In tamoxifen-treated individuals, reduced-function genetic variants in the CYP2D6 gene or inhibition of the enzyme result in low circulating endoxifen concentrations. We assessed the impact of reduced CYP2D6 activity and circulating endoxifen concentrations on breast cancer outcomes. Patients with locally advanced or stage IV hormone receptor-positive breast cancer were enrolled in this single arm phase II trial and received open label tamoxifen 20 mg PO daily. The primary objective was to assess CYP2D6 poor metabolizer (PM) vs intermediate and normal metabolizer status (IM + NM) with progression-free survival (PFS). CYP2D6 phenotype was determined from whole blood samples (Roche Amplichip), and secondary endpoint evaluated endoxifen concentrations determined from 3 month post registration plasma samples (Quest Diagnostics). From September 2010 to June 2013, 113 of planned 204 patients were registered to the trial and began protocol treatment. Accrual to the trial closed early due to lower-than-expected rate of CYP2D6 poor metabolizers. Median age was 62, 86

Supplementary Material containing Supplementary Methods, 5 Supplementary Figures, and 8 Supplementary Tables

PURPOSE:Distant metastases are present in 6% or more of patients with newly diagnosed breast cancer. In this context, locoregional therapy for the intact primary tumor has been hypothesized to improve overall survival (OS), but clinical trials have reported conflicting results. METHODS:Women presenting with metastatic breast cancer and an intact primary tumor received systemic therapy for 4-8 months; if no disease progression occurred, they were randomly assigned to locoregional therapy for the primary site (surgery and radiotherapy per standards for nonmetastatic disease) or continuing sysmetic therapy. The primary end point was OS; locoregional control and quality of life were secondary end points. The trial design provided 85% power to detect a 19.3% absolute difference in the 3-year OS rate in randomly assigned patients. The stratified log-rank test and Cox proportional hazards model were used to compare OS between arms. Cumulative incidence of locoregional progression was compared using Gray's test. Quality-of-life assessment used standard instruments. RESULTS:Of 390 participants enrolled, 256 were randomly assigned: 131 to continued systemic therapy and 125 to early locoregional therapy. The 3-year OS was 67.9% without and 68.4% with early locoregional therapy (hazard ratio = 1.11; 90% CI, 0.82 to 1.52; P = .57). The median OS was 53.1 months (95% CI, 47.9 to not estimable) in the systemic therapy arm and 54.9 months (95% CI, 46.7 to not estimable) in the locoregional therapy arm. Locoregional progression was less frequent in those randomly assigned to locoregional therapy (3-year rate: 16.3% v 39.8%; P < .001). Quality-of-life measures were largely similar between arms. CONCLUSION:Early locoregional therapy for the primary site did not improve survival in patients presenting with metastatic breast cancer. Although it was associated with improved locoregional control, this had no overall impact on quality of life.

AbstractPurpose:This open-label, multicenter, phase IB/II study evaluated sapanisertib, a dual inhibitor of mTOR kinase complexes 1/2, plus exemestane or fulvestrant in postmenopausal women with hormone receptor–positive (HR+)/HER2-negative (HER2−) advanced/metastatic breast cancer.Patients and Methods:Eligible patients had previously progressed on everolimus with exemestane/fulvestrant and received ≤3 (phase IB) or ≤1 (phase II) prior chemotherapy regimens. Patients received sapanisertib 3 to 5 mg every day (phase IB), or 4 mg every day (phase II) with exemestane 25 mg every day or fulvestrant 500 mg monthly in 28-day cycles. Phase II enrolled parallel cohorts based on prior response to everolimus. The primary objective of phase II was to evaluate antitumor activity by clinical benefit rate at 16 weeks (CBR-16).Results:Overall, 118 patients enrolled in phase IB (n = 24) and II (n = 94). Five patients in phase IB experienced dose-limiting toxicities, at sapanisertib doses of 5 mg every day (n = 4) and 4 mg every day (n = 1); sapanisertib 4 mg every day was the MTD in combination with exemestane or fulvestrant. In phase II, in everolimus-sensitive versus everolimus-resistant cohorts, CBR-16 was 45% versus 23%, and overall response rate was 8% versus 2%, respectively. The most common adverse events were nausea (52%), fatigue (47%), diarrhea (37%), and hyperglycemia (33%); rash occurred in 17% of patients. Molecular analysis suggested positive association between AKT1 mutation status and best treatment response (complete + partial response; P = 0.0262).Conclusions:Sapanisertib plus exemestane or fulvestrant was well tolerated and exhibited clinical benefit in postmenopausal women with pretreated everolimus-sensitive or everolimus-resistant breast cancer.

