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Background: Imlunestrant is a novel, orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties that result in sustained inhibition of estrogen receptor (ER)-dependent gene transcription and cell growth. In a phase 1 study, imlunestrant monotherapy showed favourable safety, pharmacokinetics (PK) and preliminary efficacy in heavily pre-treated ER-positive (ER+) advanced breast cancer patients (Jhaveri ASCO 2022). Here, we present pharmacodynamic (PD) data from the preoperative window of opportunity (WOO) study (EMBER-2, NCT04647487), evaluating the biological activity of imlunestrant monotherapy in ER+, HER2-negative (HER2-) early breast cancer (EBC). Methods: Post-menopausal women with stage I–III operable ER+ (>50%) or Allred score >5, HER2- untreated EBC ≥1 cm in diameter were randomized 1:1 to imlunestrant 400 mg once daily (QD) or imlunestrant 800 mg QD for 15 days (treatment window of -2 to +7 days) up to the surgery date. Pre- and on-treatment tumor samples were compared for changes in PD biomarkers. Primary study objective was change in ER expression (measured by IHC and quantified by H-score). Secondary objectives were change in progesterone receptor (PR) expression (measured by IHC and quantified by H-score) and Ki-67 (measured by IHC and expressed by percentage positive scoring) along with evaluation of safety and tolerability. Results: From Apr 28, 2021, to Mar 11, 2022, 58 patients were enrolled of which 54 were biomarker-evaluable for ER expression (400 mg: n = 28; 800 mg: n = 26). Patient demographics and tumor characteristics for all enrolled patients were similar across cohorts, with a median age of 64 years (50-83), 72% invasive ductal carcinoma (IDC), 28% invasive lobular carcinoma (ILC), 59% stage I, 36% stage II and 5% stage III disease. 91% of the patients had a compliance rate higher than 80%. Among biomarker evaluable patients, relative reduction in PD biomarkers after a median of 15 days (range 13 to 23 days) of treatment are presented in Table 1. There was no significant difference in PD biomarker modulation noted between the two imlunestrant doses (400 mg vs 800 mg) or based on tumor histology (IDC, ILC). Imlunestrant was well tolerated. There were no discontinuations due to adverse events (AEs). Treatment-related AEs (TRAEs) were mainly grade 1, most commonly: fatigue (10%), diarrhea (9%), hot flushes (7%), and nausea (5%). There were no TRAEs of diarrhea and nausea observed at the 400 mg dose. No grade 3 or higher TRAEs were reported. Conclusion: Imlunestrant demonstrated evidence of target engagement along with consistent biological activity across all evaluated dose levels and was well tolerated in an EBC population, further supporting continued adjuvant development in the ongoing EMBER-4 study. Additional biomarker analyses for the EMBER-2 study are also planned. Table 1. Relative reduction in PD biomarkers from Baseline to Day 15 Citation Format: Patrick Neven, Nicole Stahl, Maria Vidal, Miguel Martín, Nadia Harbeck, Peter A. Kaufman, Francois-Clement Bidard, Peter A. Fasching, Philippe Aftimos, Erika Hamilton, Stacey Carter, Peter Schmid, Duncan Wheatley, Manali Bhave, Kelly K. Hunt, Swati A. Kulkarni, Roohi Ismail-Khan, Claudia Karacsonyi, Shawn T. Estrem, Umut Ozbek, Bastien Nguyen, Eva Ciruelos. A preoperative window-of-opportunity study of imlunestrant in estrogen receptor-positive, HER2-negative early breast cancer: Results from the EMBER-2 study. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-06.

Introduction: Emerging evidence suggests that Chemotherapy (CT) treated breast cancer survivors (BCS) who have “risk variants” in genes may be more susceptible to cognitive impairment (CI) and/or poor cardiac phenotypes. The objective of this preliminary study was to examine whether there is a relationship between genetic variants and objective/subjective cognitive or cardiac phenotypes. Methods and Analysis: BCS were recruited from Moffitt Cancer Center, Morsani College of Medicine, AdventHealth Tampa and Sarasota Memorial Hospital. Genomic DNA were collected at baseline for genotyping analysis. A total of 16 single nucleotide polymorphisms (SNPs) from 14 genes involved in cognitive or cardiac function were evaluated. Three genetic models (additive, dominant, and recessive) were used to test correlation coefficients between genetic variants and objective/subjective measures of cognitive functioning and cardiac outcomes (heart rate, diastolic blood pressure, systolic blood pressure, respiration rate, and oxygen saturation). Results: BCS (207 participants) with a mean age of 56 enrolled in this study. The majority were non-Hispanic white (73.7%), married (63.1%), and received both CT and radiation treatment (77.3%). Three SNPs in genes related to cognitive functioning (rs429358 in APOE, rs1800497 in ANKK1, rs10119 in TOMM40) emerged with the most consistent significant relationship with cognitive outcomes. Among five candidate SNPs related to cardiac functioning, rs8055236 in CDH13 and rs1801133 in MTHER emerged with potential significant relationships with cardiac phenotype. Conclusions: These preliminary results provide initial targets to further examine whether BCS with specific genetic profiles may preferentially benefit from interventions designed to improve cognitive and cardiac functioning following CT.

Background: In addition to inhibiting cell cycle progression, CDK4/6 inhibitors have been found to modulate anti-cancer immune response (Goel S, et al. Nature. 2017;548:471-475). Data from preclinical studies suggested multiple mechanisms—involving changes in both cancer cells and immune cells—by which CDK4/6 inhibition can enhance anti-cancer immunity. These mechanisms include increased antigen presentation, interferon response triggering, and regulatory T-cell suppression. Clinical correlates to preclinical observations have so far been obtained using paired biopsies from neoadjuvant breast cancer trials (Johnston S, et al. J Clin Oncol. 2019;37:178-189; Hurvitz S, et al. Clin Cancer Res. 2020; ;26:566-80). Here, we describe a gene expression analysis of paired pre- and on-treatment biopsies from CLEE011A2115C and CLEE011X2107, two phase I clinical trials evaluating ribociclib in combination with ET in the metastatic breast cancer (MBC) setting. Methods: The nCounter PanCancer IO 360 Panel (NanoString) was used to quantify expression of 770 genes in 7 pairs of tumor samples (baseline vs. cycle 1 day 15) from two phase I trials in the MBC setting (5 patients from CLEE011A2115C and 2 from CLEE011X2107). All patients were treated with ribociclib and an ET. Pairwise differential gene expression analysis of individual genes and previously published immune-related gene signatures was conducted (Bedognetti D, et al. Curr Opin Oncol. 2015;27:433-444). Results: Many genes that were markedly suppressed with treatment (eg, MKI67, MYC, CDK2, CCNB1, TYMS, and DNMT1) were related to proliferation, DNA replication, and G1/S transition of the cell cycle, as expected. Interestingly, expression of numerous genes involved in immune response was increased. These were mostly interferon-regulated genes; particularly, a gene signature indicative of a T cell-inflamed tumor microenvironment (Ayers M, et al. J Clin Invest. 2017;127:2930-2940) was upregulated. Immune-related genes tended to preferentially increase with treatment in patients who later experienced a clinical response. Since bulk RNA from tumor biopsies was analyzed, we could not distinguish whether the observed expression changes reflected increased infiltration by immune cells or an endogenous interferon response in cancer cells. The latter could be triggered by DNMT1 suppression (as previously described), which then promotes T cell-mediated immunity by increasing antigen presentation and chemokine production in cancer cells. Conclusions: This analysis was conducted with a small sample size and is considered hypothesis generating; further investigation is needed. Cell cycle and proliferation markers showed robust suppression by ribociclib-based treatment regimens, as expected. Conversely, a notable increase in immune-related genes was detected that tended to occur preferentially in patients who later experienced more favorable clinical outcomes. Both changes occurred early (cycle 1 day 15). To our knowledge, this is the first clinical biomarker report of immune activation mediated by CDK4/6 inhibition in MBC. Citation Format: Dejan Juric, Chong Ma, Ralph Tiedt, Yoon-Sim Yap, Joanne Chiu, Pamela Munster, Roohi Ismail-Khan, Laura Garcia-Estevez, Ingrid A. Mayer, Carlos Becerra, Nadia Solovieff, Agnes Lteif, Faye Su, Yen-Shen Lu. Upregulation of immune response biomarkers by ribociclib plus endocrine therapy (ET) in paired tumor samples from phase I studies [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-18.

Preclinical studies have demonstrated a complex cross-talk between Notch and estrogen signaling in ERα-positive breast cancer. Gamma-secretase inhibitors (GSIs) are investigational agents that block the cleavage and activation of Notch receptors. In animal models of endocrine-resistant breast cancer, combinations of tamoxifen and GSIs produce additive or synergistic efficacy, while decreasing the intestinal toxicity of GSIs. However, results of a clinical trial of a GSI-endocrine therapy combination in the metastatic setting have not been published to date, nor had the safety of such combinations been investigated with longer term treatment. We conducted a phase 1b dose escalation trial (NCT01149356) of GSI RO4929097 with exemestane in patients with ERα+, metastatic breast cancer (MBC) Study objectives: to determine the safety, tolerability and maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of RO4929097 when administered in combination with exemestane in patients with estrogen receptor positive metastatic breast cancer Results: We enrolled 15 patients with MBC. Of 14 evaluable patients, one had a partial response, 6 had stable disease and 7 progressive disease. Twenty % of patients had stable disease for ≥ 6 months. Common toxicities included nausea (73.3%), anorexia (60%), hyperglycemia (53.3%), hypophosphatemia (46.7%), fatigue (66.7%) and cough (33.0%). Grade 3 toxicities were uncommon, and included hypophosphatemia (13%) and rash (6.3%). Rash was the only DLT observed at 140 mg/d. Results suggest a possible recommended phase 2 dose of 90 mg/d. Ten patients with evaluable archival tissue showed expression of PKCα, which correlated with expression of Notch4. Mammospheres from a PKCα-expressing, endocrine-resistant T47D cell line were inhibited by a GSI-fulvestrant combination Conclusions: Our data indicate that combinations including endocrine therapy and Notch inhibitors deserve further investigation in endocrine-resistant ERα-positive breast cancer.

