Receptor-positive Metastatic Breast Cancer Patients Research Articles

Capecitabine Plus Aromatase Inhibitor as First Line Therapy for Hormone Receptor Positive, HER2 Negative Metastatic Breast Cancer.

(1) Background: recent evidence suggests that long low-dose capecitabine regimens have a synergistic effect with endocrine therapy as aromatase inhibitors (AIs), and might increase overall survival for hormone-receptor-positive, HER2-negative, metastatic breast cancer compared to both treatments. We performed a retrospective study to confirm the efficacy and expand the safety data for capecitabine plus AI (a combination henceforth named XELIA) for this indication. (2) We conducted a single-center retrospective cohort study of 163 hormone receptor-positive metastatic breast cancer patients who received either the XELIA regimen, capecitabine, or an aromatase inhibitor (AI) as single agents in first-line treatment. The primary endpoint was progression-free survival, and the secondary endpoints were overall survival, best objective response, and toxicity incidence. (3) Results: the median progression-free survival for patients receiving XELIA, AI, and capecitabine was 29.37 months (20.91 to 37.84; 95% CI), 20.04 months (7.29 to 32.80; 95% CI) and 10.48 (8.69 to 12.28; 95% CI), respectively. The overall response rate was higher in the XELIA group (29.5%) than in the AI (14.3%) and capecitabine (9.1%) groups. However, the differences in overall survival were not statistically significant. Apart from hand-foot syndrome, there were no statistically significant differences in adverse events between the groups. (4) Conclusions: this retrospective study suggests that progression-free survival and overall response rates improved with the XELIA regimen compared to use of aromatase inhibitors and capecitabine alone. Combined use demonstrated an adequate safety profile and might represent an advantageous treatment in places where CDK 4/6 is not available. Larger studies and randomized clinical trials are required to confirm the effects shown in our study.

144P Development of a 6-color multiplex crystal digital PCR assay for the simultaneous detection of ESR1 and PIK3CA mutations in the plasma of metastatic breast cancer patients

Blood-based liquid biopsies have become a real asset for patient treatment management in the field of precision oncology over the past few years, has it allows quick and easy access to tumor genetic alterations of interest. Indeed, circulating tumor DNA (ctDNA) analysis is particularly well suited for longitudinal monitoring with the advantage of covering the potential genetic heterogeneity of metastatic lesions. For Hormone Receptor-positive (HR+) Metastatic Breast Cancer (MBC) patients, mutations on the ESR1 (encoding the estrogen receptor (ER) alpha), and PIK3CA (encoding the phosphatidylinositol-3-kinase (PI3K) catalytic subunit p110-alpha) genes are emerging clinical biomarkers that can both guide clinicians in their choice of treatment.

P16-3 Maintenance therapy in HER2 and hormone receptor-positive breast cancer

After the standard first-line treatment for HER2 and hormone receptor-positive breast cancer, maintenance therapies are still controversial. Here, we report the real-world data of trastuzumab plus endocrine therapy compared with trastuzumab plus chemotherapy in HER2 and hormone receptor-positive metastatic breast cancer. This retrospective, multicenter, observational cohort study enrolled women aged 18 years or older with measurable or evaluable HER2 and hormone receptor-positive metastatic breast cancer who received chemotherapy and trastuzumab as first-line treatment between January 2009 and October 2019. We evaluated the efficacy and safety of trastuzumab plus endocrine therapy and trastuzumab plus chemotherapy. 102 patients were selected: 67 (65.7%) patients received trastuzumab plus endocrine therapy including aromatase inhibitors, fulvestrant, tamoxifen, or toremifene. While 35 (34.3%) patients received trastuzumab plus chemotherapy including capecitabine or vinorelbine as maintenance therapy. Maintenance endocrine therapy significantly improved progression-free survival (PFS) compared with chemotherapy (median progression-free survival 10.6 months [95% CI 8.609-12.658] vs 6.7 months [5.276-8.058], respectively; adjusted hazard ratio [HR] 0.648 [95% CI 0.428-0.981], p=0.040). The median PFS in patients without brain metastasis was 10.8 months (95% CI 9.380-12.154) in the endocrine therapy group versus 6.7 months (5.202-8.132) in the chemotherapy group (HR 0.485 [95% CI 0.303-0.777]), p=0.003). The most common adverse event was arthralgia (8,12%) in the endocrine therapy group, while hand-foot syndrome (25,71%) occurred in the chemotherapy group. Maintenance endocrine therapy could improve the survival of HER2 and hormone receptor-positive metastatic breast cancer patients.

