Metastatic Hormone Receptor Research Articles

Abstract P4-13-06: Real-world experience using exemestane and everolimus in patients with hormone receptor positive/HER2 negative breast cancer with and without prior CDK4/6 inhibitor exposure

Abstract Background: For patients with metastatic hormone receptor (HR)-positive, HER2-negative breast cancer who progress on a non-steroidal aromatase inhibitor (NSAI), exemestane plus everolimus (EE) has been shown to prolong progression-free survival in comparison to exemestane alone. In the current era, many patients are now receiving a CDK4/6 inhibitor with first-line NSAI therapy. There is limited data describing the utilization and effectiveness of treatments following hormonal therapy - CDK4/6 inhibitor combinations, including EE. The aim of this study was to describe the real-world clinical experience and outcomes associated with EE amongst patients with and without prior CDK4/6 inhibitor exposure treated in our provincial jurisdiction. Methods: All patients prescribed EE from January 1, 2016 through May 10, 2018 were obtained from the Alberta Health Services CancerControl Breast Data Mart (BDM). Patients with HER2+ disease, had received <1 cycle of EE or who had been on a placebo controlled trial of hormonal therapy +/- CDK4/6 inhibitor prior to EE were excluded. Review of the electronic medical record was undertaken to obtain detailed information on lines of treatment prior to EE, EE dosing and reason for EE discontinuation. The cohort was described and analyzed in total and by prior CDK4/6 inhibitor exposure. Time on treatment (TOT) was defined as start of EE to last dose or June 11, 2018 (censoring for data extraction) and was calculated using the Kaplan Meier method. The log rank test was used to compare TOT. Results: There were 110 patients extracted and 88 eligible for analysis (3 excluded for HER2+ disease, 14 for receipt of <1 cycle EE and 5 for participation on a placebo controlled trial of hormonal therapy +/- CDK4/6 inhibitor prior to EE. Median age 62.4 years (range 32.1-86.6 years). EE was administered first line in 12.5%, second line in 46.6% and third or greater line in 40.9%. Median time from start of first line therapy to start of EE was 19.3 months (range 0.3-72.1 months). Visceral metastases at start of EE in 62.5%. EE mean starting dose 7.3 mg (SD 2.5 mg) and mean last dose recorded 7.0 mg (SD 2.7 mg). At time of data extraction, 69 patients had stopped EE, 68.1% for progression and 31.9% for toxicity or other reason. Twenty patients had hormonal therapy + CDK4/6 inhibitor prior to EE. In the first line setting, 10 patients had letrozole and palbociclib. In the second line setting or greater, 5 patients had letrozole + palbociclib, 1 patient had tamoxifen + palbociclib and 4 patients had fulvestrant + palbociclib. Median time on hormonal therapy + CDK4/6 inhibitor was 12.0 months (range 4.0-20.9 months). Those with hormonal therapy + CDK4/6 inhibitor were more likely to have visceral metastases (p=0.02). Median time on treatment for the CDK4/6 exposed vs naïve groups was similar (5.8 vs 5.3 months, p=0.952). Median overall survival not yet reached. Conclusion: In a cohort of patients who have progressed on hormonal therapy + CDK4/6 inhibitor within 2 years, subsequent EE is a clinically meaningful treatment option in the setting of HR-positive/HER2-negative metastatic breast cancer. TOT was similar for CDK4/6 inhibitor exposed and naïve patients. Citation Format: Lupichuk SM, Recaldin B, Nixon NA, Mututino A, Joy AA. Real-world experience using exemestane and everolimus in patients with hormone receptor positive/HER2 negative breast cancer with and without prior CDK4/6 inhibitor exposure [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 P4-13-06.

Abstract P6-18-39: Abemaciclib after prior palbociclib exposure in patients with metastatic hormone-receptor positive (HR+)/HER2- breast cancer

Abstract Introduction: The advent of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) has transformed the clinical practice of HR+/HER2- metastatic breast cancer. Palbociclib, ribociclib, and abemaciclib have been approved in conjunction with anti-estrogens, while abemaciclib has also been approved as monotherapy based on single agent activity in the MONARCH-1 trial (objective response rate/ORR: 19.7% and median progression-free-survival/PFS = 6.0 months; Dickler M et al CCR 2017). However, there is limited insight into the mechanisms governing resistance to CDK 4/6i and the potential utility of continued CDK4/6i after progression on a prior CDK 4/6i-based therapy. Methods: We evaluated the clinical outcomes of patients with metastatic HR+/HER2- breast cancer who had received abemaciclib following an initial course of palbociclib-based therapy at our institution. In addition, we conducted genomic analysis utilizing next-generation sequencing of tissue samples and blood (cell-free DNA/cfDNA analysis) where available. Results: From June, 2014 through July, 2018, a total of 49 patients received abemaciclib, and 14 patients had prior palbociclib exposure. One patient was deceased shortly after initiating abemaciclib and one patient was lost to follow-up. Among the 12 remaining patients, eight had sequential courses of CDK4/6-based therapy, while four patients had at least one intervening non-CDK 4/6i based regimen. At data-cutoff of 8/15/2018, five patients (41.7%) had early progression on abemaciclib (PFS equal to or less than 120 days) while three (25%) patients had ongoing benefit (PFS greater than 120 days, two of three actively on therapy). Three additional patients had recently initiated abemaciclib therapy (less than 120 days prior to current analysis). Preliminary analysis of baseline cfDNA results in patients with early progression on abemaciclib therapy after prior CDK4/6i revealed the presence of RB1 mutation, FGFR1 amplification, and TP53 mutation, among others. Additional analyses with mature clinical data (including updated PFS and ORR), toxicity assessment during secondary CDK4/6i exposure, and further analysis of genomic sequencing results will be provided at the meeting. Conclusions: The majority of patients had early disease progression on abemaciclib after prior exposure to CDK4/6i suggesting potential cross-resistance to CDK4/6i mediated by common drivers. However, a subset of patients derived clinical benefit with continued exposure to CDK4/6i, highlighting the need for additional research to evaluate potential predictive biomarkers and guide rational utilization of continued CDK4/6 blockade in metastatic HR+/HER2- breast cancer. Citation Format: Wander SA, Spring LM, Stein CR, Yuen M, Zangardi M, O'Shaughnessy J, Bardia A. Abemaciclib after prior palbociclib exposure in patients with metastatic hormone-receptor positive (HR+)/HER2- 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 P6-18-39.