PURPOSE: Most studies of adherence to treatment for breast cancer have focused on early-stage patients. Findings from these studies may not generalize to patients with metastatic breast cancer (MBC). The objective of this study was to identify barriers and facilitators of adherence to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors among patients with MBC, guided by the Social Ecologic Model (SEM). METHODS: Patients with MBC (N=25), their caregivers (N=9), and oncology providers (N=13) completed semi-structured qualitative interviews exploring their experiences with CDK4/6 inhibitors. Interviews were audio recorded, transcribed verbatim, and analyzed by three raters using a combined deductive and inductive approach. RESULTS: Qualitative analysis identified barriers and facilitators of adherence at each SEM level. Intrapersonal and interpersonal factors were most frequently discussed. Intrapersonal factors included knowledge/beliefs about CDK4/6 inhibitors, side effects, and establishing a routine. Interpersonal factors included effective communication with/coordination by the care team, support from family and friends, and information from other patients with MBC. Although less frequently discussed, policy factors (i.e., cost of CDK4/6 inhibitors) were of great concern to patients, caregivers, and providers. CONCLUSION: Barriers to adherence to CDK4/6 inhibitors exist at multiple levels. Our results underscore the potential value of a multilevel intervention (e.g., patient education, evidence-based strategies for symptom management, tips for open and assertive communication with providers, information about financial resources/support available, etc.) to support adherence in this population.

Author(s): Brown, Sherry-Ann; Yang, Eric H; Reza, Nosheen; Guha, Avirup; Ismail-Khan, Roohi; Pemmaraju, Naveen; Fradley, Michael G; Lopez-Mattei, Juan

Background: Adjuvant ET has been the standard of care for patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) EBC. A significant proportion of patients with increased risk still experience disease relapse despite available ET and more optimum ET is needed to prevent patients developing incurable metastatic cancer. Distant recurrence risk ranges from 20% to 40% after 5 years of adjuvant ET, depending on clinicopathological (clin-path) features at diagnosis. Consequently, there is a need to further optimize adjuvant treatment, particularly in those patients who are at increased risk of recurrence. Imlunestrant is an orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties and the potential to overcome ET resistance. In early phase trials, imlunestrant monotherapy showed favorable safety with pharmacokinetic (PK) exposures exceeding fulvestrant and preliminary efficacy in ER+, HER2- advanced breast cancer patients (EMBER, Jhaveri 2022) along with robust biological/pharmacodynamic activity and tolerability in EBC (EMBER-2, Neven). Trial Design: EMBER-4 is a randomized, open-label, global phase 3 study comparing imlunestrant versus physicians’ choice of ET, in patients who are at an increased risk of recurrence based on clin-path features and who have received 2 to 5 years of standard adjuvant ET. Approximately 6,000 patients will be randomized 1:1 to receive imlunestrant (400 mg daily) for 5 years or physicians’ choice of adjuvant ET (tamoxifen or an aromatase inhibitor, AI, dosed per label). Study treatment duration is 5 years. Males and pre-/peri-menopausal women will receive concomitant treatment with a GnRH agonist if receiving imlunestrant or an AI. Stratification factors include time from initial adjuvant ET, use of prior adjuvant cyclin dependent kinase 4/6 inhibitors, nodal status, menopausal status, and geographic region. Eligibility criteria: Eligible patients are adult males and females (pre-, peri- or postmenopausal) with ER+, HER2- EBC who have completed definitive locoregional therapy and have received 2 to 5 years of prior adjuvant ET without disease recurrence, but who are at increased risk of recurrence based on clin-path features at diagnosis. Prior (neo) adjuvant chemotherapy and/or targeted therapy with a CDK4/6- or PARP- inhibitor is permitted. Study endpoints: The primary endpoint is invasive disease-free survival (IDFS), excluding second non-breast primary invasive cancers. Key secondary endpoints include distant relapse-free survival, overall survival, IDFS including second non-breast primary invasive cancers, safety, PK and patient reported outcomes. Recruitment for EMBER-4 begins globally in Q4 2022. Citation Format: Komal Jhaveri, Joyce O’Shaughnessy, Fabrice Andre, Matthew P. Goetz, Nadia Harbeck, Miguel Martín, Francois-Clement Bidard, Zachary M. Thomas, Suzanne Young, Roohi Ismail-Khan, Lillian M. Smyth, Michael Gnant. EMBER-4: A phase 3 adjuvant trial of imlunestrant vs standard endocrine therapy (ET) in patients with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence who have previously received 2 to 5 years of adjuvant ET [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-01-02.

Background: Imlunestrant is a novel, orally bioavailable selective estrogen receptor degrader (SERD) with pure antagonistic properties that result in sustained inhibition of estrogen receptor (ER)-dependent gene transcription and cell growth. Preclinically, imlunestrant has favorable efficacy and pharmacokinetic (PK) properties, including antitumor activity in ESR1-mutant models, along with enhanced efficacy when combined with abemaciclib. In dose escalation (Phase 1a) and dose expansion (Phase 1b) in the EMBER study, imlunestrant monotherapy was well tolerated with favorable safety, PK and encouraging antitumor activity in heavily pre-treated ER+, HER2- advanced breast cancer (aBC) patients (Jhaveri, ASCO 2022); imlunestrant recommended phase 2 dose (RP2D) was determined as 400mg QD. Here, we present the phase 1b dose expansion of imlunestrant with abemaciclib ± aromatase inhibitor (AI) in EMBER (NCT04188548). Methods: Phase 1b enrolled patients with ER-positive (ER+), HER2-negative (HER2-) aBC [shown prior endocrine therapy (ET) sensitivity or untreated de novo aBC; ≤1 prior therapies for aBC but must not have received a prior CDK4/6 inhibitor]. Patients were randomized, based on menopausal status and presence of visceral metastases, to receive imlunestrant + abemaciclib OR imlunestrant + abemaciclib + AI. Men and premenopausal women received a concomitant GnRH agonist. Serial plasma samples were obtained for PK and ctDNA analysis. Key endpoints included safety and tolerability, PK, objective response rate (ORR) per RECIST v1.1 (ORR: complete response [CR] or partial response [PR]) in patients with measurable disease), and clinical benefit rate (CBR: CR or PR, or stable disease ≥24 weeks) in patients enrolled ≥24 weeks prior to data cut. Results: As of 26 May 2022, 85 patients have received imlunestrant [n=80 at 400 mg (RP2D); n=5 at 800 mg] in combination with abemaciclib (150mg twice daily) ± AI. Forty-eight (56%) patients had visceral disease and 9% had at least 1 ESR1 mutation detected in ctDNA at baseline. Patients were predominantly (75%) ET pre-treated, 51% with an AI; and 8% and 5%, respectively, had received prior chemotherapy or fulvestrant, for aBC. The most common treatment-emergent adverse events were diarrhea (87%), nausea (58%), fatigue (45%), neutropenia (39%) and abdominal pain (34%). The majority of treatment-related AEs (TRAEs) were Grade 1 or 2, with Grade ≥3 TRAEs occurring in 36% of patients. Most common TRAEs at RP2D (400mg) were diarrhea (81%), nausea (45%), fatigue (33%) and neutropenia (35%). No patient discontinued treatment due to an AE. Dose reductions were required of both imlunestrant and abemaciclib in 6 (7%) patients and of either imlunestrant in 3 (4%) or abemaciclib in 22 (26%) patients. Preliminary efficacy is presented in Table 1. Conclusion: Imlunestrant in combination with abemaciclib ± AI showed acceptable safety and tolerability, comparable to the MONARCH 2 trial of fulvestrant + abemaciclib, along with evidence of clinical activity in ER+, HER2- aBC patients. These data suggest no additive toxicity of imlunestrant when administered in combination with abemaciclib, along with comparable clinical benefit to that observed in MONARCH 2. Further data will be presented at the meeting. The phase 3, EMBER-3 study is ongoing; evaluating imlunestrant, investigator’s choice ET, and imlunestrant + abemaciclib in ET pre-treated ER+, HER2- aBC patients (NCT04975308). Table 1. Preliminary efficacy in combination therapies in EMBER Citation Format: Komal Jhaveri, Hwei-Chung Wang, Cynthia Ma, Elgene Lim, Jessica J. Tao, Luis Manso, Jean-Yves Pierga, Ritesh Parajuli, Yolanda Jerez Gilarranz, Yen-Shen Lu, Muralidhar Beeram, Tim Larson, Ajay Dhakal, Roohi Ismail-Khan, Claudia Karacsonyi, Shanshan Cao, Cynthia Osborne, Shawn T. Estrem, Bastien Nguyen, Yujia Li, Eunice Yuen. PD13-12 Imlunestrant, an oral selective estrogen receptor degrader, in combination with abemaciclib with or without an aromatase inhibitor, in estrogen receptor-positive advanced breast cancer: Results from the phase 1a/b EMBER study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-12.

