT) population and in the Bmkr+ subgroup of each cohort. Secondary endpoints included clinical benefit rate at 24 weeks (CBR24), best overall response, and safety. Results: A total of 247 pts were randomized (C1, n=127; C2, n=120). In C1, 50 pts (39.4%) were Bmkr+; in C2, 35 pts (29.2%) were Bmkr+. Statistically significant improvements in median PFS and CBR24 were observed only in the Bmkr+ population with no prior ET (Table). The most common adverse events (AEs) reported in the ENZA+EXE arms were nausea (39%) in C1 and fatigue (37%) in C2. In C1, 9 pts (15%) and 10 pts (16%) discontinued the study due to AEs in the ENZA+EXE and PBO+EXE arms, respectively. In C2, 11 pts (18%) and 5 pts (8%) discontinued due to AEs in the ENZA+EXE and PBO+EXE arms, respectively. Conclusions: In the first reported randomized trial of ENZA in HR+ MBC, ENZA+EXE was well tolerated with no new safety signals. The study met its primary endpoint in pts with Bmkr+ MBC with no prior ET. 1. Schwartzberg et al. Clin Cancer Res. 2017 Mar 9 [Epub ahead of print]. C1: No Prior ETC2: 1 Prior ET ITTBmkr+ITTBmkr+EXE+ENZA | PBOENZA | PBOENZA | PBOENZA | PBO n=63 | n=64n=24 | n=26n=60 | n=60n=15 | n=20Primary endpointPFS, median, months11.8 | 5.816.5 | 4.33.6 | 3.96.0 | 5.3(95% CI)(7.3, 15.9) | (3.5, 10.9)(11.0, NR) | (1.9, 10.9)(1.9, 5.5) | (2.6, 5.4)(2.3, 26.7) | (1.8, 6.7)Hazard ratio0.820.441.020.55(95% CI)(0.54, 1.26)(0.21, 0.96)(0.66, 1.59)(0.23, 1.36)P value0.36310.03350.92120.1936Secondary endpointCBR24, n (%)39 (62) | 29 (45)20 (83) | 10 (38)12 (20) | 19 (32)6 (40) | 6 (30)(95% CI)(49, 74) | (33, 58)(63, 95) | (20, 59)(11, 32) | (20, 45)(16, 68) | (12, 54)P value0.06090.00120.14430.5374 Citation Format: Krop I, Abramson V, Colleoni M, Traina T, Holmes F, Estevez L, Hart L, Awada A, Zamagni C, Morris P, Schwartzberg L, Chan S, Wheatley D, Gucalp A, Biganzoli L, Steinberg J, Gianni L, Trudeau M, Tudor IC, Markova D, Barry E, Tarazi J, Stewart R, Winer E, Yardley DA. Results from a randomized placebo-controlled phase 2 trial evaluating exemestane ± enzalutamide in patients with hormone receptor–positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS4-07.

Purpose Routine evaluation of quality measures (QMs) can drive improvement in cancer systems by highlighting gaps in care. Targeting quality improvement at QMs that demonstrate substantial variation has the potential to make the largest impact at the population level. We developed an approach that uses both variation in performance and number of patients affected by the QM to set priorities for improving the quality of systemic therapy for women with early-stage breast cancer (EBC). Patients and Methods Patients with EBC diagnosed from 2006 to 2010 in Ontario, Canada, were identified in the Ontario Cancer Registry and linked deterministically to multiple health care databases. Individual QMs within a panel of 15 QMs previously developed to assess the quality of systemic therapy across four domains (access, treatment delivery, toxicity, and safety) were ranked on interinstitutional variation in performance (using interquartile range) and the number of patients who were affected; then the two rankings were averaged for a summative priority ranking. Results We identified 28,427 patients with EBC who were treated at 84 institutions. The use of computerized physician electronic order entry for chemotherapy, emergency room visits or hospitalizations during chemotherapy, and timely receipt of chemotherapy were identified as the QMs that had the largest potential to improve quality of care at a system level within this cohort. Conclusion A simple ranking system based on interinstitutional variation in performance and patient volume can be used to identify high-priority areas for quality improvement from a population perspective. This approach is generalizable to other health care systems that use QMs to drive improvement.