Abstract 3596: Biomarkers of response to CDK4/6 inhibitor (CDK4/6i) in hormone receptor (HR) positive and HER2-positive breast cancer (BC) patient-derived xenografts (PDX)

Abstract The cell cycle G1-restriction point is frequently deregulated in HR+ BC by alterations of cyclin D1 (CCND1), p16 (CDKN2A) or pRb (RB1). CDK4/6i (ribociclib, abemaciclib and palbociclib) have shown clinical activity in metastatic HR+ BC, both as single agents and in combination with endocrine therapy. Currently, no biomarkers of response to CDK4/6i have been identified beyond HR expression and little is known about mechanisms of acquired resistance. Twenty-one PDXs were established from HR+, HER2+ or HR+/HER2+ BC patient biopsies and their response to ribociclib was evaluated in vivo and ex vivo in matrigel cultures. Acquired-resistance was generated in vivo by isolating tumors that escaped therapy overtime. In order to identify response biomarkers, genetic and proteomic analysis of PDXs were performed and correlated with ribociclib antitumor activity. Candidates were validated in a cohort of 8 tumor samples from patients treated with abemaciclib monotherapy and in vitro. Combination with the PI3K-alpha inhibitor (PI3Ki) BYL719 was explored in vivo. In vivo, ribociclib exhibited antitumor activity in five out of 21 PDXs (24%), two of which acquired resistance after continuous dosage (75mg/kg, 6IW). Ex vivo matrigel cultures recapitulated the in vivo response with 75% sensitivity and 92% specificity (p=0.01), providing a novel approach for high throughput screening. Baseline levels of ER, PR and Ki67 protein or PIK3CA/ESR1 mutations did not discriminate between ribociclib-resistant/sensitive PDXs, whereas CCND1/D2-amplification/overexpression were only found in ribociclib-resistant models. Importantly, sensitive PDXs exhibited significant Ki67 reduction upon ribociclib treatment, higher baseline pRb- and lower p16-staining compared to ribociclib-resistant PDXs (p=0.004, 0.02 and 0.03, respectively). Three out of 8 acquired-resistant tumors (37.5%) exhibited pRb loss. In vitro, RB1 knockdown and cyclin D1/D2-overexpression resulted in higher BrdU incorporation and higher IC50 than control cells upon ribociclib treatment. p16 expression was significantly lower in samples of patients exhibiting clinical benefit with abemaciclib monotherapy (p=0.04). Remarkably, combination of ribociclib with a PI3Ki resulted in appreciable antitumor activity in 18 out of 20 PDXs (90%), including two models resistant to fulvestrant given in combination with ribociclib. In conclusion, HR+, HER2+ and HR+/HER2+ BC PDXs expressing both high Rb- and low p16-protein levels are sensitive to CDK4/6i whereas deregulation of the G1-restriction point due to low pRb or high cyclin D1/D2 protein levels is associated with resistance to ribociclib monotherapy. Addition of a PI3Ki markedly improves the antitumor response of ribociclib in most of PDXs, suggesting that the PI3K pathway may play a pivotal role in limiting the efficacy of CDK4/6 inhibition. Citation Format: Marta Palafox, María Teresa Herrera-Abreu, Meritxell Bellet, Mafalda Oliveira, Alejandra Bruna, Olga Rodriguez, Marta Guzmán, Judit Grueso, Cristina Vilaplana, Joaquín Arribas, Emmanuelle di Tomaso, Faye Su, Carlos Caldas, Nicholas C. Turner, Rodrigo Dienstmann, José Baselga, Maurizio Scaltriti, Javier Cortés, Cristina Saura, Violeta Serra. Biomarkers of response to CDK4/6 inhibitor (CDK4/6i) in hormone receptor (HR) positive and HER2-positive breast cancer (BC) patient-derived xenografts (PDX) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3596.

Targeting the cancer mutanome of breast cancer.

A metastatic hormone receptor–positive breast cancer, usually resistant to immunotherapy, is successfully treated with tumor-infiltrating lymphocytes enriched for neoantigen reactivity, underscoring the broad potential of this immunotherapeutic approach.

Alteration in red cell indices during palbociclib therapy.

e13031Background: Palbociclib is a CDK 4/6 inhibitor approved for treatment of metastatic hormone receptor positive breast cancer with hormone therapy. We noticed variations in red cell indices in ...

Molecular alterations in the Ras-Raf-Erk (MAPK) pathway in metastatic hormone receptor positive (HR+)/HER2- breast cancer: Incidence and impact on clinical outcomes.

1021Background: While molecular alterations in PI3K pathway, including PIK3CA mutations, are common in HR+ breast cancer, molecular alterations in MAPK pathway, including KRAS and BRAF mutations, a...