Purpose To characterize health-related quality of life (HRQoL) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) from the NALA phase 3 study. Methods In NALA (NCT01808573), patients were randomized 1:1 to neratinib + capecitabine (N + C) or lapatinib + capecitabine (L + C). HRQoL was assessed using seven prespecified scores from the European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire core module (QLQ-C30) and breast cancer-specific questionnaire (QLQ-BR23) at baseline and every 6 weeks. Descriptive statistics summarized scores over time, mixed models evaluated differences between treatment arms, and Kaplan–Meier methods were used to assess time to deterioration in HRQoL scores of ≥ 10 points. Results Of the 621 patients randomized in NALA, patients were included in the HRQoL analysis if they completed baseline and at least one follow-up questionnaire. The summary, global health status, physical functioning, fatigue, constipation, and systemic therapy side effects scores were stable over time with no persistent differences between treatment groups. There were no differences in time to deterioration (TTD) for the QLQ-C30 summary score between treatment arms; the hazard ratio (HR) for N + C vs. L + C was 0.94 (95% CI 0.63–1.40). Only the diarrhea score worsened significantly more in the N + C arm as compared to the L + C arm, and this remained over time (HR for TTD for N + C vs. L + C was 1.71 [95% CI 1.32–2.23]). Conclusion In NALA, patients treated with N + C maintained their global HRQoL over time, despite a worsening of the diarrhea-related scores. These results may help guide optimal treatment selection for HER2-positive MBC.

Purpose This article highlights one health system's response to the market influx of biosimilars with the establishment of a process for formulary review and selection of preferred agents and support for therapeutic interchanges. Through assessment of available literature, insurance payor coverage, and manufacturer-anticipated approvals of biosimilars, a strategic stance was developed to guide biosimilar order preparation, review, adoption, and implementation. The electronic medical record (EMR) is prepared for biosimilar implementation at least 6 to 12 months ahead of anticipated formulary review. The review includes assessment of a class (reference product and available biosimilars) after at least 2 biosimilars become available. Key health-system departments and clinicians are enlisted to support review of clinical, safety, and economic implications. Implementation of a preferred product relies on standard education, formulary availability, and staff awareness to address any perceived patient safety concerns and gather provider support. The standard steps developed now apply to all future biosimilar reviews, adoption plans, and ongoing monitoring. Barriers evaluated include changes in payor coverage and challenges in preparation of the EMR for future biosimilars, meeting precertification team education needs, and providing operational support for pharmacy inventory. Conclusion To date, use of 5 preferred biosimilar products has led to significant cost savings to the institution, and the process has been endorsed by providers. The institution's successes can be attributed to clear communication with stakeholders and the development of a deliberate process, led by a multidisciplinary leadership team, for managing formulary, safety, and operational barriers in a thoughtful and systematic manner.

Patients with triple-negative breast cancer (TNBC) who have residual disease after neoadjuvant therapy have a high risk of recurrence. We tested the impact of DNA-damaging chemotherapy alone or with PARP inhibition in this high-risk population. Patients with TNBC or deleterious BRCA mutation (TNBC/BRCAmut) who had >2 cm of invasive disease in the breast or persistent lymph node (LN) involvement after neoadjuvant therapy were assigned 1:1 to cisplatin alone or with rucaparib. Germline mutations were identified with BROCA analysis. The primary endpoint was 2-year disease-free survival (DFS) with 80% power to detect an HR 0.5. From Feb 2010 to May 2013, 128 patients were enrolled. Median tumor size at surgery was 1.9 cm (0–11.5 cm) with 1 (0–38) involved LN; median Residual Cancer Burden (RCB) score was 2.6. Six patients had known deleterious BRCA1 or BRCA2 mutations at study entry, but BROCA identified deleterious mutations in 22% of patients with available samples. Toxicity was similar in both arms. Despite frequent dose reductions (21% of patients) and delays (43.8% of patients), 73% of patients completed planned cisplatin. Rucaparib exposure was limited with median concentration 275 (82–4694) ng/mL post-infusion on day 3. The addition of rucaparib to cisplatin did not increase 2-year DFS (54.2% cisplatin vs. 64.1% cisplatin + rucaparib; P = 0.29). In the high-risk post preoperative TNBC/BRCAmut setting, the addition of low-dose rucaparib did not improve 2-year DFS or increase the toxicity of cisplatin. Genetic testing was underutilized in this high-risk population.