Anti-cancer therapies including chemotherapy aim to induce tumour cell death. Cell death introduces alterations in cell morphology and tissue micro-structures that cause measurable changes in tissue echogenicity. This study investigated the effectiveness of quantitative ultrasound (QUS) parametric imaging to characterize intra-tumour heterogeneity and monitor the pathological response of breast cancer to chemotherapy in a large cohort of patients (n = 100). Results demonstrated that QUS imaging can non-invasively monitor pathological response and outcome of breast cancer patients to chemotherapy early following treatment initiation. Specifically, QUS biomarkers quantifying spatial heterogeneities in size, concentration and spacing of acoustic scatterers could predict treatment responses of patients with cross-validated accuracies of 82 ± 0.7%, 86 ± 0.7% and 85 ± 0.9% and areas under the receiver operating characteristic (ROC) curve of 0.75 ± 0.1, 0.80 ± 0.1 and 0.89 ± 0.1 at 1, 4 and 8 weeks after the start of treatment, respectively. The patients classified as responders and nonresponders using QUS biomarkers demonstrated significantly different survivals, in good agreement with clinical and pathological endpoints. The results form a basis for using early predictive information on survival-linked patient response to facilitate adapting standard anti-cancer treatments on an individual patient basis.

BACKGROUND Setting realistic targets for performance is a consistent challenge in quality improvement. In the current study, the authors used administrative data to define achievable targets for a panel of 15 previously developed quality indicators (QIs) focusing on systemic therapy in patients with early-stage breast cancer. METHODS Deterministically linked administrative databases were used to identify patients with TNM stage I to stage III breast cancer who were diagnosed between 2006 and 2010 in Ontario, Canada. For each individual indicator, data-driven empirical benchmarks were calculated using the pared-mean benchmark approach. Variation in institution-level performance for each indicator was examined through the construction of funnel plots. RESULTS A total of 28,303 patients with early-stage breast cancer were identified, 43% of whom received adjuvant chemotherapy. For the 9 QIs for which receiving the service or outcome was desirable (ie, consultation with a medical oncologist), the benchmark varied from 40.9% to 100%. For the 6 indicators for which not receiving the service or outcome was desirable (ie, incidence of febrile neutropenia), the benchmark varied from 0% to 49.0%. There was substantial variation noted with regard to the number of institutions meeting the target and the amount of interinstitution variation between the QIs. Top performing institutions varied by indicator, with no individual institution meeting the benchmark for all indicators. For the majority of indicators, institution size was not found to be correlated with performance. CONCLUSIONS Data-derived benchmarking can be used to facilitate quality improvement by identifying areas of both good as well as suboptimal performance while defining an achievable target for which to strive. Cancer 2017. © 2017 American Cancer Society.

Currently, there is no formal curriculum addressing geriatric oncology within Canadian radiation oncology (RO) residency programs. Knowledge related to geriatric medicine may help radiation oncologists modify RT based on frailty status and geriatric considerations. Understanding specific learning needs allow program coordinators to align the current curriculum with residents' geriatric oncology learning needs. The purpose of this study is to determine the geriatric oncology educational needs of the Canadian RO residents and to inform Canadian RO residency training. A cross-sectional survey, with Likert, multiple choice, and open-ended questions, was pretested and distributed electronically by program directors to Canadian RO residents over 6 weeks. Responses were analyzed with descriptive statistics and common themes. One-hundred and thirty-five Canadian RO residents were contacted and 63 responded (47%). Half (49%) lacked confidence managing the elderly with multiple comorbidities, polypharmacy, functional and cognitive impairment, and challenging social circumstances;73% agreed additional training would be helpful. Forty-four percent lacked confidence regarding psychogeriatric referrals, fall prevention, palliative and hospice care, and community resources preventing re-hospitalization; 63% agreed additional training would be helpful. Seventy-six percent believed discussion groups, continuing education, geriatric oncology electives, and journal clubs would provide learning opportunities. Seventy-one percent agreed integrating geriatric assessment into RO curricula would improve care. Seventy-nine percent believed geriatric oncology principles have not been adequately integrated into radiation oncology curricula. There are significant gaps specific to geriatric assessment and management of older cancer patients in the current Canadian RO curricula. Most residents agreed that it is important to integrate geriatric oncology training to improve and personalize the care of older cancer patients.