Background: IDO1 is a mediator of tumor immune suppression through alteration of tryptophan metabolism. Indoximod (1-methyl-tryptophan) is an IDO1 pathway inhibitor. There is preclinical evidence that indoximod acts synergistically with chemotherapy such as taxanes (Uyttenhove, 2003) in an immune dependent fashion. Previous studies demonstrated the safety and activity of indoximod combined with docetaxel in patients with advanced solid tumors, including breast cancer (Soliman, 2014). A phase 2 clinical trial was designed to study the efficacy of indoximod plus taxanes in metastatic breast cancer (MBC) patients (pts). Method: This is a phase II randomized, 1:1 placebo controlled clinical trial, that enrolled MBC pts in multiple centers in the US and Poland. Eligibility criteria included ER+ or ER- HER2- MBC, ability to receive taxane therapy, PS 0-1, normal organ function and absence of autoimmune disease. Pts were randomized to taxane (either weekly paclitaxel 80mg/m2 3 on 1 off or q3wk docetaxel at 75mg/m2 per treating physician’s discretion) + placebo (TP) or taxane + indoximod 1200mg PO BID (TI) as first line treatment for MBC. Primary endpoint was PFS. The sample size of 154 patients was designed to detect a HR of .64 with one sided α=.1 and β=.2 after 95 events. Archival tumor tissue was stained with IHC for IDO1 expression when available. Aperio digital pathology positive pixel algorithm was used for scoring, with manual verification. Median value was used as cut-off for IDO positivity. Results: 164 pts were randomized and treated (85 TI, 79 TP). Demographics and tumor features are shown in table 1. Treatment discontinuation was due to disease progression (60%), adverse events (10%), other (30%). Objective response rate was 40% in TI and 37% in TP arm (p=.74). The median PFS was 6.0 (95% CI, 4.5, 8.1) months in the TI arm and 8.4 (95% CI, 5.6, 9.8) in the TP arm, HR of 1.14 (0.81, 1.60). The median OS was 21.6 months (CI 95%, 16, 39.1) in the TI arm and 21.2 (CI 95%, 19.1, 32.1) in the TP arm. The median follow up was 17.4 (range 0.1, 39.4) months. Grade ≥3 treatment emergent adverse events were observed in 60% of patients in both arms with neutropenia, fatigue, anemia, diarrhea being most common but not significantly different between arms. An exploratory analysis of IDO staining with outcomes in 42 samples (22 in TI and 20 TP) suggested a difference in median PFS in pts with high IDO expression assigned to TI vs. TP (10.3 vs 4 months, p=.047). No other prognostic or predictive associations were observed based on IDO status in the analysis. Conclusions: The combination of indoximod with a taxane in 1st line HER2- MBC was safe and did not result in added toxicity. In an unselected population, no improvement in clinical outcomes was observed for the combination over taxane alone. However, higher tumor IDO expression may select for MBC pts who benefit more from indoximod and should be investigated as a predictive biomarker in future studies. Demographics and tumor featuresIndoximodPlaceboOverallParameterStatistic(N=85)(N=79)(N=164)Age (years)n8579164median (min, max)58 (29,76)57 (29,85)58 (29,85)GenderMalen (%)1 (1.2)2 (2.5)3 (1.8)Femalen (%)84 (98.8)77 (97.5)161 (98.2)RaceWhiten (%)71 (83.5)66 (83.5)137 (83.5)African Americann (%)12 (14.1)10 (12.7)22 (13.4)Asiann (%)1 (1.2)01 (0.6)Othern (%)1 (1.2)3 (3.8)4 (2.4)ECOG status0n (%)41 (48.8)43 (54.4)84 (51.5)1n (%)44 (52.2)36 (44.3)80 (46.6)Hormone Receptor StatusNegativen (%)23 (27.1)23 (29.1)46 (28.0)Positiven (%)62 (72.9)56 (70.9)118 (72.0)Choice of TaxaneDocetaxeln (%)62 (72.9)59 (74.7)121 (73.8)Paclitaxeln (%)23 (27.1)20 (25.3)43 (26.2) Citation Format: Veronica Mariotti, Shou-Ching Tang, Patrick Dillon, Alberto Montero, Andrew Poklepovic, Susan Melin, Ibrahim Nuhad, Petros Nikolinakos, Eugene Kennedy, Hyo Han, Roohi Ismail-Khan, Daniel Bruetman, Oana Danciu, Paul Gilman, Boguslawa Karaszewska, Krzysztof Lesniewski-Kmak, Timothy Panella, Dhimant Patel, Malgorzata Suszko-Kazarnowicz, Fabio Volterra, Hatem Soliman. Results of a phase II double-blinded, randomized, placebo-controlled clinical trial of Indoximod, an Indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, in combination with Taxane chemotherapy in metastatic breast cancer (MBC) [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 PD1-04.

Background: The TEEL Study was an open labeled, non-randomized; phase I dose escalation followed by a planned phase Ib dose expansion trial of Tamoxifen (Tam) with Ribociclib (Ribo) in adult patients with advanced ER+ (HER2 negative) breast cancer. Ribo is an inhibitor of cyclin D1/CDK4 and CDK6 and has been successfully combined with Letrozole to improve PFS. This trial was done to examine the safety of the combination of Tam and Ribo in pre- and post-menopausal pts. The goal of the phase 1 expansion was to help confirm safety and develop a daily dosing schedule. Both Tam and Ribo were known to cause QTC prolongation and this was a major safety concern of the study. Method: This was an open labeled, non-randomized, phase I escalation study with a phase Ib dose expansion. The phase I portion of the study was a dose escalation to determine the safety of the combination and to determine the MTD and the RP2D for Ribo with Tam. Breast cancer patients with HR+/HER2- locally advanced or metastatic breast cancer with any prior endocrine therapy and up to two lines of prior cytotoxic chemotherapy regimens administered in the metastatic or locally advanced setting. The planned Phase Ib dose expansion was not done but was planned to better characterize the toxicity profile and assess the anti-tumor activity Ribo + Tam and to further evaluate the safety of the combination. Triplicate EKG were done at baseline, at C1D1, C1D15, C1D22, and then every subsequent cycle at day 1. Results: A total of 12 patients were screened and 7 patients were enrolled (with 5 screen failures). Ribociclib was given at 400 mg po daily for 21 days on and 7 days off. Tamoxifen was given per standard at 20 mg daily. The best response was partial response. Each cycle was 4 weeks and 1 patient remained on this combination for at least 12 cycles with PR, after cycle 3 and SD thereafter. Two patients developed significant QTC prolongation. Pt. # 3 was taken off study for QTC prolongation after cycle 8 with QTC >501. Prior to that, her treatment had been interrupted twice due to QTC prolongation. Her First EKG was manually calculated at: QT 370ms, QTcb 427ms, QTcf 407ms. Her Longest EKG: QT 402ms, QTcb 514ms, QTcf 473ms. Pt #12 was also taken off study during cycle 6 due to QTC>501. Her first EKG: QTc382ms, QTcb 480ms, QTcf 445ms. “Longest ekg” QTc 432ms, QTcb 496ms, QTcf 473ms. Both of these patients had prolonged QTC based on manual EKG. Dose limiting toxicity was noted in patient #10 who was noted to develop progression of disease (new leptomeningeal disease) after cycle 1 and subsequently had a CVA off study, thought to be associated with progressive disease. Table 1 describes highest QTC vs. cycle of therapy and there does not appear to be evidence of worsening prolongation with the number of cycles on study drugs. Other AEs were noted - please see table 2 for AEs. Conclusions: The combination of Tam and Ribo was not considered to be safe and there were two DLTs in the phase 1 part of the study, leading to the early stopping. The phase I expansion was not completed. There were 5 events of prolonged QTC, one event was determined to be a DLT. The other DLT was a CVA described above (associated with CNS disease). Unfortunately, the combination was limited by the synergistic effects of QTC prolongation of both Tam and Ribo. The importance of manually calculating the EKGs and utilizing the Fridericia formula was noted in this study. The Fidercicia is more accurate in oncology patients as it demonstrates less overcorrection than the Bazzett formula at faster heart rates which a were re quite common in cancer patients. Rational limits must be implemented to ensure patient safety without unnecessary withholding of potentially lifesaving cancer therapies. The relative risk of arrhythmia is 1.2 for QT intervals >500ms and is exceedingly low at QT intervals less than 500ms. QTC duirng each cycleCyclesC1C3C5C7C9C10C11C12Pt. 1475475468465477457481477Pt. 2412421412Pt. 3463462494689479Pt. 8450443Pt. 10420Pt. 11431435437Pt. 12480475513525 Citation Format: Roohi Ismail-Khan, Hatem Soliman, Deanna Hogue, Hyo Sook Han, Martine Extermann, Michael Fradley. The cardo-oncology concerns of combining tamoxifen and ribociclib based on the TEEL trial [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 P5-11-05.

Background Chimeric antigen receptors redirect T cells (CAR-T) to target cancer cells. There are limited data characterizing cardiac toxicity and cardiovascular (CV) events among adults treated with CAR-T. Objectives The purpose of this study was to evaluate the possible cardiac toxicities of CAR-T. Methods The registry included 137 patients who received CAR-T. Covariates included the occurrence and grade of cytokine release syndrome (CRS) and the administration of tocilizumab for CRS. Cardiac toxicity was defined as a decrease in the left ventricular ejection fraction or an increase in serum troponin. Cardiovascular events were a composite of arrhythmias, decompensated heart failure, and CV death. Results The median age was 62 years (interquartile range [IQR]: 54 to 70 years), 67% were male, 88% had lymphoma, and 8% had myeloma. Approximately 50% were treated with commercial CAR-T (Yescarta or Kymriah), and the remainder received noncommercial products. CRS, occurring a median of 5 days (IQR: 2 to 7 days) after CAR-T, occurred in 59%, and 39% were grade ≥2. Tocilizumab was administered to 56 patients (41%) with CRS, at a median of 27 h (IQR: 16 to 48 h) after onset. An elevated troponin occurred in 29 of 53 tested patients (54%), and a decreased left ventricular ejection fraction in 8 of 29 (28%); each occurred only in patients with grade ≥2 CRS. There were 17 CV events (12%, 6 CV deaths, 6 decompensated heart failure, and 5 arrhythmias; median time to event of 21 days), all occurred with grade ≥2 CRS (31% patients with grade ≥2 CRS), and 95% of events occurred after an elevated troponin. The duration between CRS onset and tocilizumab administration was associated with CV events, where the risk increased 1.7-fold with each 12-h delay to tocilizumab. Conclusions Among adults, cardiac injury and CV events are common post–CAR-T. There was a graded relationship among CRS, elevated troponin, and CV events, and a shorter time from CRS onset to tocilizumab was associated with a lower rate of CV events.

Triple-negative breast cancer (TNBC) has few therapeutic targets, making nonspecific chemotherapy the main treatment. Therapies enhancing cancer cell sensitivity to cytotoxic agents could significantly improve patient outcomes. A BCL2-associated agonist of cell death (BAD) pathway gene expression signature (BPGES) was derived using principal component analysis (PCA) and evaluated for associations with the TNBC phenotype and clinical outcomes. Immunohistochemistry was used to determine the relative expression levels of phospho-BAD isoforms in tumour samples. Cell survival assays evaluated the effects of BAD pathway inhibition on chemo-sensitivity. BPGES score was associated with TNBC status and overall survival (OS) in breast cancer samples of the Moffitt Total Cancer Care dataset and The Cancer Genome Atlas (TCGA). TNBC tumours were enriched for the expression of phospho-BAD isoforms. Further, the BPGES was associated with TNBC status in breast cancer cell lines of the Cancer Cell Line Encyclopedia (CCLE). Targeted inhibition of kinases known to phosphorylate BAD protein resulted in increased sensitivity to platinum agents in TNBC cell lines compared to non-TNBC cell lines. The BAD pathway is associated with triple-negative status and OS. TNBC tumours were enriched for the expression of phosphorylated BAD protein compared to non-TNBC tumours. These findings suggest that the BAD pathway it is an important determinant of TNBC clinical outcomes.