Abstract Background: The FDA approved neratinib (N), an irreversible pan-HER tyrosine kinase inhibitor, in combination with capecitabine (C) for patients with HER2+ advanced or metastatic breast cancer who have received ≥2 prior HER2-directed regimens in the metastatic setting based on the NALA clinical study, where N+C significantly improved PFS vs. lapatinib (L)+C. Characterizing HRQoL associated with this regimen can help inform treatment decision-making for these patients. The objective of this analysis was to characterize HRQoL among patients with HER2+ metastatic breast cancer from the NALA clinical study. Methods: NALA was a multinational, randomized, open-label, phase III clinical study of N+C vs. L+C in patients with HER2+ metastatic breast cancer and ≥2 prior HER2-directed regimens. From May 2013 to July 2017, patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid 14d/21d) with loperamide prophylaxis during the first cycle, or to L (1250 mg qd) + C (1000 mg/m2 bid 14d/21d). HRQoL, a prespecified secondary endpoint of the NALA study, was measured using the EORTC QLQ-C30 and the breast cancer-specific QLQ-BR23 at baseline and every 6 weeks (±3 days) until the end of treatment (data collection through treatment cycle 19, 12.5 months). The QLQ-C30 summary and global health status scores range from 0 (worst) to 100 (best) and the systemic therapy side-effects scores range from 0 (best) to 100 (worst). Patients were included in the analysis for a particular scale if they had a baseline assessment and at least 1 follow-up assessment. For these analyses, a change of ≥10 points was considered to be clinically meaningful. Descriptive statistics summarized observed scores and changes from baseline, Kaplan-Meier and log-rank tests were used for time-to-deterioration (TTD) of ≥10 points and mixed models estimated the change over time for 7 prespecified scales: QLQ-C30 summary score, global health status, physical functioning, fatigue, constipation and diarrhea, and the EORTC QLQ-BR23 systemic therapy side effects subscale. No adjustments for multiplicity were performed. Results: 621 patients from 28 countries were randomized (307 N+C; 314 L+C). The mean completion rate of the QLQ-C30 over the course of the study was 91% for both treatment arms. Discontinuation due to any treatment-emergent adverse event (TEAE) was lower in the N+C vs. L+C arm (14% vs. 18%). At baseline, the mean (SD) QLQ-C30 summary scores were 79.8 (14.1) for N+C and 79.9 (15.7) for L+C. After 19 treatment cycles, the mean (SD) QLQ-C30 summary scores were similar to baseline scores: 81.8 (16.7) for N+C and 81.3 (15.3) for L+C. There were no differences in TTD of ≥10 points for the QLQ-C30 summary score between treatment arms; the HR for N+C vs. L+C was 0.94 (95% CI 0.63-1.40). All prespecified HRQoL subscales had similar statistically non-significant results for TTD with the exception of diarrhea (HR=1.71; 95% CI 1.32-2.23). The mixed models analyzing change in HRQoL from baseline did not demonstrate persistent declines nor meaningful differences between the treatment arms. Conclusion: In these results from the NALA study, among patients with HER2+ metastatic breast cancer, at study end and throughout most of the study, there were no differences observed between the two treatment arms in HRQoL scores. HRQoL was sustained over the study period despite the early transient presence of diarrhea in some patients. Discontinuation due to any TEAE was lower in the N+C vs. the L+C arm. These results may help guide healthcare providers, patients and carers in selection of optimal treatment for HER2+ metastatic breast cancer. Citation Format: Beverly Moy, Mafalda Oliveira, Cristina Saura, William Gradishar, Sung-Bae Kim, Adam Brufsky, Sara Hurvitz, Larisa Ryvo, Daniele Fagnani, Nancy Chan, Sujith R Kalmadi, Paula Silverman, Suzette Delaloge, Richard Bryce, Kiana Keyvanjah, Judith Bebchuk, Bo Zhang, Nina Oestreicher, Ron Bose. Neratinib + capecitabine sustains health-related quality of life (HRQoL) while improving progression-free survival (PFS) in patients with HER2+ metastatic breast cancer and ≥2 prior HER2-directed regimens [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 PS9-02.