Impact of body mass index on the efficacy of endocrine therapy in patients with metastatic breast cancer - A retrospective two-center cohort study

BakgroundThe aim of this study was to investigate the impact of body mass index (BMI) on the efficacy of endocrine therapy in postmenopausal women with metastatic hormone receptor breast cancer (HR+BC) as well as to identify if the potential difference in efficacy was associated with Fulvestrant only or both aromatase inhibitors (AIs) and Fulvestrant. MethodsA consecutive cohort of postmenopausal women with HR+metastatic breast cancer that have received endocrine therapy including Fulvestrant as a metastatic treatment strategy at the Departments of Oncology in Eskilstuna and Uppsala, Sweden, between 2008 and 2016 were identified. The primary outcome of the study was time to disease progression (TTP) during the treatment with Fulvestrant in overweight and obese women compared to patient with normal BMI. ResultsIn total, 173 patients were enrolled in the study cohort, amongst these, 141 patients received both Fulvestrant and AIs and 32 received only Fulvestrant. No statistical significant association was observed between the three BMI categories and TTP, during Fulvestrant treatment (p = 0.136). The rates of objective response and clinical benefit due to Fulvestrant were similar among patients with normal weight, overweight and obesity, respectively. ConclusionsNo difference in treatment efficacy was seen between normal, overweight and obese women with metastatic HR+BC, when treated with Fulvestrant. Until further research with prospective studies is available, there is no evidence to support any modification in how Fulvestrant treatment is used in patients with metastatic breast cancer in regard to BMI.

Abstract PD4-14: GDC-0077 is a selective PI3Kalpha inhibitor that demonstrates robust efficacy in PIK3CA mutant breast cancer models as a single agent and in combination with standard of care therapies

Abstract The phosphatidylinositol 3 kinase (PI3K)/AKT/ mechanistic target of rapamycin (mTOR) signaling pathway is a major regulator of tumor cell growth, proliferation and survival. Dysregulation of the PI3K/AKT/mTOR signaling pathway through multiple different mechanisms has been described in solid tumor malignancies, including activating and transforming mutations and amplification of PIK3CA, that encodes the p110alpha subunit of PI3K. Indeed, PIK3CA hotspot mutations are highly prevalent in breast cancer, occurring in approximately 40% of HR+ tumors. The clinical candidate GDC-0077 is a potent inhibitor of PI3Kalpha (IC50 = 0.038 nM) and exerts its activity by binding to the ATP binding site of PI3K, thereby inhibiting the phosphorylation of PIP2 to PIP3. Biochemically, GDC-0077 is >300-fold more selective for PI3Kalpha over the other class I PI3K isoforms (beta, delta, and gamma) and >2000-fold more selective over PIK family members. Furthermore, GDC-0077 is more selective for mutant versus wild-type PI3Kalpha in cell based assays. The improved biochemical selectivity of GDC-0077 relative to PI3Kdelta translated in human CD69+ B-cells, which are primarily dependent on PI3Kdelta for proliferation and survival, and were more sensitive (based on reduction of cell number) to the PI3Kalpha/delta selective inhibitor taselisib (GDC-0032) than to GDC-0077. Mechanism of action (MOA) studies indicate that GDC-0077 selectively degrades mutant PI3Kalpha in a proteasome-dependent fashion resulting in reduction of PI3K pathway activity biomarkers such as pAKT and pPRAS40, inhibition of cell proliferation, and increased apoptosis in human PIK3CA-mutant breast cancer cell lines to a greater extent when compared to PIK3CA wild-type cells. In vivo, oral daily treatment of patient-derived PIK3CA-mutant breast cancer xenograft models with GDC-0077 resulted in tumor regressions, induction of apoptosis, and a reduction of pAKT, pPRAS40, and pS6RP in a dose-dependent fashion. In vivo efficacy in a PIK3CA-mutant human breast cancer xenograft model was also improved when GDC-0077 was combined with therapies for hormone-receptor positive (HR+) breast cancer such as anti-estrogens (fulvestrant) or a CDK4/6 inhibitor (palbociclib). Collectively, preclinical studies provide rationale for evaluating GDC-0077, a PI3Kalpha selective inhibitor that degrades mutant p110alpha protein, as a single agent and in combination with endocrine and targeted therapies that may provide additional benefit to patients with locally advanced or metastatic hormone receptor+ breast cancers that harbor PIK3CA mutations. Citation Format: Hong R, Edgar K, Song K, Steven S, Young A, Hamilton P, Arrazate A, De La Cruz C, Chan C, Pang J, Salphati L, Belvin M, Nannini M, Staben S, Friedman L, Sampath D. GDC-0077 is a selective PI3Kalpha inhibitor that demonstrates robust efficacy in PIK3CA mutant breast cancer models as a single agent and in combination with standard of care therapies [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 PD4-14.

Abstract OT1-02-02: A phase II study of pembrolizumab in combination with palliative radiotherapy for metastatic hormone receptor positive breast cancer