Purpose of Review To give an overview of the role of social media (SoMe) in cardio-oncology during the COVID-19 pandemic. Recent Findings SoMe has been critical in fostering education, outreach, awareness, collaboration, dissemination of information, and advocacy in cardio-oncology. This has become increasingly evident during the COVID-19 pandemic, during which SoMe has helped share best practices, community, and research focused on the impact of COVID-19 in cardiology and hematology/oncology, with cardio-oncology at the interface of these two subspecialty fields. Summary A strength of SoMe is the ability to amplify a message in real-time, globally, with minimal investment of resources. This has been particularly beneficial for the emerging field of cardio-hematology/cardio-oncology, a field focused on the interplay of cancer and cardiovascular disease. SoMe field especially during the COVID-19 pandemic. We illustrate how social media has supported innovation (including telemedicine), amplification of healthcare workers’ voice, and illumination of pre-existing and continued health disparities within the field of cardio-oncology during the pandemic.

Cardiovascular disease and cancer are the leading causes of death in the United States, and hormone-dependent cancers (breast and prostate cancer) are the most common noncutaneous malignancies in women and men, respectively. The hormonal (endocrine-related) therapies that serve as a backbone for treatment of both cancers improve survival but also increase cardiovascular morbidity and mortality among survivors. This consensus statement describes the risks associated with specific hormonal therapies used to treat breast and prostate cancer and provides an evidence-based approach to prevent and detect adverse cardiovascular outcomes. Areas of uncertainty are highlighted, including the cardiovascular effects of different durations of hormonal therapy, the cardiovascular risks associated with combinations of newer generations of more intensive hormonal treatments, and the specific cardiovascular risks that affect individuals of various races/ethnicities. Finally, there is an emphasis on the use of a multidisciplinary approach to the implementation of lifestyle and pharmacological strategies for management and risk reduction both during and after active treatment.

Purpose of Review This study aims to assess the current state of cardio-oncology in reference to advocacy efforts, access to care, and perspective of stakeholders in their ability to provide patient care as well as development of “across the aisle” synergy among cardiologists and oncologists and academic and non-academic centers in various worldwide locations. Recent Findings During the last decade, there has been a significant and diverse growth in cardio-oncology. We reviewed the experience from cardiologists and oncologists across different healthcare systems, the global trends, the role of collaborative networks, and the importance of advocacy efforts. Summary Cardio-oncology will continue to grow, but there is an unmet need to increase awareness, improve education, and expand access to care to larger segments of the cancer population in order to have a more significant impact on their health. The growing collaboration through professional societies and collaborative networks provides an opportunity to advance the cardiovascular care of cancer patients to meet the projected needs in a growing and more diverse population.

Objective Women with breast cancer (BCA) and cardiovascular disease (CVD) risk factors are at increased risk of developing cardiovascular complications when exposed to potentially cardiotoxic cancer therapy. The benefit of aggressive CVD risk factor modification to reduce adverse treatment-related psychologic and biologic effects is not well established. Methods Using a single group pre-test, post-test design, 33 women with BCA receiving anthracycline and/or trastuzumab therapy participated in a 6-month comprehensive CVD risk reduction program involving formal cardio-oncology evaluation along with regular motivational counseling for improved nutrition and physical activity. Study parameters were assessed at baseline and 6 months with paired t-tests used to evaluate changes after the intervention. Results The mental component summary score assessed by SF-36V2 improved significantly after program completion (45.0 to 48.8, effect size 0.37, p = 0.017), however the physical component summary score declined (46.2 to 40.9, effect size − 0.53, p = 0.004). Despite this decline in perceived physical health, markers of health-related fitness and nutritional status were maintained or improved. Systolic and diastolic blood pressure also improved after the intervention (136.7 to 124.1 mmHg, p = 0.001 and 84.0 to 78.7 mmHg, p = 0.031, respectively). No significant change in resting heart rate, body mass index, lipids, hemoglobin A1C, or left ventricular ejection fraction was observed. Conclusions Patient-reported mental health improved significantly in women with BCA enrolled in a comprehensive CVD risk reduction program despite exposure to potentially cardiotoxic therapies. This study provides preliminary data for future randomized controlled trials evaluating the effects CVD risk reduction program in high-risk breast cancer cohorts.

Importance Indoleamine 2,3-dioxygenase 1 (IDO1) causes tumor immune suppression. The IDO1 pathway inhibitor indoximod combined with a taxane in patients with ERBB2-negative metastatic breast cancer was tested in a prospective clinical trial. Objective To assess clinical outcomes in patients with ERBB2-negative metastatic breast cancer treated with indoximod plus a taxane. Design, setting, and participants This phase 2 double-blinded randomized 1:1 placebo-controlled clinical trial enrolled patients at multiple international centers from August 26, 2013, to January 25, 2016. Eligibility criteria included ERBB2-negative metastatic breast cancer, ability to receive taxane therapy, good performance status, normal organ function, no previous immunotherapy use, and no autoimmune disease. The study was discontinued in June 2017 because of lack of efficacy. Data analysis was performed from February 2019 to April 2020. Interventions A taxane (paclitaxel [80 mg/m2] weekly 3 weeks on, 1 week off, or docetaxel [75 mg/m2] every 3 weeks) plus placebo or indoximod (1200 mg) orally twice daily as first-line treatment. Main outcomes and measures The primary end point was progression-free survival (PFS); secondary end points were median overall survival, objective response rate, and toxic effects. A sample size of 154 patients would detect a hazard ratio of 0.64 with 1-sided α = .1 and β = .2 after 95 events. Archival tumor tissue was stained with immunohistochemistry for IDO1 expression as an exploratory analysis. Results Of 209 patients enrolled, 169 were randomized and 164 were treated (85 in the indoximod arm; 79 in the placebo arm). The median (range) age was 58 (29-85) years; 166 (98.2%) were female, and 135 (79.9%) were White. The objective response rate was 40% and 37%, respectively (indoximod vs placebo) (P = .74). The median (range) follow-up time was 17.4 (0.1-39.4) months. The median PFS was 6.8 months (95% CI, 4.8-8.9) in the indoximod arm and 9.5 months (95% CI, 7.8-11.2) in the placebo arm (hazard ratio, 1.2; 95% CI, 0.8-1.8). Differences between the experimental and placebo arms in median PFS (6.8 vs 9.5 months) and overall survival (19.5 vs 20.6 months) were not statistically significant. Grade 3 or greater treatment-emergent adverse events occurred in 60% of patients in both arms. Conclusions and relevance This randomized clinical trial found that, among patients with ERBB2-negative metastatic breast cancer, addition of indoximod to a taxane did not improve PFS compared with a taxane alone. Trial registration ClinicalTrials.gov Identifier: NCT01792050.

BackgroundRe-allocation of resources during the COVID-19 pandemic has resulted in delays in care delivery to patients with cardiovascular disease and cancer. The ability of health care providers to provide optimal care in this setting has not been formally evaluated.ObjectivesTo assess the impact of COVID-19 resource re-allocation on scheduling, testing, elective procedures, telemedicine access, use of new COVID-19 therapies, and providers’ opinions on healthcare policies among oncology and cardiology practitioners.MethodsAn electronic survey was conducted by a cardio-oncology collaborative network through regional and state chapters of the American College of Cardiology , American Society of Clinical Oncology, and the International Cardio-Oncology Society. Descriptive statistics were reported by frequency and proportion for analyses, and stratified categorically by geographic region and specialty.Results1,415 providers (43 countries) participated: 986 cardiologists, 306 oncologists, and 118 trainees/internal medicine. 63% (195/306) of oncologists vs 92% (896/976) of cardiologists reported cancellations of treatments/elective procedures (p=0.01). 46% (442/970) of cardiologists and 25% (76/303) of oncologists modified the scope of their practice (p=ConclusionsThese results support initiatives to promote expanded coverage for telemedicine, increased access to PPE, better testing availability and involvement of medical professional societies to help with preparedness for future health care crisis.Appendix: Link to the Survey: https://www.surveymonkey.com/r/C8ZDYNW

Background: IFN-γ, a cytokine that plays diverse roles in innate and adaptive immunity, has been shown to be essential in anti-tumor immune response. In vitro and in vivo studies have shown the synergistic effect of IFN-γ in combination with HER2-targeting monoclonal antibodies with or without taxane chemotherapy. We have conducted a phase 1 clinical trial of systemic IFN-γ in combination with trastuzumab, pertuzumab, and paclitaxel in HER2-positive metastatic breast cancer. Methods: Two dose levels (DL) of IFN-γ, 50 (DL1) and 75 mcg/m2 (DL2), were evaluated. IFN-γ was given as subcutaneous injection three times weekly starting on day 1 of therapy for 12 weeks. Paclitaxel was administered intravenously (IV) weekly at 80mg/m2 in combination with trastuzumab IV (8 mg/kg loading dose, then 6 mg/m2 q 21 days) and pertuzumab IV (840 mg loading dose, then 420 mg q 21 days). Eligible patients had measurable metastatic HER2-positive breast cancer, were candidates to receive paclitaxel chemotherapy, and had an ECOG PS 0-1. The primary objective of this study was to evaluate the safety and tolerability of the combination therapy during the 12 weeks of treatment and to determine the recommended phase II dose (RP2D). Dose-limiting toxicity (DLT) during cycle one was defined as follows: Non-hematologic or hematologic toxicities that are ≥ grade 3 and probably or definitely related to study therapy which lead to chemotherapy treatment delays > 14 days. Results: A total of nine patients (3 on DL1 and 6 on DL2) were enrolled between 2/2017 and 11/2017. No DLT was observed. For DL1, no serious adverse events (SAE) or significant adverse events (AE) were observed among 3 patients who completed 12 weeks of treatment. For DL2, two out of 6 patients had SAEs including grade 3 pneumonitis (at week 8; treatment was subsequently discontinued) and grade 3 non-neutropenic fever (at week 6), which were possibly related to study treatment. These toxicities, however, did not meet the protocol definition of DLT. Based on these findings suggesting an improved tolerability of DL1 (50 mcg/m2), DL1 was selected as the RP2D. The most frequently observed grade 1 and 2 AEs that were at least possibly related to IFN-γ were fatigue (45%) nausea (36%), myalgia (36%), and fever (27%) diarrhea (18%). No grade 4 AE was noted. Grade 3 AEs included diarrhea, nausea, pneumonitis, non-neutropenic fever. Three out of 9 patients achieved partial response and 6 patients had stable disease per RECIST criteria. Conclusion: IFN-γ in combination with trastuzumab, pertuzumab, and paclitaxel was well tolerated in patients with HER2-positive metastatic breast cancer. Updated results will be presented and the phase 2 neoadjuvant trial is ongoing to further assess the efficacy of this approach. Citation Format: Han HS, Khong H, Costa R, Loftus L, Goodridge D, Henry T, Soliman H, Ismail-Khan R, Fridley B, Czerniecki B. A phase I study of interferon-gamma (γ)plus weekly paclitaxel, trastuzumab and pertuzumab in patients with HER-2 positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-15.