e14103 Background: The rapid development of digital technology holds enormous potential to transform the delivery of cancer care. Despite these digital innovations, we still face significant challenges in healthcare in using these emerging digital technologies in the clinical setting. Clinicians generally underestimate the severity and extent of chemotherapy toxicity of patients. This project seeks to conduct an exploratory field study to collect patient feedback on their experiences, and the design/functionality of the prototype of the digital health service platform designed to monitor their symptoms. Methods: Using the National Cancer Institute item library addressing the most common symptoms for chemotherapy toxicity, a digital health platform was designed by Samsung Research America (SRA) and University Hospitals. Patients age ≥ 18 years old, willingness to agree to the consent document, ability to understand use of wearable device and willingness to answer patient reported outcomes questions were included in this study. Patients who are not undergoing oral chemotherapy treatment for their cancer were excluded. Patients were given a phone that had our designed platform along with a watch. The watch had the capability of tracking blood pressure, heart rate, and pulse oximetry. Patients were set up with an electronic account that queried them on patient Reported Outcomes (PRO) regarding potential toxicity they may be experiencing. They were also able to track medication consumption and input their weight. Subjects were be asked to use the wearable device and phone for at least 28 days and no more than 90 days. At the end of the study, a phone survey was attempted. Results: Total patients enrolled: 21. 18/21 (85.7%) patients completed the 90 days of the study. Only 9 patients provided PRO with total number of side effects reported 28 times. Watch device was only utilized by 15/21 (71.4%) patients. On an average across 90 days, these patients wore the watch 430 minutes per day. At the end of the treatment, 5 patients agreed to participate in the phone survey. Three patients stated that they would do similar study in the future noting that the digital platform helped them stay on track and monitor symptoms accurately. Every patient questioned had a complaint regarding the watch functionality. Patients also found it difficult to carry a second phone in addition to their personal phone. Conclusions: Improving our digital health service platform will get us closer to achieving effective bi-lateral patient communication and ultimately improving patient care.

Abstract Background. Oncotype Dx Recurrence Score (RS) is a 21-gene assay used to predict recurrence in early stage breast cancer and guide chemotherapy decisions. After the completion of the TAILORx trial in 2017, there were changes in the cutoffs for the risk categories and found that there was chemotherapy benefit for women age <50 and RS 16-25. The aim of this study was to re-categorize patients using the TAILORx cutoffs and reassess clinical outcome based on recurrence and metastasis.Materials and Methods. With IRB approval, the CoPath pathology database was queried for patients who were newly diagnosed with breast cancer from 2012 to 2017 and Oncotype scores. The original pathology report and chart was reviewed to assess treatment decisions, recurrences and/or metastasis and their follow-up. Patients with hormone receptor negative, HER2 positive or lymph node macrometastasis were excluded. The patient were re-categorized based on TAILORx cutoffs and subgroup analysis was performed based on age, RS, recurrences and metastasis.Results. There was a total of 620 patients. The mean age was 60.19 years (range, 25-81 years). The mean follow-up was 36.67 months (0-262 months). Forty-seven patients were added to the high-risk category based on the lower TAILORx cutoff (recurrence scores =26-30). An additional 56 patients were recommended chemotherapy based on RS 16-25 and age <50. Recurrence was present in 26/620 patients. The recurrence rate was higher in younger patients (age <50) (8% vs 3.4%, p=0.033) and also higher in patients who refused chemotherapy than the patients who received chemotherapy (13% vs 6%, p=0.013). The recurrence rate was lower in patients who received hormonal therapy (2.4% vs 5%, p=0.007). When the patients were stratified based on age and RS, younger patients who refused chemotherapy with higher RS (> 16) showed even higher recurrence than those who received chemotherapy (33% vs 6%). The older patients with higher RS (> 25) showed no significant difference for recurrence between the group who received chemotherapy and who did not receive/refuse chemotherapy. There was a total of 17/620 patients with metastasis. It was frequent in younger patients (age <50) and higher tumor grade (p=0.014 and 0.032, respectively). There was no significant difference for metastasis in patients who received or did not receive/refused chemotherapy. Interestingly, there were no metastasis in 11 old patients with higher RS >25) who refused chemotherapy. Conclusion. Based on the TAILORx trial recommendations, the number of patients receiving chemotherapy almost tripled in our cohort. The recurrence and metastatic rate were more frequent in younger patients. The recurrence rate was found to be higher in younger patients (RS >16) who refused chemotherapy and lower in patients who received hormonal therapy. There was no significant difference for metastasis in the groups who received chemotherapy or not. All of the older patients with higher RS who refused chemotherapy did not develop a local recurrence or metastasis. Age <50 and Recurrence rate based on cutoff for chemotherapyLow cutoff (RS<16) (p=0.009)High cutoff (RS> 16) (p=0.041)Chemotherapy RecurrenceNo recurrenceTotalRecurrenceNo RecurrenceTotalReceived 2 (50%)2 (50%)42 (6%)31 (94%)33Not received2 (5%)38 (95%)401 (4%)26 (96%)27Refused 0 (0%)2 (100%)22 (33%)4 (67%)6Total4 (9%)42 (91%)465 (8%)61 (92%)66Age >50 and Recurrence based on cutoff for chemotherapyLow cutoff (RS<25) (p=0.019)High cutoff (RS> 25) (p=0.256)Chemotherapy RecurrenceNo recurrenceTotalRecurrenceNo RecurrenceTotalReceived 2 (5%)36 (95%)382 (3%)55 (97%)57Not received 9 (3%)342 (97%)3511 (6%)15 (94%)16Refused 2 (17%)10 (83%)120 (0%)11 (100%)11Total1338840138184Age < 50 and Metastasis based on cutoff for chemotherapyLow cutoff (RS<16) (p=0.111)High cutoff (RS> 16) (p=0.605)Chemotherapy MetastasisNo metastasisTotalMetastasisNo MetastasisTotalReceived 1 (25%)3 (75%)42 (6%)29 (94%)31Not received 1 (3%)38 (97%)393 (11%)24 (89%)27Refused 0 (0%)2 (100%)20 (0%)6 (100%)6Total2434555964Age > 50 and Metastasis based on cutoff for chemotherapyLow cutoff (RS<25) (p=0.111)High cutoff (RS> 25) (p=0.118)Chemotherapy MetastasisNo metastasisTotalMetastasisNo metastasisTotalReceived 1 (3%)37 (97%)383 (5%)53 (95%)56Not received 4 (1%)344 (99%)3481 (6%)15 (94%)16Refused 1 (8%)11 (92%)120 (0%)11 (100%)11Total639239847983 Citation Format: Akisha Glasgow, Philip Bomiesl, Paula Silverman, Hannah Gilmore, Aparna Harbhajanka. Reassessment of traditional oncotype scoring using TAILORx criteria: A large institutional review [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 P3-08-35.