Abstract BACKGROUND: Despite recent advances in the treatment of patients with metastatic hormone receptor positive (HR+)/HER2- breast cancer (BC), it remains an incurable disease. The activity of immune checkpoint inhibitors (ICI) as monotherapy in patients with metastatic HR+/HER2- BC has been limited. Therefore, the addition of other strategies that elicit an immunogenic tumor microenvironment may be needed. We hypothesize that radiation therapy (RT) will potentiate the efficacy of the PD-1 inhibitor pembrolizumab in patients with metastatic HR+/HER2- BC. METHODS: Trial Design: This is a phase II single arm study assessing objective response rate (ORR) according to RECIST 1.1 in patients with metastatic HR+/HER2- BC who will receive pembrolizumab in combination with palliative RT. Pembrolizumab 200 mg intravenously will be administered 2-7 days before day 1 of RT, and will be given every 21 days until disease progression. Biopsies will be performed in the same lesion at baseline (mandatory if tumor tissue is accessible outside the field of RT) and during cycle 2 within 7-14 days before the day 1 of cycle 3 of pembrolizumab. Key Eligibility Criteria: Patients with metastatic HR+/HER2- BC, with measurable disease outside the field of radiation, for whom palliative RT to at least one bone, lymph node, or soft tissue lesion is indicated. Radiation of visceral lesions (such as lung or hepatic lesions) is not permitted. Although prior RT is allowed, patients must be at least 3 months free from RT; Re-irradiation of the same field is not allowed. There is no limit to the number of previous treatments, and systemic treatment naive patients for metastatic disease are also eligible. Specific Aims: The primary aim is to evaluate the efficacy of the combination, as defined by objective response rate (ORR) outside the field of RT according to RECIST 1.1. Secondary objectives include to determine the ORR according to immune-related criteria, the progression-free survival, the abscopal response rate, the clinical benefit rate, the safety and the tolerability of the combination. In addition, correlative studies will be performed to explore the correlation of immunosuppressive and/or immune-stimulating immune marker profiles at baseline and after cycle 2 to disease response to therapy. Statistical Methods: Using the Simons “optimal” method, in the first stage, 8 patients will be enrolled. If there is at least 1 response, accrual will continue to the second stage where up to 19 additional patients will be enrolled. If at least 3 of these 27 patients have an objective response (≥10%), the regimen will be considered worthy of further study. With this design, the probability of stopping the trial early is 78% if the true response rate is 3%. If the true response rate is 20% the chance that the regimen is declared worthy of further study is 80%. Patient accrual and target accrual: The trial opened in April/2017, and so far, has accrued 2 patients with a target accrual of 27 patients. Accrual should be complete in 14-25 months. Clinical trial information: NCT03051672. Citation Format: Barroso-Sousa R, Gao H, Barry WT, Krop IE, Schoenfeld JD, Tolaney SM. A phase II study of pembrolizumab in combination with palliative radiotherapy for metastatic hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-02-02.

Abstract OT3-05-09: A randomized phase II trial of fulvestrant with or without ribociclib after progression on aromatase inhibition plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or metastatic hormone receptor positive, HER2 negative breast cancer (Maintain trial)

Abstract Background Cyclin dependent kinase 4/6 inhibitors (CDK4/6i), including palbociclib and ribociclib (R), have demonstrated remarkable benefit in progression free survival (PFS) in patients (pts) with hormone receptor positive (HR+), HER2- metastatic breast cancer (MBC) when combined with anti-estrogen therapy. Switching between anti-estrogen therapies at disease progression is standard of care in the treatment of HR+ MBC. We evaluate the strategy of switching anti-estrogen therapy to fulvestrant (F) and maintaining CDK4/6 inhibition with R in pts with HR+, HER2- MBC who have progressed on an aromatase inhibitor (AI) + CDK4/6i. Trial Design Phase II, multi-center, randomized, double-blind, placebo-controlled trial to evaluate F +/- R in pts with HR+, HER2- MBC who have previously progressed on any AI + CDK4/6i. Pts can be screened and registered at two different time points: Scenario 1: Before receiving any CDK4/6i Scenario 2: At the time of progression of disease (POD) while being treated with an AI + CDK4/6i In scenario 1, the study will provide pts with letrozole + R, but pts will not be randomized until they demonstrate POD. At randomization, pts will be assigned 1:1 to either a) F + R or b) F + placebo, with treatment given in 4-week cycles. F will be given as a 500 mg dose intramuscularly every 2 weeks for 3 times and then every 4 weeks, as per standard of care. R or placebo will be given orally at 600 mg daily, 3 weeks on/1 week off. CT scans and bone scan are to be performed prior to every third cycle. Serum and whole blood samples and optional tissue biopsies for biomarker assessment will be performed prior to study treatment (scenario 1), prior to randomization to R +/- F, and when the patient goes off study. Main Eligibility Criteria 1. Age ≥ 18 years with unresectable or metastatic BC 2. Estrogen and/or progesterone receptor positive, HER2 negative, as per ASCO-CAP 3. Postmenopausal status or receiving ovarian suppression 4. Measurable or unmeasurable disease; stable CNS disease allowed Specific Aims Primary: Progression free survival (PFS), defined as the time from randomization to POD or death. Secondary: Objective response rate (ORR), clinical benefit rate (CBR = ORR + stable disease rate), overall survival (OS), and duration of response. Pts in scenario 1 will also be assessed for PFS, OS, CBR, and safety while receiving AI + R (pre-randomization). Biomarker assessment will include amplification of cyclin D1 and cyclin E, phosphoRb and TK1 expression, Rb1 and p16 loss, and ctDNA for ESR1 and PIK3CA mutations. Target Accrual 132 pts accrued from 11 academic medical centers in the U.S, with a goal of completing accrual in two years (˜60 to 72 pts in each scenario). Statistical Methods Assuming a median PFS of 3.8 months with F alone, we predict that F + R will lead to a median PFS of at least 6.5 months. A one-sided log-rank test with a sample size of N=120 and alpha=0.025, achieves 80% power to detect a difference in PFS of 2.7 months. N=132 pts allows for a 10% drop-out rate. Contact Kevin Kalinsky, MD, MS 212-305-1945 kk2693@cumc.columbia.edu. Citation Format: Kalinsky K, Mundi PS, Chiuzan C, Accordino MK, Trivedi MS, Sparano JA, Oh SY, Tiersten A, O'Regan R, Esteva FJ, Jain S, Mayer IA, Forero A, Vaklavas C, Baer L, Crew K, Hershman DL. A randomized phase II trial of fulvestrant with or without ribociclib after progression on aromatase inhibition plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or metastatic hormone receptor positive, HER2 negative breast cancer (Maintain trial) [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 OT3-05-09.