BACKGROUND The objective of this study was to determine the impact of modeling cancer drug wastage in economic evaluations because wastage can result from single-dose vials on account of body surface area– or weight-based dosing. METHODS Intravenous chemotherapy drugs were identified from the pan-Canadian Oncology Drug Review (pCODR) program as of January 2015. Economic evaluations performed by drug manufacturers and pCODR were reviewed. Cost-effectiveness analyses and budget impact analyses were conducted for no-wastage and maximum-wastage scenarios (ie, the entire unused portion of the vial was discarded at each infusion). Sensitivity analyses were performed for a range of body surface areas and weights. RESULTS Twelve drugs used for 17 indications were analyzed. Wastage was reported (ie, assumptions were explicit) in 71% of the models and was incorporated into 53% by manufacturers; this resulted in a mean incremental cost-effectiveness ratio increase of 6.1% (range, 1.3%-14.6%). pCODR reported and incorporated wastage for 59% of the models, and this resulted in a mean incremental cost-effectiveness ratio increase of 15.0% (range, 2.6%-48.2%). In the maximum-wastage scenario, there was a mean increase in the incremental cost-effectiveness ratio of 24.0% (range, 0.0%-97.2%), a mean increase in the 3-year total incremental budget costs of 26.0% (range, 0.0%-83.1%), and an increase in the 3-year total incremental drug budget cost of approximately CaD $102 million nationally. Changing the mean body surface area or body weight caused 45% of the drugs to have a change in the vial size and/or quantity, and this resulted in increased drug costs. CONCLUSIONS Cancer drug wastage can increase drug costs but is not uniformly modeled in economic evaluations. Cancer 2017. © 2017 American Cancer Society.

Estrogen receptor (ER) negative (−) breast cancer (BC) patients have better tumor response rates than ER-positive (+) patients after neoadjuvant chemotherapy (NCT). We conducted a retrospective review using the institutional database “Biomatrix” to assess the value of quantitative ER status in predicting tumor response at surgery and to identify potential predictors of survival outcomes. Univariate followed by multivariable regression analyses were conducted to assess the association between quantitative ER and tumor response assessed as tumor size reduction and pathologic complete response (pCR). Predictors of recurrence-free survival (RFS) were identified using a cox proportional hazards model (CPH). A log-rank test was used to compare RFS between groups if a significant predictor was identified. 304 patients were included with a median follow-up of 43.3 months (Q1–Q3 28.7–61.1) and a mean age of 49.7 years (SD 10.9). Quantitative ER was inversely associated with tumor size reduction and pCR (OR 0.99, 95% CI 0.99–1.00, p = 0.027 and 0.98 95% CI 0.97–0.99, p

Primary caregivers for victims of chronic illness and or trauma experience both positive and negative emotional consequences. These are broadly classified as compassion satisfaction (CS) and compassion fatigue (CF). Because one of the components of CF, burnout, varies with chronotype and sleep quality, we assessed the influence of chronobiological features on the broader constructs of CS and CF. Responses from primary ambulatory care oncology staff working dayshifts were assessed for potential relationships of chronotype and sleep quality with CS and CF using the professional quality of life scale. These were analyzed further in a multivariate model that included personality and job satisfaction as cofactors. We found that sleep quality was a key contributor to CS development and CF reduction. Morningness was positively linked to CS, but the univariate association was masked in the multivariate model. Job satisfaction (contingent rewards, nature of work and operating procedures) heavily influenced CS and CF development. Agreeableness and openness showed positive correlations with CS and negative with burnout, while emotional stability was linked to reduced CF. While job satisfaction and personality predictably played roles in the development of CS and CF, sleep quality and chronotype contributed significantly to benefits and negative consequences of providing care.

Purpose: Diffuse optical spectroscopy (DOS) has been demonstrated capable of monitoring response to neoadjuvant chemotherapy (NAC) in locally advanced breast cancer (LABC) patients. In this study, we evaluate texture features of pre-treatment DOS functional maps for predicting LABC response to NAC. Methods: LABC patients (n = 37) underwent DOS-breast imaging before starting neoadjuvant chemotherapy. Breast-tissue parametric maps were constructed and texture analyses were performed based on grey level co-occurrence matrices (GLCM) for feature extraction. Ground-truth labels as responders (R) or non-responders (NR) were assigned to patients based on Miller-Payne pathological response criteria. The capability of DOS-textural features computed on volumetric tumour data before the start of treatment (i.e. “pre-treatment”) to predict patient responses to NAC was evaluated using a leave-one-out validation scheme at subject level. Data were analysed using a logistic regression, naïve Bayes, and k-nearest neighbour (k-NN) classifiers.\ud Results: Data indicated that textural characteristics of pre-treatment DOS parametric maps can differentiate between treatment response outcomes. The HbO2-homogeneity resulted in the highest accuracy amongst univariate parameters in predicting response to chemotherapy: sensitivity (%Sn) and specificity (%Sp) were 86.5 and 89.0%, respectively and accuracy was 87.8%. The highest predictors using multivariate (binary) combination features were the Hb-Contrast + HbO2-Homogeneity which resulted in a %Sn/%Sp = 78.0/81.0% and an accuracy of 79.5%.\ud Conclusions: This study demonstrated that pre-treatment tumour DOS-texture features can predict breast cancer response to NAC and potentially guide treatments.