Ovarian suppression with gonadotropin-releasing hormone (GnRH) agonists has been shown to be effective as an adjuvant therapy for patients with early-stage breast cancer.1 Recent randomized clinical trials have analyzed the effect of ovarian suppression among premenopausal women with estrogen receptor (ER)-positive breast cancers who retained ovarian function after chemotherapy treatment.2

LBA2 Background: About 6% of newly diagnosed breast cancer patients present with Stage IV disease and an intact primary tumor (IPT). Locoregional treatment (LRT) for the IPT is hypothesized to improve survival based on retrospective analyses, but randomized trials have provided conflicting data. We now report the results of E2108, a Phase 3 trial that examined the worth of LRT for the IPT following initial systemic therapy. Methods: Stage IV patients with IPT were registered, treated with optimal systemic therapy (OST) based on patient and tumor characteristics; those who did not progress during 4-8 months of OST were randomized to LRT for the IPT, or no LRT. The primary endpoint was overall survival (OS), with locoregional disease control as a secondary endpoint. Stratified log rank test and Cox proportional hazard model were used to compare OS between treatment groups. Cumulative incidence of locoregional recurrence/progression was estimated and Gray test was used for treatment group comparisons. The trial was designed to detect an improvement in 3 year OS rate from 30% with OST alone to 49.3% for OST+LRT (power 95%, 1-sided alpha 0.05) with full information expected after 152 deaths; the data monitoring committee recommended data release after 80% of full information. Results: 390 patients were enrolled between 2/8/11 and 7/23/15, and received OST. Of these, 256 eligible patients were randomized to either continued OST alone (N = 131) or OST+LRT (N = 125).There were 121 deaths and 43 locoregional progression events after a median follow up 59 months (range: 0-91). There was no significant difference in OS (3-year OS rate 68.4% in OST+LRT vs. 67.9% OST alone arm, stratified log-rank p = 0.63, HR = 1.09, 90% CI: 0.80, 1.49) or in progression-free survival (p = 0.40). The locoregional recurrence/progression was significantly higher in the OST alone arm (3-year rate 25.6% vs 10.2%, Gray test p = 0.003). Health-related quality of life (HRQOL) measured by FACT-B Trial Outcome Index was significantly worse in the OST+LRT arm than OST alone arm at 18 months post randomization (60% completion, Wilcoxon rank sum test p = 0.01), but no difference was observed at time points 6 months (74% completion) or 30 months (56% completion). Conclusions: Early local therapy does not improve survival in patients with de novo metastatic breast cancer and an IPT. Although there was a 2.5-fold higher risk of local disease progression without LRT, LRT of the IPT did not lead to improved HRQOL. Clinical trial information: NCT01242800 .