Abstract PD8-07: Identifying steroid hormone receptor gene mutations in patients with newly diagnosed estrogen receptor positive metastatic breast cancer

Abstract Background: Resistance to endocrine therapy remains a challenge for patients with metastatic hormone receptor positive breast cancer. Mutations in the gene encoding estrogen receptor alpha (ESR1) have been identified in patients with endocrine resistance and correlates with reduced survival. The occurrence of mutations in the gene for progesterone receptor (PGR), another important biomarker in breast cancer, has not been reported. Objective: Determine the frequency of mutations in ESR1 and PGR in patients with newly diagnosed metastatic ER+ breast cancer treated with adjuvant endocrine therapy at our institution, and identify whether these mutations are associated with worse patient survival. Methods: This is an IRB-approved, HIPAA-compliant retrospective study of patients with ER+ metastatic breast cancer identified from our comprehensive cancer center registry. Eligible patients must have received at least 6 months of adjuvant endocrine therapy with biopsy-proven diagnosis of metastatic or locally recurrent disease. Next-generation sequencing of the coding regions of ESR1 and PGR was performed on extracted tumor genomic DNA. Analysis was limited to protein coding mutations. Clinicopathologic data was collected and correlated with the genomic information for each patient. Associations between mutation status and clinicopathologic factors were analyzed using Fisher's exact test. Kaplan-Meier method with log-rank test was used to analyze overall survival (OS) from time of metastatic diagnosis. Results: The study included 35 women (35-88 yr old). Metastatic sites included bone (N=13), brain (N=6), chest wall (N=2), liver (N=4), lung/pleura (N=4), and lymph nodes (N=6). PGR mutations were identified in 66% of patients (23/35; 95%CI 48-81%), and were more common than ESR1 mutations (10/35; 29%; 95%CI 15-46%). Mutations in both PGR and ESR1 were identified in 26% (9/35), and neither mutation was identified in 31% (11/35). Neither mutation was associated with prior adjuvant aromatase inhibitor or tamoxifen therapy. There was no significant association between ESR1 or PGR mutations and metastatic site, although 75% (3/4) of patients with liver metastases had an ESR1 mutation compared to 23% (7/31) without liver metastases (p=0.061). The differences in median OS between ESR1 wildtype vs mutant (1.6 mo vs 1.0 mo, p=0.14) and PGR wildtype vs mutant (2.6 mo vs 1.3 mo, p=0.56) were not significant. However, patients with both mutations may have worse median OS compared patients with neither or only one mutation (1.0 mo vs 1.6 mo vs 4.0 mo, p = 0.073). Conclusions: The overall survival of metastatic ER+ breast cancer patients with ESR1 or PGR mutations were not statistically significant compared with those without mutations. Despite the small sample size, there is a trend that patients with mutations in both genes may have worse survival. To the best of our knowledge, the PGR mutation rate in metastatic breast cancer has not previously been reported. Interestingly in our data set, PGR mutations were identified more commonly than mutations in ESR1. The significance of PGR mutations is not known, nor whether this could be a future indicator of treatment resistance or a target for therapy. Citation Format: Fowler AM, Rassman S, DeGrave M, Ong I, Powers GL, Salem K, Kumar M, Woo K, Mahajan AM. Identifying steroid hormone receptor gene mutations in patients with newly diagnosed estrogen receptor positive metastatic 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 PD8-07.

Abstract OT3-05-10: A single arm phase II study of palbociclib in combination with tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer

Abstract Background: Hormone receptor positive breast cancer is the most commonly diagnosed subset of breast cancer (60-65%). Endocrine therapy is effective for this subset of breast cancer, in both the adjuvant and metastatic settings. Despite advances in endocrine therapy, many patients relapse during or after completing adjuvant therapy and metastatic breast cancer remains incurable. Palbociclib is a reversible, oral, small molecule inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6). CDK4 and CDK6 together with cyclin D have important roles in regulation of the G1/S transition via regulation of the phosphorylation state of retinoblastomaprotein (Rb). Palbociclib showed significantly improved progression-free survival taken together with endocrine agents in treatment of metastatic breast cancer. Preclinical data showed that in combination with tamoxifen, palbociclib had synergistic growth inhibitory activity as well as efficacy in a model of acquired tamoxifen resistance. Combining palbociclib with tamoxifen in first line treatment of metastatic hormone receptor positive breast cancer may offers an appealing alternative to other endocrine combinations. Methods: This is a non-randomized, open-label, single-arm, multicenter, phase II study of palbociclib in combination with tamoxifen in patients with hormone receptor positive/HER2 negative advanced breast cancer. The primary objective is to determine the objective response rate (complete or partial response) based on RECIST 1.1 or MDA Criteria (for patients with bone only disease). Secondary objectives are: safety and tolerability, progression-free survival, clinical benefit rate, 2-year overall survival. Correlative objectives will explore alterations in circulating tumor DNA and changes in gene expression pattern at the time of progression. Eligibility criteria: women or men with diagnosis of hormone receptor positive/ HER2 negative locally advanced or metastatic breast cancer, not amenable to curative surgery; no prior systemic anti-cancer therapy for advanced hormone receptor positive breast cancer; adequate organ function; pre and post menopausal women are allowed. Drug administration: palbociclib dose will be 125 mg orally once daily on days 1-21 of each 28-day cycle; tamoxifen dose will be 20 mg orally once daily for every day of the 28-day cycle. As of June 2017, the study enrolled 10/71 patients and it is still open to enrollment. NCT 02668666; ocdanciu@uic.edu Citation Format: Danciu OC, Hoskins K, Tamkus D, Truica C, Blaes A, Green L, Liu L, Toppmeyer D, Wisinski K. A single arm phase II study of palbociclib in combination with tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-05-10.