Background:Androgen receptor (AR) expression has been observed in up to 77% of human epidermal growth factor receptor 2–positive (HER2+) breast cancer (BC).References:1 Enzalutamide (ENZA) is a potent AR inhibitor approved for patients (pts) with metastatic castration-resistant prostate cancer. In vitro, ENZA enhances antitumor activity of trastuzumab in HER2+ AR+ cell lines and inhibits proliferation in trastuzumab-resistant HER2+ cell lines.2 Methods:Pts with metastatic or locally advanced BC that was HER2+ AR+ by local or central laboratory assessment were enrolled in a single-arm, Simon 2-stage phase 2 study (NCT02091960). Key eligibility criteria included availability of a tissue sample, presence of measurable or evaluable disease per RECIST v1.1, progression on prior trastuzumab and ≥1 prior line of anti-HER2 therapy as the most recent regimen. Brain metastases and history of seizure were exclusionary. Evaluable pts were those with centrally confirmed nuclear AR expression≥10% by immunohistochemistry who received ≥1 dose of ENZA and had ≥1 postbaseline tumor assessment. Pts received ENZA 160 mg daily and trastuzumab 6 mg/kg every 21 days until disease progression. The primary objective was clinical benefit rate at 24 weeks (CBR24), defined as complete or partial response (CR or PR) or stable disease (SD) for ≥24 weeks in evaluable pts. Additional endpoints included safety and progression-free survival (PFS). CBR24 in ≥3 of 21 evaluable pts was required to continue to stage 2 and enrollment of up to 66 evaluable pts total. This design yields a 1-sided type 1 error of 5% and 90% power when the true response is 25%. Results:Here we present results from stage 1 (data cutoff: Mar 23, 2016), with 22 evaluable pts enrolled (pts 21 and 22 enrolled simultaneously); 18 had received ≥4 prior lines of therapy. Median duration of ENZA exposure was 144 days (range, 22-495), mean number of complete trastuzumab infusions was 6.5. CBR24 was 27.3% (95% confidence interval [CI], 10.7-50.2); 2 confirmed PR and 4 SD ≥24 weeks. Median PFS was 108 days (95% CI, 56-144). All pts experienced ≥1 adverse event (AE) any grade; 5 pts experienced AEs grade ≥3. ENZA-related AEs were reported in 16 pts (72.7%), the most common (in ≥10% of pts) were fatigue (22.7%), nausea (18.2%), diarrhea (13.6%) and arthralgia (13.6%). Serious AEs were reported in 6 pts (27.3%; 2 each of infection and back pain, 1 each of abdominal pain, nausea, vomiting, pyrexia, urinary retention and pulmonary edema). Two pts discontinued due to drug-related AEs: 1 related to both drugs, 1 related to trastuzumab. One on-study death from pulmonary edema was reported, which was not considered related to either drug. Conclusion:Stage 1 met its primary objective. No new safety signals were identified, and the safety profile in this study was similar to that in men with prostate cancer and women with other BC subtypes treated with ENZA. These results are encouraging for a heavily pretreated population with advanced HER2+ AR+ BC. Enrollment in stage 2 continues with the combination of ENZA and trastuzumab. 1. Micello D et al. Virchows Arch. 2010;457:467-476. 2. Richer J. Presented at AACR Advances in Breast Cancer, San Diego, CA, 2013. Citation Format: Krop I, Cortes J, Miller K, Huizing MT, Provencher L, Gianni L, Chan S, Trudeau M, Steinberg J, Sugg J, Liosatos M, Paton VE, Peterson A, Wardley A. A single-arm phase 2 study to assess clinical activity, efficacy and safety of enzalutamide with trastuzumab in HER2+ AR+ metastatic or locally advanced breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-08.