Abstract Background: Roughly 10-30% of metastatic breast cancer patients will develop brain metastases (BM) over the course of their disease. The prognosis for breast cancer patients with BM remains poor due to the deficiency of effective targeted therapies in this setting. A comprehensive characterization of deregulated signaling networks in breast cancer brain metastases would enable the delineation of pathways mediating metastases to the brain thus improving treatment options for this deadly disease. Using our novel systems biology paradigm (InFlo) that robustly infers deregulated signaling networks in individual tumor samples (Oncogene, 2017), we report genome-scale characterization of signaling network deregulations in breast cancer BM and matched primary tumor samples. Methods: Pathology records were searched for patients who underwent surgical resection of breast cancer BM and primary breast tumors (PB). Archival FFPE material and clinical data was obtained for a total of 76 breast cancer patients. Tumor DNA/RNA was extracted from 2 mm macrodissected FFPE cores followed by transcriptome profiling using Affymetrix HTA 2.0 arrays. Transcriptome profiles for a total of 133 FFPE samples included 72 BM and 31 PB, counting 31 BM/PB pairs from the same patient. PAM50 subtypes were derived for BM and PB samples, and InFlo was employed to interrogate genome scale signaling network deregulations in BM and PB as compared to normal breast controls. InFlo-derived signaling deregulations in the 72 BM were contrasted against the 31 PB using a Wilcoxon rank-sum test, followed by paired analyses in the matched 31 BM/PB pairs using the Wilcoxon signed-rank test. The immune microenvironment of BM/PB was assessed using model-based deconvolution of transcriptomic profiles, along with independent assessment of tumor infiltrating lymphocytes (TILs) in accordance with the International TILs Working Group standards. Results: We identified subtype switching between BM and matched PB in 5/31 pairs (16.1%) and loss of ER in 6/31 pairs (19.4%). Changes in receptor status were not associated with concurrent BM and only occurred in patients with two or more years between excision of the primary tumor and diagnosis/resection of BM. Consistent with prior studies, BM exhibited significantly lower TILs as compared to PB (P = 0.001) by both pathologist assessment and transcriptomic deconvolution. InFlo-based analyses revealed recurrent and subtype-independent hyperactivation of signaling networks in BM as compared to PB, including RhoA (62.5% of BM; P = 0.023) and anti-apoptotic BCL signaling (69.4% of BM; P = 0.003). In contrast, PPARα signaling was activated in 15.3% of BM (P = 0.003) and FGFR2 signaling was activated in 11.1% of BM (P = 0.005), with the Basal-like subtype exhibiting the highest rates of activation of these networks (PPARα, 21.7%; FGFR2, 17.4%). Activated HER3 signaling was observed in 13.9% of BM (P = 0.023) with the highest activation rates (28.6%) occurring within the Luminal A subtype. Conclusions: This first of its kind systems biology interrogation of genome-scale signaling network deregulations in BM in breast cancer reveals highly recurrent and subtype-specific pathway activations. The highly recurrent activation of pro-survival BCL-signaling specific to BM has high translational significance given recent positive developments of BH3 mimetics in the clinic. Furthermore, our observance of substantial differences in signaling network activities in brain metastases as compared to matched primary tumors points to the plasticity of breast cancer cells as they adapt to their metastatic niche. Overall, our study underscores the need to decode the molecular dependencies of metastatic lesions in order to develop effective therapeutic interventions targeting breast cancer metastases to the brain. Citation Format: Hannah Elizabeth Hill, Salendra Singh, Kristy Miskimen, Paula Silverman, Jill Barnholtz-Sloan, Andrew Sloan, Hannah Gilmore, Vinay Varadan. Genome-scale systems biology analyses reveal potentially targetable signaling networks in breast cancer brain metastases [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 PD8-09.