Receptor Conversion in Distant Breast Cancer Metastases: A Systematic Review and Meta-analysis.

In metastatic breast cancer, hormone and/or human epidermal growth factor receptor 2 (HER2)-targeted therapy decision-making is still largely based on tissue characteristics of the primary tumor. However, a change of estrogen receptor alpha (ERα), progesterone receptor (PR), and HER2 status in distant metastases has frequently been reported. The actual incidence of this phenomenon has been debated. We performed a meta-analysis including 39 studies assessing receptor conversion from primary breast tumors to paired distant breast cancer metastases. We noted the direction of change (positive to negative or vice versa) and performed subgroup analyses for different thresholds for positivity, the type of test used to assess HER2 receptor status, and metastasis location-specific differences (two-sided tests). Overall, the incidence of receptor conversion varied largely between studies. For ERα, PR, and HER2, we found that random effects pooled positive to negative conversion percentages of 22.5% (95% confidence interval [CI] = 16.4% to 30.0%), 49.4% (95% CI = 40.5% to 58.2%), and 21.3% (95% CI = 14.3% to 30.5%), respectively. Negative to positive conversion percentages were 21.5% (95% CI = 18.1% to 25.5%), 15.9% (95% CI = 11.3% to 22.0%), and 9.5% (95% CI = 7.4% to 12.1%). Furthermore, ERα discordance was statistically significantly higher in the central nervous system and bone compared with liver metastases (20.8%, 95% CI = 15.0% to 28.0%, and 29.3%, 95% CI = 13.0% to 53.5%, vs 14.3%, 95% CI = 11.3% to 18.1, P = .008 and P < .001, respectively), and PR discordance was higher in bone (42.7%, 95% CI = 35.1% to 50.6%, P < .001) and liver metastases (47.0%, 95% CI = 41.0% to 53.0%, P < .001) compared with central nervous system metastases (23.3%, 95% CI = 16.0% to 32.6%). Receptor conversion for ERα, PR, and HER2 occurs frequently in the course of disease progression in breast cancer. Large prospective studies assessing the impact of receptor conversion on treatment efficacy and survival are needed. Meanwhile, reassessing receptor status in metastases is strongly encouraged.

Metastatic Hormone and Her-2 Positive Breast Cancer: A Community Approach

Metastatic hormone-receptor and HER-2 positive (triple-positive) breast cancer provides a treatment dilemma for oncologic clinicians. The current National Comprehensive Cancer Network (NCCN) Guidelines offer a variety of options in the first and second line for metastatic breast cancer. However, a more tailored treatment approach may be needed for the triple-positive metastatic breast cancer population. The aim of this study is to trend the therapeutic treatment selections for patients with metastatic, triple-positive breast cancer at a single, academic-affiliated community practice in the United States. The patient population included individuals with triple-positive, metastatic breast cancer who were treated over the span of six years at this institution. Ultimately, this patient population demonstrated variability across the various treating oncologists choice of therapy in the first, second and fourth line of treatment. The majority of patients (twelve out of fifteen) received combination therapy with trastuzumab in the first line of therapy. In the second line, seven out of eight patients received trastuzumab as part of their treatment regimen. In the third line, all three patients received trastuzumab emtansine as part of their therapy regimen. For patients who were able to survive until the fourth line and beyond, several other treatment options were utilized. Therefore, although metastatic, triple-positive breast cancer represents a subset of patients with vast treatment variability throughout the various lines of therapy, and there is a general lack of consensus on how to best treat this patient population. This study provides an opportunity for more expansive research in the field in order to help elucidate a treatment algorithm for all oncologic practitioners for patients with triple positive, metastatic breast cancer.

Real world experience with exemestane and everolimus for advanced HR-positive breast cancer.

e12538 Background: BOLERO-2 demonstrated a significant progression free survival (PFS) advantage for EvEx compared to Ex alone in the treatment of metastatic hormone receptor positive breast cancer (HP-MBC) following failure with aromatase inhibitor (AI) in menopausal patients. Benefits and harms reported in clinical trials do not always mirror real life, thus we examined the frequency of dose modifications for toxicity and PFS in a real-world population. Methods: Women with HP-MBC started on EvEx between Dec. 2, 2013 and Nov. 1, 2015 in any one of five cancer centres in British Columbia, Canada were identified via the provincial pharmacy database. Clinical and prior treatment details, adverse events, and outcomes were compared to those of the BOLERO-2 study participants. Results: We identified151 patients treated with EvEx: median age was 53 (range 25 – 85), and 60 (40%) were ≤49. ECOG performance status was 0-1 in 122 (81%) and 2-3 in 29 (19%). 135 (89%) received prior treatment for MBC, which included non-steroidal AI in 117 (87%) and chemotherapy in 74 (55%). 94 (62%) received EvEx as 3rd line treatment and beyond. Median follow-up was 714 days (range 10 – 1127); 66 (44%) were alive at time of analysis. Dose reductions, interruptions and discontinuations of everolimus due to toxicity occurred in 32%, 31%, and 30%, respectively, higher than reported in BOLERO-2. Median PFS was 6.1 months (95% CI: 4.9 – 7.7) in our cohort, similar to that of the investigator assessed EvEx arm of BOLERO-2. Majority, 52%, of dose reductions/interruptions occurred within the first month of treatment initiation. Conclusions: We observed similar PFS forEvEx in a real world population compared with BOLERO-2. Dose interruptions and reductions were frequent, but may have enabled patients to tolerate therapy for longer. Discontinuation rates for toxicity were high and may limit the efficacy of the combination in the real world. Recent findings of primary prophylaxis against mucositis may help enhance continuation and dose maintenance (Beck et al. JCO 2016). Alternately, starting at a lower dose of Ev and increasing to tolerance may be worth exploring, as despite higher rates of dose modifications, our PFS rate was similar to that in BOLERO-2.