In response to the coronavirus disease 2019 (COVID-19) pandemic, the Cardio-Oncology and Imaging Councils of the American College of Cardiology offers recommendations to clinicians regarding the cardiovascular care of cardio-oncology patients in this expert consensus statement. Cardio-oncology patients—individuals with an active or prior cancer history and with or at risk of cardiovascular disease—are a rapidly growing population who are at increased risk of infection, and experiencing severe and/or lethal complications by COVID-19. Recommendations for optimizing screening and monitoring visits to detect cardiac dysfunction are discussed. In addition, judicious use of multimodality imaging and biomarkers are proposed to identify myocardial, valvular, vascular, and pericardial involvement in cancer patients. The difficulties of diagnosing the etiology of cardiovascular complications in patients with cancer and COVID-19 are outlined, along with weighing the advantages against risks of exposure, with the modification of existing cardiovascular treatments and cardiotoxicity surveillance in patients with cancer during the COVID-19 pandemic.

Background: The host anti-tumor immune response plays an important role in determining natural history and therapy response for early stage breast cancer. Tumors with high levels of lymphocytic infiltration appear to have a superior prognosis and response rate to neoadjuvant chemotherapy. However, these tumors are in the minority so methods to enhance tumor lymphocyte infiltration should be identified. The oncolytic virus, talimogene laherparpvec (TVEC) is a genetically modified HSV1 virus which selectively replicates in transformed cells while sparing normal tissue. This leads to lysis of infected tumor cells along with co-expression of GM-CSF to elicit an enhanced anti-tumor immune response. Prior data has shown TVEC can be safely combined with chemotherapy in other indications, so we launched an investigator initiated study to determine the safety and efficacy of combining TVEC with neoadjuvant dose dense chemotherapy in stage II-III TNBC. Study design: The study is a phase 1 (2 dose levels of TVEC, 3+3 design) and phase 2 single arm Simon two stage combination trial. Primary endpoints of phase 1 is safety of intratumoral TVEC (DL1=106 PFU x 5 injections, DL2=106 PFU x 1 then 108 PFU x 4 injections) administered q2-3 weeks concurrently with weekly paclitaxel followed by standard dose dense AC x 4 and local therapy as indicated. Phase 2 primary endpoint is pCR rate of the study treatment, secondary endpoints include DFS, OS, immune correlates in resected tumor specimens. Eligibility criteria includes females >17 years old, newly diagnosed T2-3N0-3 TNBC, adequate organ function, primary tumor amenable to injection with TVEC, no immunosuppressive or autoimmune conditions, no inflammatory or bilateral/multifocal disease. Sample size is up to 49 patients (12 phase 1, 37 phase 2) with 80% power to detect increase in pCR rate from 30% to 50% with one sided p=.1 in phase 2. Study status: This novel Amgen supported investigator initiated study activated to accrual 3/2017 and first patient on study was on 5/2017. The study is currently open only at the Moffitt Cancer Center. Target study completion date 8/2021. (NCT02779855) Citation Format: Soliman HH, Hogue D, Han H, Lee C, Ismail-Khan R, Khong H, Niell B, Czerniecki B. Phase 1/2 trial of the oncolytic virus, talimogene laherparpvec, in combination with neoadjuvant chemotherapy in stage II/III triple negative 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 OT2-07-01.

// Hatem Soliman 1, 2 , Fatema Khambati 2 , Hyo S. Han 1 , Roohi Ismail-Khan 1 , Marilyn M. Bui 3 , Daniel M. Sullivan 4 and Scott Antonia 2, 5 1 Breast Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 2 Immunology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 3 Anatomic Pathology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 4 Malignant Hematology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 5 Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA Correspondence to: Hatem Soliman, email: hatem.soliman@moffitt.org Keywords: indoximod; adenovirus-p53 transduced dendritic cell vaccine; cancer vaccine; immunotherapy; indoleamine 2,3-dioxygenase Received: October 03, 2017 Accepted: November 28, 2017 Published: January 10, 2018 ABSTRACT Background : Indoleamine 2, 3-dioxygenase is an enzyme that causes immunosuppression in tumors. Indoximod inhibits the indoleamine 2, 3-dioxygenase pathway and enhances immunologic responses to dendritic cell (DC) vaccines preclinically. Adenovirus p53 (Ad.p53) is used to generate DC vaccines against p53. A phase-1/2 trial of indoximod with Ad.p53-DC vaccine was conducted. Materials and Methods : The phase-1 study combined 7 indoximod dose levels with < 6 Ad.p53-DC vaccinations every 2 weeks. Primary endpoints were maximum-tolerated dose in phase 1 and objective response in phase 2. Flow cytometry measured immune responses. Results : Thirty-nine patients were treated. In combination with Ad.p53-DC vaccine, the maximum-tolerated dose of indoximod was 1600 mg twice daily. Attributable toxicities were grade 1–2. Best response was stable disease in 4 patients. Immunologic responses were detected in 7 out of 23 evaluable patients. Median progression-free survival was 13.3 weeks (95% confidence interval, 12.97–21.85) and median overall survival was 20.71 weeks (95% confidence interval, 25.75–46.15). Nine out of 22 patients (40%) benefitted from chemotherapy after vaccination. Median overall survival in chemotherapy responders was 69.4 weeks (30.1–122.1). Conclusions : Indoximod 1600 mg twice daily with Ad.p53-DC was well tolerated. There may have been a chemosensitization effect. Future trials should explore combining this treatment with chemotherapy.

Advances in cancer screening and improved treatment approaches have led to an increase in survivorship and, consequently, recognition of an association between cancer treatments and the development of cardiovascular complications. In addition, as the population becomes proportionally older, comorbid cardiovascular risk factors are more prevalent in the population and compound the risk of developing cancer treatment–related cardiovascular toxicity. Cardio-oncology has emerged as a new subspecialty of medicine that provides a multidisciplinary approach, bringing together oncologists, cardiologists, and allied health care providers who are tasked with optimizing the cardiovascular health of patients exposed to potentially cardiotoxic cancer therapy. Using a case-based approach, practical advice on how to identify, monitor, and treat patients with cancer who are at risk for developing cancer treatment–related cardiovascular dysfunction is discussed. Cardiovascular risk factors (e.g., age, hypertension, diabetes) and cancer therapies (chemotherapy, targeted therapy, radiation) associated with cardiovascular toxicity are presented. Current cardiac monitoring strategies such as two- and three-dimensional echocardiography, cardiac MRI, and biomarkers (troponin and brain natriuretic peptide [BNP]) are discussed. Last, the current literature on pharmacologic (e.g., angiotensin-converting enzyme inhibitors, β-blockers, statins) and lifestyle (diet and exercise) strategies to mitigate cardiovascular toxicity during and following completion of cancer therapy are reviewed.

Additional file 1. Link to the Survey: https://www.surveymonkey.com/r/C8ZDYNW .

Background: XPO1 (also known as CRM1) is the exclusive nuclear exporter of multiple tumor suppressor proteins (TSP) including p53, p21, BRCA1/2, pRB, FOXO. XPO1 inhibition forces nuclear accumulation of TSPs, thus inducing apoptosis in cancer cells. Selective Inhibitors of Nuclear Export (SINE) compounds are novel, small molecule, slowly reversible inhibitors of XPO1. SINE compounds showed potent cytotoxicity in the majority of TNBC cell lines in vitro and xenografts. Methods: Eligible patients had measurable metastatic TNBC, received at least one prior line of chemotherapy in the setting of metastatic disease (including anthracycline and taxane), and had an ECOG PS 0-1. Selinexor was given at 60 mg orally twice weekly (day 1& 3 of each week), three of each four-week cycle. The primary objective of this study was to determine the clinical benefit rate (CBR, defined as complete response + partial response + stable disease (SD) ≥12 weeks) from Selinexor in patients with TNBC. This study used a Simon two-stage design (null hypothesis CBR 5%, alternate hypothesis CBR 20%) Results: Ten patients with a median age of 60 years (range 44-71) were enrolled between 7/2015 and 1/2016. The median number of prior chemotherapy lines was 2 (range 1-5). A planned interim analysis for the first stage per protocol was performed. Three patients had SD and 7 had progressive disease. The median duration of SD was 84 days (range 17-130 days) and all patients experienced progressive disease with a median PFS of 38 days (range 17-130 days). Based on these results, the error probability of observing no response among the first 10 patients is 0.107 under the alternative hypothesis, i.e., P of response =20%, using the Exact binomial test. This false negative error rate is under the planned type II error 0.20, which is consistent with the predefined stopping rule of the study: the study would be halted if no patient achieved objective response (complete or partial response) in the first 10 eligible patients (stage I). The most frequent grade 1 and 2 observed adverse events that were possibly related to Selinexor were nausea 30% (all grade 1), vomiting 50% (40% grade 1), constipation 50% (40% grade 1, 10% grade 2), diarrhea 20%, anorexia 30%, thrombocytopenia 30%, blurred vision 30%. No grade 4 toxicity was noted. Grade 3 toxicity included reversible encephalopathy (10%), irritability (10%), and thrombocytopenia (10%). Conclusion: Selinexor was well tolerated in patients with advanced TNBC but did not result in objective responses in this patient population. Further combination studies can be explored. Citation Format: Han HS, Ismail-Khan R, Carney D, Extermann M, Hogue D, Soliman H, Loftus L, Lee JK, Sullivan D. Phase II trial of selinexor for metastatic triple negative 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 P4-22-23.