e12571 Background: There is no approved drug therapy for CNS mets from mBC. Eribulin mesylate (eribulin) is a microtubule inhibitor approved for treatment of mBC patients (pts) who have received at least 2 prior chemotherapy regimens. Previously reported cases have demonstrated significant CNS responses in mBC pts treated with eribulin. This study evaluates the CNS response in pts with mBC treated with eribulin. Methods: CASE7113 was a prospective phase II single-arm study to evaluate the 12-week CNS progression free survival (12-wk CNS-PFS) of pts with mBC and CNS mets treated with eribulin. 20 pts were to be enrolled to demonstrate a 40% 12-wk CNS-PFS (95% CI, 8.5% - 61.5%). All pts had radiologically confirmed mBC CNS lesions with at least one lesion that did not receive prior radiation or surgical resection. Eribulin was administered at standard dose of 1.4mg/m2 IV on days 1 and 8 of a 21 day-cycle. Pts underwent baseline and 12-week brain MRI. The study was closed due to slow accrual; an analysis of enrolled pts was performed. Results: 9 female pts were enrolled; median age was 56 (32-82) years. 55% and 67% had ER+ and/or PR+ and Her2+ mBC respectfully. 1 pt had triple negative breast cancer (TNBC). Median number of prior therapies was 3 (0-12). The 12-wk CNS-PFS (95% CI) was 88.9% (51.8% - 99.7%), the median PFS (95% CI) was 22.6 (4.3 - 31.9) weeks, the median OS (95% CI) was 15.7 (4.0 - 27.3) months. 4 pts achieved stable disease and 1 pt had a partial response. There were no unexpected toxicities. Conclusions: For mBCa pts with CNS mets, this estimate of 12-wk CNS-PFS suggests activity of eribulin and merits further investigation in this population in the context of clinical trials. Clinical trial information: NCT02581839.

Objective: To assess the feasibility of a team-based prognosis and treatment goal discussion for women living with advanced breast cancer. Methods: Female patients diagnosed with advanced breast cancer (n = 25) participated in a mixed methods study that evaluated the feasibility and effects of a planned and structured prognosis discussion. Audio analysis of the intervention appointments was conducted to assess intervention feasibility. Patient self-reports of prognosis related beliefs and treatment preferences were compared across intervention and usual care groups. Results: Most patients found the T-PAT appointment challenging but worthwhile. Intervention uptake by clinicians was good, but some fidelity disruptions were noted. T-PAT participants were more likely to hold realistic beliefs about disease curability after the appointment. Conclusion: Productive prognosis discussions can be delivered effectively by a practice-based clinical team within a semi-structured patient education appointment. It was perceived by patients with advanced breast cancer as both valuable and acceptable. T-PAT clinicians found the intervention easy to deliver. Practice implications: Regular implementation of T-PAT may help clinicians' build prognosis discussion communication skills. T-PAT documentation provides valuable information that can be used to tailor ongoing care. (c) 2018 Published by Elsevier B.V.

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for common physical and psychosocial consequences of cancer and cancer treatment to help healthcare professionals who work with survivors of adult-onset cancer in the posttreatment period. This portion of the guidelines describes recommendations regarding the management of anthracycline-induced cardiotoxicity and lymphedema. In addition, recommendations regarding immunizations and the prevention of infections in cancer survivors are included.

The transcription factor SOX10 mediates the differentiation of neural crest–derived cells, and SOX10 by immunohistochemistry (IHC) is used primarily for the diagnosis of melanoma. SOX10 expression has been previously documented in benign breast myoepithelial cells. However there is limited literature on its expression in triple-negative breast carcinoma (TNBC). The aim was to study the clinical, pathologic and molecular profiles of SOX10+ tumors in TNBC. Tissue microarrays of TNBC were evaluated for SOX10 expression in 48 cases. SOX10 expression was correlated with clinical and pathologic features such as age, grade, and stage. Gene expression was analyzed on RNA extracted from formalin-fixed paraffin-embedded (FFPE) specimens with Affymetrix 2.0 HTA. Co-expression of SOX10 with androgen receptor (AR), WT1, gross cystic disease fluid protein-15 (GCDFP-15), mammaglobin, epidermal growth factor receptor (EGFR), CK5/6 and GATA transcription factor 3 (GATA3) were also assessed. The mean age was 59.38 (range, 28-90 years). Overall, 37.5% cases (18/48) were SOX10+. There was no association between SOX10 expression and age, grade or stage of patients; 6 of 10 (60%) cases of basal-like 1 (BL1), and 5 of 8 cases of unstable (UNS) molecular subtype were SOX10+. One of 5 basal-like-2 (BL2), 1 of 6 immunomodulatory (IM), 1 of 4 mesenchymal (M), 1 of 5 luminal androgen receptor (LAR) and 2 of 8 mesenchymal stem cell (MSL) showed lower frequencies of SOX10 expression. There was negative correlation between SOX10 and AR+ subtypes (P < .002). SOX10 was positively correlated with WT1 (P = .05). SOX10 did not show significant correlation with mammaglobin, GCDFP15, EGFR, CK5/6 and GATA3. SOX10 expression in the basal-like and unstable molecular subtypes supports the concept that these neoplasms show myoepithelial differentiation.