Oral care and oral assessment guide in breast cancer patients receiving everolimus and exemestane: subanalysis of a randomized controlled trial (Oral Care-BC).

Oral mucositis is a clinically significant adverse event linked to cancer therapy; it reduces the quality of life of patients and may result in the discontinuation of treatment and a poorer prognosis. Based on level 3 evidence, the Mucositis Study Group of Multinational Association for Supportive Care in Cancer and the International Society of Oral Oncology recommend oral care for all patients receiving cancer chemotherapy and radiotherapy, although no data from large-scaled randomized controlled trials support the efficacy of oral care in preventing oral mucositis. Therefore, this randomized, controlled, multicenter, open-label, phase III study sought to determine whether professional oral care reduces oral mucositis in everolimus and exemestane-treated estrogen receptor-positive metastatic breast cancer patients. Altogether, 169 patients were randomized into the professional oral care (n=82) and control (n=87) groups. The professional oral care group received oral health instruction, professional mechanical tooth and tongue cleaning, gargling with a benzethonium chloride mouthwash, and dexamethasone ointment when grade 1 mucositis manifested. The control group received oral health instruction and gargling. Eight weeks after the everolimus and exemestane administration, the oral status (Oral Assessment Guide criteria) and oral mucositis status (Common Terminology Criteria for Adverse Events functional and clinical examinations) were evaluated. The incidence of oral mucositis of any grade and grade 2 severe mucositis was significantly lower in the professional oral care group, based on the Common Terminology Criteria for Adverse Events functional and clinical examinations. The total Oral Assessment Guide score, total Oral Assessment Guide grade, and Oral Assessment Guide score of teeth/dentures and mucous membranes were significantly different between the two groups. The Oral Assessment Guide grade for swallow, lip, teeth/dentures, mucous membrane, tongue, and saliva significantly correlated to oral mucositis severity. Professional oral care may prevent oral mucositis and improve teeth/denture conditions in patients receiving everolimus and exemestane.

Secondary endpoints analysis in patients with estrogen receptor-positive metastatic breast cancer treated with everolimus and exemestane enrolled in Oral Care-BC

BackgroundThe Oral Care BC-trial reported that professional oral care (POC) reduces the incidence and severity of oral mucositis in patients receiving everolimus (EVE) and exemestane (EXE). However, the effect of POC on clinical response among patients receiving EVE and EXE was not established. We compared outcomes for estrogen receptor-positive metastatic breast cancer patients who received POC to those who had not, and evaluated clinical prognostic factors. All patients simultaneously received EVE and EXE.MethodsBetween May 2015 and Dec 2017, 174 eligible patients were enrolled in the Oral Care-BC trial. The primary endpoint was the comparative incidence of grade 1 or worse oral mucositis, as evaluated for both the groups over 8 weeks by an oncologist. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collected after a follow-up period of 13.9 months.ResultsThere were no significant differences in PFS between the POC and Control Groups (P = 0.801). A BMI < 25 mg/m2 and non-visceral metastasis were associated with longer PFS (P = 0.018 and P = 0.003, respectively) and the use of bone modifying agents (BMA) was associated with shorter PFS (P = 0.028). The PFS and OS between the POC and control groups were not significantly different in the Oral-Care BC trial.ConclusionsPOC did not influence the prognosis of estrogen receptor-positive metastatic breast cancer patients. Patients with non-visceral metastasis, a BMI < 25 mg/m2, and who did not receive BMA while receiving EVE and EXE may have better prognoses.Trial registrationThe study protocol was registered online at the University Hospital Medical Information Network (UMIN), Japan (protocol ID 000016109), on January 5, 2015 and at ClinicalTrials.gov (NCT02376985).