Background: Aromatase inhibitors are the standard first-line treatment for patients (pts) with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC). However, resistance via disruption of the cyclin D–cyclin-dependent kinase (CDK)4/6–inhibitor of CDK4–retinoblastoma pathway is common. The oral, selective CDK4/6 inhibitor ribociclib has demonstrated synergistic activity with letrozole in preclinical models of ER+ breast cancer. This Phase Ib study investigated ribociclib plus letrozole in ER+, HER2– aBC (NCT01872260). Methods: Postmenopausal pts with ER+, HER2− aBC received ribociclib (600 mg/day; 3-weeks-on/1-week-off) plus letrozole (2.5 mg; continuous). The primary objective of the expansion phase was to evaluate safety and tolerability. Secondary and exploratory objectives included efficacy, pharmacokinetics (PK), and biomarkers. Results: As of October 30, 2015, 47 pts received ribociclib plus letrozole: 19 pts in the initial enrollment and 28 pts in the expansion phase. In the initial enrollment, 17/19 pts (89%) were previously treated for aBC (PT group); in the expansion phase, 27/28 pts (96%) were treatment-naïve for aBC (first-line group). All 19 PT pts and 10 first-line pts (62% of all pts) have discontinued treatment. Common (>5% of pts) treatment-related Grade 3/4 adverse events included neutropenia (43%), neutrophil count decreased (11%), and white blood cell count decreased (6%). Complete response (CR) was observed in 1 pt (4%) in the first-line group. In the PT and first-line groups, 1 pt (5%) and 10 pts (36%) had a partial response (PR), 7 pts (37%) and 4 pts (14%) had neither CR nor progressive disease (PD), 7 pts (37%) and 10 pts (36%) had stable disease (SD), and 4 pts (21%) and 3 pts (11%) had PD, respectively. Among pts with measurable disease, overall response rate (ORR; CR + PR) was 9% (95% confidence interval [CI]: 0–41%) for 11 PT pts and 46% (95% CI: 26–67%) for 24 first-line pts, and clinical benefit rate (CBR; CR + PR + SD ≥24 weeks) was 18% (95% CI: 2–52%) for 11 PT pts and 79% (95% CI: 58–93%) for 24 first-line pts. Ribociclib PK data were consistent with single-agent data and indicated no drug–drug interaction with letrozole. Notable genetic alterations detected by next-generation sequencing included PIK3CA mutations (4/10 PT pts [40%]; 14/22 first-line pts [64%]) and ESR1 mutations (2/10 PT pts [20%]). Responses were observed in pts harboring PIK3CA mutations (1 CR [first-line pt], 1 unconfirmed CR [first-line pt], 3 PR [1 PT pt, 2 first-line pts], and 3 unconfirmed PR [first-line pts]). Progression-free survival data for ribociclib plus letrozole, in addition to updated ORR and CBR, will be presented at the symposium. Conclusions: The combination of ribociclib plus letrozole demonstrated encouraging clinical activity, particularly in pts treatment-naïve for aBC, with an acceptable safety profile that is in line with CDK4/6 inhibition. These results, which are consistent with the positive results of the MONALEESA-2 study (NCT01958021), provide additional safety and efficacy evidence for the use of ribociclib plus letrozole for the first-line treatment of postmenopausal aBC. Citation Format: Munster P, Ismail-Khan R, Garcia-Estevez L, Mayer IA, Becerra C, Hamilton E, De Boer R, Wardley AM, Im S-A, Teixeira L, Wang Y, Su F, Germa C, Hirawat S, Juric D. Phase Ib safety, efficacy, and molecular analysis of ribociclib (LEE011) plus letrozole for the treatment of ER+, HER2– 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 P4-22-18.

Background: Metastatic breast cancer is a common and devastating diagnosis. New strategies for treatment are needed to help improve outcomes. Eribulin is an anti-microtubule agent approved in 2010 for advanced breast cancer. Combination with other chemotherapeutic agents provides an alternative treatment option for these patients. Purpose: This study evaluates the safety, tolerability and activity of eribulin and weekly carboplatin in a dose-escalation schema in patients with metastatic breast cancer. Methods: Patients were treated with eribulin and carboplatin AUC 2 administered on the first and eighth days of a 21-day cycle. Three doses of eribulin (0.9, 1.1 and 1.4 mg/m2) were examined. An additional 10 patients were enrolled into an expansion cohort at the recommended Phase 2 dose. Results: A total of 19 patients were treated, including 10 patients in the dose expansion cohort. There was no dose limiting toxicity related to the study therapy in the dose escalation cohorts. Grade 3 toxicities included neutropenia (21%), anemia (10%), fatigue (10%), peripheral sensory neuropathy (10%), infusion related reactions (5%), pericardial effusion (5%), diarrhea (5%) and pleural effusion (5%). Twenty-six percent of patients had grade 4 neutropenia, but there were no events of sepsis or febrile neutropenia. The maximum tolerated dose (MTD) of eribulin in combination with carboplatin AUC 2 was determined to be 1.4 mg/m2. Four patients experienced clinical benefit, 2 patients with stable disease greater than 6 months and 2 patients with partial response, demonstrating a clinical benefit rate of 21%. Conclusion: Eribulin and weekly carboplatin appeared to be safe and well tolerated with demonstrated clinical benefit. The recommended Phase 2 dose level was 1.4 mg/m2 of eribulin. Further studies can be pursued for this combination regimen to establish its efficacy.

Purpose There are currently no targeted therapies approved for triple-negative breast cancer (TNBC). A tumor necrosis factor α ( TNFα)–based gene expression signature (GS) predictive of sensitivity to LCL161, inhibitor of apoptosis antagonist, was translated into a clinical assay and evaluated in a neoadjuvant trial. Patients and Methods Women with localized TNBC (T2/N0–2/M0) were prospectively stratified by GS status and randomly assigned (1:1) to receive oral LCL161 (1,800 mg once per week) and intravenous paclitaxel (80 mg/m2 once per week; combination arm) or paclitaxel alone (control arm) for 12 weeks, followed by surgery. The primary objective was to determine whether neoadjuvant LCL161 enhances efficacy of paclitaxel, defined by > 7.5% increase in the pathologic complete response (pCR, breast) rate, stratified by GS. Results Of 209 patients enrolled (207 with valid GS scores), 30.4% had GS-positive TNBC. In the GS-positive group, pCR was higher in the combination versus the control arm (38.2% v 17.2%), with 88.8% posterior probability of > 7.5% increase in pCR. However, in the GS-negative group, the pCR was lower in the combination group (5.6% v 16.4%), with 0% posterior probability of > 7.5% increase in pCR. A higher incidence of grade 3 or 4 adverse events in the combination arm included neutropenia (24.5%) and diarrhea (5.7%). Overall, 19 patients (18.1%) in the combination arm discontinued treatment because of adverse events, including pyrexia (n = 5), pneumonia (n = 4), and pneumonitis (n = 4), versus five patients (4.9%) in the control arm. Conclusion This neoadjuvant trial provides evidence supporting a biomarker-driven targeted therapy approach for selected patients with GS-positive TNBC and demonstrates the utility of a neoadjuvant trial for biomarker validation and drug development, but also highlights toxicity risk. Future neoadjuvant clinical trials should carefully weigh these considerations for targeted therapy development in biomarker-defined TNBC.

Genetic variations of breast cancer survivors (BCS) may contribute to level of residual symptoms, such as depression, stress, fatigue, and cognitive impairment. The objective of this study was to investigate whether particular single-nucleotide polymorphisms (SNPs) moderated symptom improvement resulting from the Mindfulness-Based Stress Reduction for Breast Cancer (MBSR[BC]) program. An overarching goal of personalized medicine is to identify individuals as risk for disease and tailor interventions based on genetic profiles of patients with diseases including cancer. BCS were recruited from Moffitt Cancer Center and University of South Florida’s Breast Health Program and were randomized to either the 6-week MBSR(BC) program (n = 92) or Usual Care (n = 93). Measures of symptoms, demographic, and clinical history data were attained at baseline, 6 weeks, and 12 weeks. A total of 10 SNPs from eight genes known to be related to these symptoms were studied using genomic DNA extracted from blood. Our results were examined for effect sizes, consistency, and statistical significance (p < .05). Three SNPs (rs4680 in COMT, rs6314 in HTR2A, and rs429358 in APOE) emerged as having the strongest (though relatively weak) and most consistent effects in moderating the impact of the MBSR program on symptom outcomes. Although effects were generally weak, with only one effect withstanding multiple comparisons correction for statistical significance, this translational behavioral research may help start the identification of genetic profiles that moderate the impact of MBSR(BC). The ultimate goal of this study is the development of personalized treatment programs tailored to the genetic profile of each patient.

// hatem h. soliman 1 , susan e. minton 1 , hyo sook han 1 , roohi ismail-khan 1 , anthony neuger 1 , fatema khambati 1 , david noyes 1 , richard lush 1 , alberto a. chiappori 1 , john d. roberts 2 , charles link 3 , nicholas n. vahanian 3 , mario mautino 3 , howard streicher 4 , daniel m. sullivan 1 and scott j. antonia 1 1 h. lee moffitt cancer center and research institute, tampa, florida, usa 2 massey cancer center, virginia commonwealth university, richmond, virginia, usa 3 newlink genetics inc., ames, iowa, usa 4 cancer therapeutics evaluation program, national cancer institute, bethesda, maryland, usa correspondence to: hatem h. soliman, email: // keywords : indoleamine 2,3 dioxygenase, 1-methyl-d-tryptophan, indoximod, immunomodulator received : february 11, 2016 accepted : march 10, 2016 published : march 20, 2016 abstract purpose: indoximod is an oral inhibitor of the indoleamine 2,3-dioxygenase pathway, which causes tumor-mediated immunosuppression. primary endpoints were maximum tolerated dose (mtd) and toxicity for indoximod in patients with advanced solid tumors. secondary endpoints included response rates, pharmacokinetics, and immune correlates. experimental design: our 3+3 phase i trial comprised 10 dose levels (200, 300, 400, 600, and 800 mg once/day; 600, 800, 1200, 1600, and 2000 mg twice/day). inclusion criteria were measurable metastatic solid malignancy, age ≥18 years, and adequate organ/marrow function. exclusion criteria were chemotherapy ≤ 3 weeks prior, untreated brain metastases, autoimmune disease, or malabsorption. results: in 48 patients, mtd was not reached at 2000 mg twice/day. at 200 mg once/day, 3 patients previously treated with checkpoint inhibitors developed hypophysitis. five patients showed stable disease >6 months. indoximod plasma auc and cmax plateaued above 1200mg. cmax (~12 μm at 2000 mg twice/day) occurred at 2.9 hours, and half-life was 10.5 hours. c reactive protein (crp) levels increased across multiple dose levels. conclusions: indoximod was safe at doses up to 2000 mg orally twice/day. best response was stable disease >6 months in 5 patients. induction of hypophysitis, increased tumor antigen autoantibodies and crp levels were observed.