Introduction: Patients with Estrogen Receptor negative breast cancer (BC) are known to have higher tumor response rates than ER positive patients when treated with neoadjuvant chemotherapy (NCT). Few studies have assessed ER status as a quantitative continuous measure in predicting tumor response in this setting. We aimed to study the association between quantitative ER status and tumor response at surgery in BC patients treated with NCT at our institution, and identify potential predictors of better survival outcomes. Methods: A retrospective review using a neoadjuvant BC database (The "Sunnybrook Biomatrix") identified 304 eligible patients that were included in the analyses. A univariate followed by a multivariable logistic regression analyses were conducted to assess the association between quantitative ER (expressed in percentage) and tumor response (good vs. poor response defined as < vs. ≥ 50% reduction in tumor size) while controlling for potential confounders. For the secondary outcome, the Kaplan Meier method was used to estimate the recurrence free survival (RFS) in this cohort. Predictors of RFS were identified using a cox proportional hazards model (CPH) to adjust for clinically relevant variables. A log-rank test was used to compare RFS between groups for any significant binary predictor. Results: The median follow up of all patients was 43.3 months (Q1-Q3: 28.7-61.1). Quantitative ER was inversely associated with tumor response in a multivariable logistic regression model (Odds Ratio 0.99 95%CI: 0.99-1.00, p=0.027). A cut-off of 60% seemed to best predict the association based on the c-statistic (c=0.67) and the receiver operating characteristic curve. However, quantitative ER was not associated with RFS; pathologic complete response (pCR) was shown to be an independent predictor of RFS in a CPH model (Hazard Ratio: 0.17, 95% CI: 0.07, 0.43, p=0.0002) in all patients, after controlling for potential confounders. At 5 years, 93% of patients with pCR and 72% of patients with residual tumor (no pCR) were recurrent-free respectively (log-rank test p=0.0012). Conclusion: This study suggests that BC patients with ER status < 60% are more likely to respond to NCT. Although ER status itself did not predict for relapse-free survival, patients with a pCR had better RFS, and this association was seen amongst all tumor phenotypes. The role of quantitative ER in predicting and maximizing tumour response to NCT (including optimizing pCR rate) needs to be better defined in prospective studies. Key words: Estrogen receptors, breast cancer, quantitative, tumor response, pathologic complete response. Citation Format: Raphael J, Trudeau M, Paramsothy T, Lee N, Gandhi S. The role of quantitative estrogen receptor status in predicting breast tumor response to neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-39.

Little data exist for comparing cardiac safety and survival outcomes of trastuzumab/pertuzumab or ado-T emtansine (TDM1) in metastatic breast cancer (MBC) patients enrolled in randomized clinical trial (RCT) vs the real-world.This was a retrospective population-based cohort of all patients with MBC treated with trastuzumab/pertuzumab or TDM1 (2012-2017) in Ontario, Canada. Outcomes were incident heart failure (HF) and overall survival (OS). RCT data were obtained from digitizing survival curves and compared with cohort data using Kaplan-Meier analysis. Age-based comparison of outcomes was conducted for patients ≥ 65 years old vs younger than 65.The two cohorts composed of 833 and 397 patients treated with trastuzumab/pertuzumab and TDM1, of whom 5.5% and 7.6% had baseline HF, respectively. Incident HF following trastuzumab/pertuzumab or TDM1 was low (trastuzumab/pertuzumab 1.8 events/100 person years; TDM1 0.02 events/100 person years). The median OS was 39.2 and 56.4 months in the trastuzumab/pertuzumab population-based cohort and CLEOPATRA, respectively. The median OS was 15.4 and 30.9 months in the TDM1 population-based cohort and EMILIA, respectively. Cohort OS was significantly worse than RCT OS (trastuzumab/pertuzumab HR 1.67, 95% CI 1.37-2.03, p 0.0001; TDM1 HR 2.80, 95% CI 2.27-3.44, p 0.0001). Older patients had worse OS than younger patients for trastuzumab/pertuzumab (HR 1.60, 95% CI 1.19-2.16, p = 0.0018), but not for TDM1 (HR 1.16, 95% CI 0.81-1.66, p = 0.43).HF incidence during trastuzumab/pertuzumab or TDM1 therapy in this real-world cohort was low. Survival in this cohort was worse compared to RCT, suggesting that recruitment of patients similar to the real-world population is required.