FGFR gene amplification and response to endocrine therapy in metastatic hormone receptor positive (HR+) breast cancer.

1013 Background: Amplification in Fibroblast Growth Factor Receptor (FGFR) genes occurs in 10% of breast cancers, is associated with poor prognosis, and appears to drive resistance to endocrine therapies in vitro. However, the role of FGFR in modulating the clinical response to endocrine therapies is unclear, and could have important implications given that FGFR is a potential therapeutic target. This study aims to evaluate the association between FGFR amplification and clinical response to endocrine therapy in HR+ metastatic breast cancer (MBC). Methods: Primary or metastatic tumor specimens from patients with HR+/HER2 negative MBC underwent dual-color fluorescence in situ hybridization (FISH) of the FGFR1 locus on chromosome 8p. FISH ratios of ≥2 were considered positive for gene amplification (FGFR+). Time to progression (TTP) on first line endocrine therapy was evaluated in FGFR+ versus wild type (WT) patients using actuarial analysis. Results: Between 2012 and 2016, we identified 95 patients with HR+ MBC who underwent FGFR FISH testing. Of these, 24 (25.3%) were FGFR+. FGFR+ and WT patients did not differ in being postmenopausal at initial breast cancer diagnosis (28.6% vs. 31.7%; p = 1.0), having de-novo MBC (16.7% vs. 21.1%; p = 0.773), having received adjuvant chemotherapy (75% vs. 76.8%; p = 1.0) or having received adjuvant endocrine therapy (90% vs. 91.1%; p = 1.0). However, FGFR+ patients tended to be younger than WT patients (54.3 vs. 59.3 years; p = 0.045), and more likely to have PR-negative MBC (50.0% vs. 19.1%; p = 0.011). While there was no difference in TTP on first-line chemotherapy in FGFR+ vs. WT patients (5.0 vs. 6.2 months; p = 0.8), FGFR+ patients had a shorter median TTP on first-line endocrine therapy than WT (8.5 vs. 10.8 months; p = 0.047). These results were similar when stratified by presence of de-novo metastatic disease. Conclusions: In patients with HR+ MBC, FGFR gene amplification is associated with shorter time to progression on first line endocrine therapy. Further studies are needed to confirm these findings, and to investigate potential strategies for endocrine therapy and FGFR-directed combinatorial therapy in FGFR+ breast cancer.

A randomized phase II trial of fulvestrant with or without ribociclib after progression on aromatase inhibition plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or metastatic hormone receptor positive, HER2 negative breast cancer.

TPS1112 Background: CDK4/6i, including palbociclib and ribociclib (R), have demonstrated remarkable benefit in progression free survival (PFS) in patients (pts) with HR+, HER2- MBC with anti-estrogen therapy. Switching between anti-estrogen therapies at disease progression is standard of care in the treatment of HR+ MBC. We evaluate the strategy of switching anti-estrogen therapy to fulvestrant (F) and maintaining CDK4/6 inhibition with R in pts with HR+, HER2- MBC who have progressed on an AI + CDK4/6i. Methods: Trial Design Phase II, multi-center, randomized, double-blind, placebo-controlled trial to evaluate F +/- R in pts with HR+, HER2- MBC who have previously progressed on any AI + CDK4/6i: Screened at 2 different scenarios: Scenario 1: Before receiving any CDK4/6i Scenario 2: Time of progression of disease (POD) while being treated with an AI + CDK4/6i Intervention At randomization, pts assigned 1:1 to either a) F + R or b) F + placebo, with treatment given in 4-week cycles. Major Eligibility Criteria 1, Metastatic BC, 2. HR+ HER2-, 3. Measurable or unmeasurable disease Specific Aims Primary: PFS. Secondary: Objective response rate, clinical benefit rate, overall survival, and duration of response. Biomarker assessment: amplification of cyclin D1 and cyclin E, phosphoRb and TK1 expression, Rb1 and p16 loss, and ctDNA for ESR1 and PIK3CA mutations. Statistical Methods Assuming a median PFS of 3.8 months with F alone, we predict that F + R will lead to a median PFS of at least 6.5 months. A one-sided log-rank test with a sample size of N = 120 and alpha = 0.025, achieves 80% power to detect a difference in PFS of 2.7. With a 10% dropout, n = 132. Clinical trial registry number NCT02632045.

New Strategies in Metastatic Hormone Receptor-Positive Breast Cancer: Searching for Biomarkers to Tailor Endocrine and Other Targeted Therapies.