Real-world experience of palbociclib and ribociclib: novel oral therapy in metastatic breast cancer.

Background Palbociclib and ribociclib are novel oral agents in hormone receptor-positive metastatic breast cancer. Neutropenia is a common adverse event associated with these treatments and its clinical management often requires regimen changes, such as cycle delays and dose adjustments. Objective To provide a real-world experience of the effectiveness and toxicities associated with these drugs and to evaluate the impact of regimen changes in disease progression. Setting This study was performed at Hospital Universitario La Paz, in Spain. Methods Observational, retrospective study which included hormone receptor-positive metastatic breast cancer patients who initiated treatment with palbociclib or ribociclib between March 1st, 2018 and March 1st, 2019. Main outcome measure The primary effectiveness variable was progression-free survival. Safety evaluation was performed to determine neutropenia-incidence and severity, as well as its clinical management, including dose adjustments and treatment interruptions. Correlations between these regimen changes and effectiveness were also evaluated. Results Sixty-one patients were included, 33 treated with palbociclib and 28 with ribociclib. Palbociclib was mainly used as second line of treatment in the metastatic setting (81.8%) and ribociclib as first line (67.9%). The median progression-free survival was 12.76months (95% CI 7.5 to not estimable) in palbociclib and not reached in ribociclib. After 12months, the progression-free survival rate was 51.5% (95% CI 34-69) in palbociclib and 78.6% (95% CI 63-94.1) in ribociclib. Neutropenia was the most common adverse event with an incidence rate of 87.9% in palbociclib and 82.1% in ribociclib. Cycle delays were needed in more than half of the patients treated with palbociclib and ribociclib (63.6% and 64.3%). Dose adjustments were seen in 42.4% and 53.6% of the patients receiving palbociclib and ribociclib, respectively. Regimen changes did not involve statistically significant differences in 12-month PFS rates in the cohort investigated. Conclusion Palbociclib and ribociclib outcomes are comparable to those reached in the phase III trials, PALOMA-3 and MONALEESA-2, respectively, and cannot be compared as they were used in different treatment settings. The toxicity profile is favourable, being neutropenia the most common adverse event, easily managed with regimen changes. Further studies are needed to confirm the observed tendency of no detrimental impact on effectiveness of these regimen changes.

Clinical Significance of Circulating Tumor Cells in Hormone Receptor–positive Metastatic Breast Cancer Patients who Received Letrozole with or Without Bevacizumab

We evaluated the prognostic and predictive value of circulating tumor cells (CTCs) hormone receptor-positive (HR+) metastatic breast cancer (MBC) patients randomized to letrozole alone or letrozole plus bevacizumab in the first-line setting (CALGB 40503). Blood samples were collected at pretreatment and three additional time points during therapy. The presence of ≥5 CTCs per 7.5 mL of blood was considered CTC positive. Association of CTCs with progression-free survival (PFS) and overall survival (OS) was assessed using Cox regression models. Of 343 patients treated, 294 had CTC data and were included in this analysis. Median follow-up was 39 months. In multivariable analysis, CTC-positive patients at baseline (31%) had significantly reduced PFS [HR, 1.49; 95% confidence interval (CI), 1.12-1.97] and OS (HR, 2.08; 95% CI, 1.49-2.93) compared with CTC negative. Failure to clear CTCs during treatment was associated with significantly increased risk of progression (HR, 2.2; 95% CI, 1.58-3.07) and death (HR, 3.4; 95% CI, 2.36-4.88). CTC-positive patients who received only letrozole had the worse PFS (HR, 2.3; 95% CI, 1.54-3.47) and OS (HR, 2.6; 95% CI, 1.59-4.40). Median PFS in CTC-positive patients was significantly longer (18.0 vs. 7.0 months) in letrozole plus bevacizumab versus letrozole arm (P = 0.0009). Restricted mean survival time analysis further revealed that addition of bevacizumab was associated with PFS benefit in both CTC-positive and CTC-negative patients, but OS benefit was only observed in CTC-positive patients. CTCs were highly prognostic for the addition of bevacizumab to first-line letrozole in patients with HR+ MBC in CALGB 40503. Further research to determine the potential predictive value of CTCs in this setting is warranted.