Background: Indoleamine 2,3 dioxygenase (IDO) is a tryptophan-catabolizing enzyme that causes immunosuppression in the tumor microenvironment. Indoximod is an IDO pathway inhibitor. Preclinical data suggests indoximod enhancs the activity of dendritic cell (DC) vaccines. Ad.p53 is an adenovirus used to generate autologous dendritic cell (DC) vaccines against p53 epitopes. We initiated a phase 1/2a trial of indoximod + Ad.p53DC to explore the safety and efficacy of the combination along with response to subsequent chemo. The phase 1 safety data were previously presented and the treatment was well tolerated with no DLTs. (Soliman, ASCO 2013) This abstract includes new phase 2a safety/efficacy data and updated outcomes on all phase 1/2 metastatic breast cancer patients who received Adp53DC+indoximod and any subsequent response to salvage chemo. Methods: The phase 2a study combined indoximod 1600mg PO BID with up to 6 Ad.p53 DC vaccinations q2wks. The trial used a single arm, Simon two stage design (n=12 in 1st stage, 25 in 2nd stage) with objective response as the primary endpoint. One response out of 12 was required for progression into second stage. The study had 90% power to detect 20% response rate with a p=.09. Patients with measurable, metastatic breast cancer, 5%, ECOG 0-2, no autoimmune disease were eligible. Study treatment continued until disease progression or unacceptably toxicity. Results: Twelve phase 2 patients were accrued, 9 (7 TNBC, 2 ER+/HER2-) received ≥ 1 dose of Ad.p53DC+indoximod (3 did not due to rapid disease progression during vaccine preparation). Six patients had ≥ 1 prior line of chemo. Seven (58%) subjects experienced any grade AE, there were no treatment related AEs ≥G3. All treatment attributable AEs were G1-2, Conclusions: Indoximod+Ad.p53DC was well tolerated. Across phase 1/2 the best response to immunotherapy alone was SD in 4 pts while 10 of 21 (47%) (including 1 CR) responded to subsequent chemotherapy in this largely pretreated cohort. There may be a chemosensitization effect of indoximod+Ad.p53DC. Future trials should combine this treatment with chemotherapy in appropriately selected patients. Citation Format: Hatem H Soliman, Susan E Minton, Roohi Ismail-Khan, Hyo S Han, Nicholas N Vahanian, Charles J Link, Gene Kennedy, Howard Streicher, Daniel Sullivan, Scott J Antonia. A phase 1/2 study of Ad.p53 DC vaccine with indoximod immunotherapy in metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-15-04.

Objectives There is little information about arrhythmia burden in cancer survivors with chemotherapy-induced cardiomyopathy (CIC). We hypothesise that the rates and risk of arrhythmias will be similar in CIC when compared with other non-ischaemic cardiomyopathy (NICMO) aetiologies. Methods We retrospectively identified nine patients with CIC and an implantable defibrillator and 18 age and sex-matched control patients (nine patients with NICMO and nine patients with ischaemic cardiomyopathy (ICMO)). Rates and odds of arrhythmias were calculated by type of cardiomyopathy, adjusting for days since implantable cardioverter defibrillator implantation, history of atrial fibrillation and length of follow-up using logistic regression analysis. Results Compared with patients with NICMO, rates and adjusted odds were similar for patients with CIC for atrial arrhythmias (44.4% vs 33.3%; adjusted OR=1.89; 95% CI0.17 to 21.03; P=0.61), non-sustained ventricular tachycardia (NSVT) (44.4% vs 33.3%; OR=2.10; 95% CI 0.21 to 20.56; P=0.53), and the combined outcome of NSVT, sustained ventricular tachycardia and/or ventricular fibrillation (44.4% vs 44.4%; OR=2.70; 95% CI 0.25 to 29.48; P=0.42). Conversely, compared with patients with NICMO, patients with ICMO demonstrated higher rates and adjusted odds of the combined outcome (88.9% vs 44.4%; OR=28.60; 95% CI 1.26 to 648.2; P=0.04) and NSVT (77.8% vs 33.3%; OR=8.95; 95% CI 0.90 to 88.94; P=0.06). Conclusions While tentative based on sample size, rates of arrhythmias in patients with CIC appear to be similar to those experienced by patients with other forms of NICMO.

Cardio-oncology is a multidisciplinary field focusing on the management and prevention of cardiovascular complications in cancer patients and survivors. While the initial focus of this specialty was on heart failure associated with anthracycline use, novel anticancer agents are increasingly utilized and are associated with many other cardiotoxicities including hypertension, arrhythmias and vascular disease. Since its inception, the field has developed at a rapid pace with the establishment of programs at many major academic institutions and community practices. Given the complexities of this patient population, it is important for providers to possess knowledge of not only cardiovascular disease but also cancer subtypes and their specific therapeutics. Developing a cardio- oncology program at a stand-alone cancer center can present unique opportunities and challenges when compared to those affiliated with other institutions including resource allocation, cardiovascular testing availability and provider education. In this review, we present our experiences establishing the cardio-oncology program at Moffitt Cancer Center and provide guidance to those individuals interested in developing a program at a similar independent cancer institution.

// Hatem H. Soliman 1 , Erica Jackson 2 , Tony Neuger 1 , E. Claire Dees 3 , R. Donald Harvey 4 , Hyo Han 1 , Roohi Ismail-Khan 1 , Susan Minton 1 , Nicholas N. Vahanian 5 , Charles Link 5 , Daniel M. Sullivan 1 , Scott Antonia 1 1 H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 2 University of South Florida, Tampa, FL 3 University of North Carolina/Lineberger Cancer Center, Chapel Hill, NC 4 Winship Cancer Institute of Emory University, Atlanta, GA 5 NewLink Genetics Inc, Ames, IA Correspondence to: Dr. Hatem Soliman MD, e-mail: Hatem.soliman@moffitt.org Keywords: Indoximod, 1-methyl-D-tryptophan, immunomodulator, docetaxel, indoleamine 2, 3 dioxygenase Received: June 12, 2014 Accepted: August 16, 2014 Published: August 21, 2014 ABSTRACT Background: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to create a state of immunosuppression. Indoximod is an IDO pathway inhibitor. Preclinical studies demonstrated that indoximod combined with chemotherapy was synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed to study the combination of docetaxel and indoximod. Methods: Docetaxel was administered at 60 mg/m 2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m 2 for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO twice daily continuously for levels 1-5, respectively. Serum drug levels were measured. Results: Twenty-seven patients were treated, with 22 evaluable for response. DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%). There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug interactions were noted. Conclusions: Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.

Lessons Learned Single-agent selinexor has limited activity in heavily pretreated patients with metastatic triple-negative breast cancer. Selinexor 60 mg by mouth twice weekly was generally well tolerated with a side-effect profile consistent with previous clinical trials. Future studies of selinexor in this population should focus on combination approaches and a biomarker-driven strategy to identify patients most likely to benefit. Background This phase II trial evaluated the safety, pharmacodynamics, and efficacy of selinexor (KPT-330), an oral selective inhibitor of nuclear export (SINE) in patients with advanced triple-negative breast cancer (TNBC). Methods This phase II trial was designed to enroll 30 patients with metastatic TNBC. Selinexor was given at 60 mg orally twice weekly on days 1 and 3 of each week, three of each 4-week cycle. The primary objective of this study was to determine the clinical benefit rate (CBR), defined as complete response + partial response + stable disease (SD) ≥12 weeks. Results Ten patients with a median age of 60 years (range 44–71 years) were enrolled between July 2015 and January 2016. The median number of prior chemotherapy lines was 2 (range 1–5). A planned interim analysis for the first stage per protocol was performed. Three patients had SD and seven had progressive disease. On the basis of these results and predefined stoppage rules, the study was halted. Conclusion Selinexor was fairly well tolerated in patients with advanced TNBC but did not result in objective responses. However, clinical benefit rate was 30%, and further investigation of selinexor in this patient population should focus on combination therapies.

Background: Inhibitor of apoptosis proteins (IAPs) negatively regulate cell death through a variety of mechanisms. LCL161 is an oral small-molecule antagonist of IAPs that has demonstrated single-agent activity and synergy with paclitaxel in breast cancer tumor models. In preclinical studies, a gene expression signature has been shown to enrich for response to LCL161. The recommended dose of LCL161 1800 mg once weekly has demonstrated preliminary antitumor activity with paclitaxel in an ongoing Phase Ib study in patients with breast cancer. Trial design: This is a Phase II, randomized, open-label study of neoadjuvant paclitaxel with or without LCL161 in women with operable, newly diagnosed triple-negative breast cancer (NCT01617668). Key inclusion criteria include women with histologically confirmed diagnosis of triple-negative breast cancer; clinical stages T2, N0–N2, M0; candidates for mastectomy or breast-conserving surgery; ECOG performance status ≤1; known status of the LCL161-predictive gene expression signature (positive and negative gene signature is a stratification factor); and adequate bone marrow and organ function. Key exclusion criteria are: bilateral or inflammatory breast cancer; locally recurrent breast cancer; patients currently receiving systemic therapy for any other malignancy, or having received systemic therapy for a malignancy in the preceding 3 months; impaired gastrointestinal function that may affect the absorption of LCL161; or uncontrolled cardiac disease. Patients are randomized 1:1 to receive paclitaxel IV (80 mg/m2 weekly) with or without oral LCL161 (1800 mg once weekly) for 12 weeks (corresponding to 4 treatment cycles). Each treatment arm is stratified 1:1 based on gene expression signature status (positive or negative). Endpoints: The primary endpoint is pathologic complete response (pCR), defined as the absence of invasive disease in the breast after 12 weeks of therapy, analyzed separately in the gene expression signature positive and negative groups. The key secondary endpoint is the pCR rate following treatment with LCL161 and paclitaxel in gene expression signature-positive or -negative tumors. Other secondary endpoints include: pCR rate in breast after 12 weeks of therapy in the full study population, and in patients with gene expression signature-positive and -negative tumors treated with paclitaxel alone; pCR rate in breast, regional nodes and axilla; biomarker evaluation including caspase 3 activation in tumor; safety; and pharmacokinetics of LCL161. Statistical methods: pCR analysis will be performed according to treatment group and gene expression signature status. An absolute increase of at least 7.5% in pCR rate of the experimental arm over the control arm will be considered as evidence of clinically relevant efficacy. Target accrual: Approximately 200 patients will be randomized into this study. Recruitment is ongoing across America, Europe, and Asia. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-4-04.