Although major advances in our understanding of the molecular underpinnings of hormone receptor-positive (HR+) breast cancer have led to new therapies that have substantially improved patient outcomes, endocrine-resistant disease still remains a leading cause of breast cancer mortality. Comprehensive molecular profiling of breast cancers has highlighted tremendous tumor heterogeneity, and analysis of paired primary and metastatic tumors has shown the evolution that can occur during acquired resistance to systemic therapies. Novel techniques for monitoring tumor load under treatment pressure, including "liquid biopsy" techniques, such as circulating free tumor DNA (cfDNA) and circulating tumor cells, have shown promise as biomarkers to direct treatment without invasive tumor biopsies. However, more research is needed to deepen our understanding of breast cancer alterations under treatment pressure to reveal mechanisms of drug resistance and apply precision medicine in biomarker-driven clinical trials. Clin Cancer Res; 23(5); 1126-31. ©2016 AACR.

Abstract OT2-01-19: A randomized phase II trial of fulvestrant with or without ribociclib after progression on aromatase inhibition plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or metastatic hormone receptor positive, HER2 negative breast cancer

Abstract Background Cyclin dependent kinase 4 and 6 inhibitors (CDK4/6i), including palbociclib and ribociclib (R), have demonstrated remarkable benefit in progression free survival (PFS) in patients (pts) with hormone receptor positive (HR+), HER2- metastatic breast cancer (MBC) when combined with anti-estrogen therapy. Switching between anti-estrogen therapies at disease progression is standard of care in the treatment of HR+ MBC. We evaluate the strategy of switching anti-estrogen therapy to fulvestrant (F) and maintaining CDK4/6 inhibition with R in pts with HR+, HER2- MBC who have progressed on an aromatase inhibitor (AI) + CDK4/6i. Trial Design Phase II, multi-center, randomized, double-blind, placebo-controlled trial to evaluate F +/- R in pts with HR+, HER2- MBC who have previously progressed on any AI + CDK4/6i. Pts can be screened and registered at two different time points: Scenario 1: Before receiving any CDK4/6i Scenario 2: At the time of progression of disease (POD) while being treated with an AI + CDK4/6i In scenario 1, the study will provide pts with letrozole + R, but pts will not be randomized until they demonstrate POD. At randomization, pts will be assigned 1:1 to either a) F + R or b) F + placebo, with treatment given in 4-week cycles. F will be given as a 500 mg dose intramuscularly every 2 weeks for 3 times and then every 4 weeks, as per standard of care. R or placebo will be given orally at 600 mg daily, 3 weeks on/1 week off. CT scans and bone scan are to be performed prior to every third cycle. Serum and whole blood samples and optional tissue biopsies for biomarker assessment will be performed prior to study treatment (scenario 1), prior to randomization to R +/- F, and when the patient goes off study. Main Eligibility Criteria: 1. Age ≥ 18 years with unresectable or metastatic BC 2. Estrogen and/or progesterone receptor positive, HER2 negative, as per ASCO-CAP 3. Postmenopausal status or receiving ovarian suppression 4. Measurable or unmeasurable disease; stable CNS disease allowed 5. No clinically significant cardiac disease 6. No concomitant CYP3A4/5 inducer or inhibitor Specific Aims Primary: Progression free survival (PFS), defined as the time from randomization to POD or death. Secondary: Objective response rate (ORR), clinical benefit rate (CBR = ORR + stable disease rate), overall survival (OS), and duration of response. Pts in scenario 1 will also be assessed for PFS, OS, CBR, and safety while receiving AI + R (pre-randomization). Biomarker assessment will include amplification of cyclin D1 and cyclin E, phosphoRb and TK1 expression, Rb1 and p16 loss, and ctDNA for ESR1 and PIK3CA mutations. Target Accrual 132 pts accrued from 11 academic medical centers in the U.S, with a goal of completing accrual in two years (∼60 to 72 pts in each scenario). Statistical Methods Assuming a median PFS of 3.8 months with F alone, we predict that F + R will lead to a median PFS of at least 6.5 months. A one-sided log-rank test with a sample size of N=120 and alpha=0.025, achieves 80% power to detect a difference in PFS of 2.7 months. N=132 pts allows for a 10% drop-out rate. Citation Format: Mundi PS, Codruta C, Accordino MK, Sparano J, Andreopoulou E, Vadhat LT, Tiersten A, Esteva F, O'Regan R, Jain S, Mayer I, Forero A, Crew KD, Hershman DL, Kalinsky KM. A randomized phase II trial of fulvestrant with or without ribociclib after progression on aromatase inhibition plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or metastatic hormone receptor positive, HER2 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 OT2-01-19.

Breast cancer: updates and advances in 2016.

Approximately 1 in 8 US women (12%) will develop invasive breast cancer over the course of her lifetime. In 2016, an estimated 246,660 new cases of invasive breast cancer are expected to be diagnosed and approximately 40,450 would die as a result of it. The global burden of breast cancer exceeds all other cancers and the incidence is increasing. The heterogeneity of breast cancer makes it a challenging solid tumor to diagnose and treat. This review focuses on the recent advances in breast cancer therapy including hormonal treatment of metastatic breast cancer, targeting cyclin-dependent kinases (CDK) 4/6 in breast cancer, updates in targeting human epidermal growth factor receptor 2 (HER2) positive breast cancer, adaptive randomization trial design and cancer genetic risk assessment. Breast cancer is a heterogeneous disease and targeted therapy is improving the outcomes of women. The use of cyclin-dependent kinase inhibitors (CDK) 4/6 have demonstrated a substantial improvement in progression-free survival in the first line setting of metastatic hormone receptor positive breast cancer. And newer agents directed at HER2 continue to revolutionize HER2-positive breast cancer treatment. This review highlights the recent updates in breast cancer treatment, new concepts in clinical trial design and provides a current overview of cancer genetic risk assessment.