The Breast JournalVolume 24, Issue 4 p. 676-677 COMMENTARY A breast multi-disciplinary genomic tumor board is feasible and can provide timely and impactful recommendations Karen Tsung BA, Karen Tsung BA University Hospitals Seidman Cancer Center, Cleveland, OH, USASearch for more papers by this authorCheryl L. Thompson PhD, Cheryl L. Thompson PhD Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USASearch for more papers by this authorJoy M. Knight MS, Joy M. Knight MS Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USASearch for more papers by this authorSteve Maximuk BS, Steve Maximuk BS University Hospitals Seidman Cancer Center, Cleveland, OH, USASearch for more papers by this authorNavid Sadri MD, Navid Sadri MD University Hospitals Seidman Cancer Center, Cleveland, OH, USASearch for more papers by this authorHannah Gilmore MD, Hannah Gilmore MD University Hospitals Seidman Cancer Center, Cleveland, OH, USA Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USASearch for more papers by this authorRuth A. Keri PhD, Ruth A. Keri PhD Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USASearch for more papers by this authorShaveta Vinayak MD, Shaveta Vinayak MD University Hospitals Seidman Cancer Center, Cleveland, OH, USA Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USASearch for more papers by this authorLyndsay Harris MD, Lyndsay Harris MD National Cancer Institute, Bethesda, MD, USASearch for more papers by this authorPaula Silverman MD, Corresponding Author Paula Silverman MD Paula.Silverman@uhhospitals.org orcid.org/0000-0001-7818-8793 University Hospitals Seidman Cancer Center, Cleveland, OH, USA Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA Correspondence Paula Silverman, MD, University Hospitals Seidman Cancer Center, Cleveland, OH, USA. Email: Paula.Silverman@uhhospitals.orgSearch for more papers by this author Karen Tsung BA, Karen Tsung BA University Hospitals Seidman Cancer Center, Cleveland, OH, USASearch for more papers by this authorCheryl L. Thompson PhD, Cheryl L. Thompson PhD Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USASearch for more papers by this authorJoy M. Knight MS, Joy M. Knight MS Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USASearch for more papers by this authorSteve Maximuk BS, Steve Maximuk BS University Hospitals Seidman Cancer Center, Cleveland, OH, USASearch for more papers by this authorNavid Sadri MD, Navid Sadri MD University Hospitals Seidman Cancer Center, Cleveland, OH, USASearch for more papers by this authorHannah Gilmore MD, Hannah Gilmore MD University Hospitals Seidman Cancer Center, Cleveland, OH, USA Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USASearch for more papers by this authorRuth A. Keri PhD, Ruth A. Keri PhD Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USASearch for more papers by this authorShaveta Vinayak MD, Shaveta Vinayak MD University Hospitals Seidman Cancer Center, Cleveland, OH, USA Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USASearch for more papers by this authorLyndsay Harris MD, Lyndsay Harris MD National Cancer Institute, Bethesda, MD, USASearch for more papers by this authorPaula Silverman MD, Corresponding Author Paula Silverman MD Paula.Silverman@uhhospitals.org orcid.org/0000-0001-7818-8793 University Hospitals Seidman Cancer Center, Cleveland, OH, USA Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA Correspondence Paula Silverman, MD, University Hospitals Seidman Cancer Center, Cleveland, OH, USA. Email: Paula.Silverman@uhhospitals.orgSearch for more papers by this author First published: 08 March 2018 https://doi.org/10.1111/tbj.13027Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume24, Issue4July/August 2018Pages 676-677 RelatedInformation

1082 Background: Patients (pts) with triple negative breast cancer (TNBC) with residual disease after neoadjuvant therapy have a high risk of recurrence. Methods: Pts with BRCA mutations and/or TNBC with lymph node (LN) or u003e 2 cm of invasive disease after anthracycline (A) and/or taxane (T) neoadjuvant therapy were assigned 1:1 to cisplatin (C: 75 mg/m2D1 q3 wks x 4) +/- rucaparib (R: 24-30 mg IV D1,2,3 q3 wks x 4 followed by R 30 mg IV or 100 mg orally wkly for 24 wks). BROCA analysis identified deleterious germline mutations. Pharmacokinetic sampling to assess R exposure was obtained during IV and oral dosing. The primary objective was 2-yr DFS. Results: From Feb 2010 to May 2013, 128 pts were enrolled. Median tumor size at surgery was 1.9 cm (0-11.5) with median LN involvement 1 (0-38); median Residual Cancer Burden (RCB) score was 2.6. Neoadjuvant therapy included A in 57% and T in 91%. 86.7% of pts received radiation therapy prior to entry. BROCA identified deleterious mutations (8 BRCA 1, 12 BRCA 2,...

Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).