Anthracycline-based cardiotoxicity is concerning for women with breast cancer and portends a dose-dependent risk of developing left ventricular dysfunction. Overall, the prevalence of heart failure (HF) is ≈2% of the total US population; however, BRCA-deficient mice have shown increased HF. We evaluated for the inherent risk of HF in women with BRCA mutations to determine whether treatment with anthracycline-based therapy increased this risk. We obtained results on BRCA mutation carriers regarding cancer treatment and HF, identified through the BRCA patient advocacy organization Facing Our Risk for Cancer Empowered (FORCE) and the Moffittbased Inherited Cancer Registry. In our patient group (232 BRCA1 and 159 BRCA2 patients; 10 with both mutations), 7.7% reported HF, with similar proportions in BRCA1 versus BRCA2 carriers (7.4% and 8.2%, respectively). These proportions are significantly higher than published rates (p < 0.001). There was no statistically significant difference in HF rates comparing anthracycline-treated versus anthracycline-naïve patients however (7.1% vs. 8.3%; p = 0.67). In addition, 9.1% of BRCA1 carriers and 8.2% of BRCA2 carriers reported arrhythmias. BRCA mutation carriers showed increased risk of cardiotoxicity versus the general population and an overall increased risk of cardiotoxicity from anthracycline-based therapy. Our study supports data that BRCA carriers have increased noncancer mortality from cardiotoxicity. A prospective trial to determine HF and conduction abnormalities in this population is warranted.

CONTEXT. Breast cancer survivors (BCS) face adverse physical and psychological symptoms, often co-occurring. Biologic and psychological factors may link symptoms within clusters, distinguishable by prevalence and/or severity. Few studies have examined the effects of behavioral interventions or treatment of symptom clusters. OBJECTIVES. The aim of this study was to identify symptom clusters among post-treatment BCS and determine symptom cluster improvement following the Mindfulness-Based Stress Reduction for Breast Cancer (MBSR(BC)) program. METHODS. Three hundred twenty-two Stage 0–III post-treatment BCS were randomly assigned to either a six-week MBSR(BC) program or usual care. Psychological (depression, anxiety, stress, and fear of recurrence), physical (fatigue, pain, sleep, and drowsiness), and cognitive symptoms and quality of life were assessed at baseline, six, and 12 weeks, along with demographic and clinical history data at baseline. A three-step analytic process included the error-accounting models offactor analysis and structural equation modeling. RESULTS. Four symptom clusters emerged at baseline: pain, psychological, fatigue, and cognitive. From baseline to six weeks, the model demonstrated evidence of MBSR(BC) effectiveness in both the psychological (anxiety, depression, perceived stress and QOL, emotional well-being) (P = 0.007) and fatigue (fatigue, sleep, and drowsiness) (P < 0.001) clusters. Results between six and 12 weeks showed sustained effects, but further improvement was not observed. CONCLUSION. Our results provide clinical effectiveness evidence that MBSR(BC) works to improve symptom clusters, particularly for psychological and fatigue symptom clusters, with the greatest improvement occurring during the six-week program with sustained effects for several weeks after MBSR(BC) training. TRIAL REGISTRATION. Name and URL of Registry: ClinicalTrials.gov. Registration number: NCT01177124.

Background: RO4929097 is a potent and oral selective inhibitor of γ-secretase (GSI), producing inhibitory activity of Notch 1–4 signaling in tumor cells. Preclinical studies have demonstrated synergism of GSIs in combination with endocrine therapy, in ERα-positive xenografts. This suggests that optimal treatment of ER+ BC would benefit from an antiestrogen and GSI combination. Materials and Methods: To explore the safety, tolerability and preliminary antitumor activity of Exemestane (25 mg/d) with R04929097 combination, we conducted a Phase Ib trial in patients with ER+/ HER2− MBC, whose disease relapsed during treatment with or within 6 months of discontinuation of an adjuvant nonsteroidal aromatase inhibitor or Tamoxifen, or whose MBC progressed during treatment with 1st or 2nd line endocrine therapy. Goserelin (3.6 mg q28 days Sub-Q) was given to all premenopausal patients. R04929097 was administered orally daily for 3 consecutive days, followed by 4 days off on a 21 day cycle. Doses of R04929097 were escalated on a standard 3+3 design over 5 doses (20, 30, 45, 90, and 140 mg). Patients were fully evaluated for dose limiting toxicity (DLT) for 3 weeks. Patients were treated until disease progression or occurrence of unacceptable toxicity. Results: A total of 15 patients were enrolled. Median age was 56; average number of chemotherapies received in the adjuvant or metastatic setting was 3.3. Eleven patients had received adjuvant endocrine therapy. One patient received this as 1st line endocrine therapy, eleven patients received this study as 2nd line endocrine therapy; and three patients received this study as 3rd line endocrine therapy in the metastatic setting. Of the 14 patients evaluable, 1 had a partial response, 6 had stable disease, and 7 had progressive disease. All patients have discontinued the study at this time, 11 due to progression, 2 due to toxicity, and 1 withdrew after beginning protocol therapy. Twenty percent of patients had stable disease for six months or greater. Of the patients with stable disease for six months, one patient progressed at 9 months and 2 patients progressed at 10 months. The most common toxicities were nausea (73.3%), anorexia (60%), hyperglycemia (53.3%), hypophosphatemia (46.7%), fatigue (66.7%), and cough (33.0%). Grade 3 toxicities were uncommon and included hypophosphatemia (13.0%) and rash (6.3%). There were no grade 4 toxicities. Rash was the only DLT and was seen at 140 mg. Conclusion: The combination of R04929097 and Exemestane was overall well tolerated, but MTD was not determined as access to drug ended. Further studies with GSIs in combination with endocrine therapy are warranted on the basis of a favorable safety profile and preliminary evidence of stable disease seen in patients with ER+ MBC refractory to previous endocrine therapies. PK, PD and biomarker analysis is ongoing. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-14-04.

Background: Entinostat is a novel, oral, class I-selective histone deacetylase inhibitor (HDACi) that has been shown pre-clinically to inhibit mechanisms of aromatase inhibitor (AI) resistance through epigenetically driven down-regulation of activated growth factor signaling pathways and normalization of estrogen receptor levels. This provided a strong rationale for the entinostat breast cancer (BC) program, which was designed to evaluate entinostat's ability to increase and/or restore sensitivity to treatment with an AI. Methods: Postmenopausal women with ER+ advanced BC who had ≤ 1 prior chemotherapy and had progressed on a non-steroidal AI were randomized 1:1 to exemestane 25 mg daily + entinostat 5 mg or placebo weekly. Progression free survival (PFS) was the primary endpoint; objective response rate and clinical benefit rate were secondary endpoints and overall survival (OS) was an exploratory endpoint. Prospectively defined subsets of interest included patients with “AI-sensitive and AI-resistant disease”. AI-sensitive was defined as having had a PR, CR or SD for ≥6 months (mos) in the metastatic setting or having completed and remained disease free for ≥12 months post adjuvant therapy. All others were considered AI-resistant. Treatment continued until disease progression or unacceptable toxicity. Response assessments were performed every 8 weeks. Results: 130 women were enrolled (64 exemestane+entinostat [E+E]; 66 exemestane+placebo [E+P]. All but 1 patient had Stage IV disease. 82% had measurable disease, of which 60% had visceral involvement. 42% had 1 prior line of hormonal therapy; 58% had >1. Analysis of the intent-to-treat (ITT) population showed significantly (defined prospectively as p Conclusions: Adding entinostat to exemestane resulted in improved PFS, the study's primary endpoint. At a median follow-up of 18 mos, the exploratory endpoint of OS was also increased in the E+E arm. Importantly for a phase II study, the PFS benefit in all subsets evaluated was consistent with the overall improvement seen in the ITT. These data demonstrate that the addition of entinostat to AI therapy may prolong the duration of AI therapy, thereby delaying the initiation of subsequent therapies such as chemotherapy, a goal for many breast cancer patients. A phase III study is planned. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD01-04.

Background An estimated 1 million cases of breast cancer are diagnosed annually worldwide. Of these, more than 170,000 are described as triple-negative. Triple-negative breast cancer (TNBC) is defined by the lack of protein expression of estrogen receptor (ER) and progesterone receptor (PR) and the absence of HER2 protein overexpression. TNBC is a subtype of breast cancer that overlaps with the “basal-like” breast cancer. TNBC has significant clinical implications. Methods The epidemiology, diagnosis, clinical course, prognosis, and pathology of this subtype of breast cancer are reviewed. The authors compare the “triple-negative” and “basal-like” definitions of breast cancer. A discussion of both standard and experimental treatments for TNBC is included. Results The poor prognosis of high-grade TNBC relates to poor disease-free interval in the adjuvant setting, shortened progression-free survival in the metastatic setting, and the lack of targeted therapy. However, not all TNBCs are associated with a poor prognosis. Conclusions Although chemotherapy is the main current treatment of this subtype of breast cancer, new agents such as PARP inhibitors, which show promise in the treatment of TNBC, are currently in clinical trials.