305P Patterns of acquired mutations in estrogen receptor-positive metastatic breast cancer (MBC) patients identified by comprehensive genomic profiling (CGP)

305P Patterns of acquired mutations in estrogen receptor-positive metastatic breast cancer (MBC) patients identified by comprehensive genomic profiling (CGP)

Abstract 29: Utility of novel clinico-genomic data to understand patient characteristics, treatments, and outcomes according to PIK3CA mutation status among hormone receptor-positive metastatic breast cancer patients

Abstract Background: Hormone receptor-positive (HR+) breast cancer (BC) comprises 60-65% of all BC. Activating mutations in PIK3CA are the most common oncogenic alteration in HR+ BC, yet little is known about the prognostic utility of single (SM) and multiple (MM) PIK3CA mutations. A novel database with next-generation sequencing (NGS) data from Foundation Medicine, Inc. (FMI) linked to electronic health records-derived clinical data from Flatiron Health allows investigation of the prognostic utility of genomic alterations including PIK3CA. Using this database, this study seeks to understand HR+/human epidermal growth factor receptor 2-negative (HER2-) metastatic BC (mBC) patient (pt) testing behavior, characteristics, and survival according to PIK3CA mutation status. Methods: Pt-level data from US pts diagnosed with HR+/HER2- mBC from January 1, 2011 to December 31, 2018 were selected from the de-identified Flatiron Health-FMI Clinico-Genomic Database (CGDB). Kaplan-Meier methods were used to estimate median (95% confidence interval [CI]) survival time, defined as time from mBC diagnosis to death. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs. Index date was mBC diagnosis date, but adjustments were made in survival analyses to account for delayed dataset entry due to FMI results date occurring after mBC diagnosis date. Descriptive statistics and chi-square and Kruskal-Wallis tests for significance were used to compare pt characteristics. Results: Of 1349 HR+/HER2- mBC pts included in this study, 807 pts (60%) were wild-type (WT) for PIK3CA, 436 (32%) were SM, and 106 (8%) were MM. Only 2% of pts had an FMI results date before mBC diagnosis date. Most pts had an FMI results date either during (26%) or after (59%) first-line treatment. Median time from mBC diagnosis to FMI results date was longer for MM (19 mo) vs. SM (13 mo) and WT (13 mo) pts (p=0.15). SM and MM pts were older than WT pts at mBC diagnosis (median: 59.9 yr [MM] vs. 59.6 yr [SM] vs. 56.2 yr [WT], p&amp;lt;0.001) and more often had progesterone receptor (PR)-positive BC (88.6% [MM] vs. 86.5% [SM] vs. 74.6% [WT], p&amp;lt;0.001). Median survival times for WT, SM, and MM pts were 20, 23, and 30 mo, respectively (p=0.40). After adjusting for age, site of metastasis at mBC diagnosis, and estrogen receptor/PR status, there was no association with overall survival for MM vs. WT (HR=0.96, p=0.53) or SM vs. WT (HR=1.03, p=0.80). Conclusions: These data showed that PIK3CA mutations were not associated with survival in this patient population and underscore the utility of linked clinical and genomics data for understanding the relationship between genetic alterations and patient outcomes. The majority of HR+/HER2- mBC pts received FMI results more than a year after mBC diagnosis, suggesting that NGS testing is used to guide decisions after pts have failed standard therapy. Additional studies with larger sample sizes and longer follow-up are needed to confirm these observations. Citation Format: Mary K. Downer, Peter Lambert, Sami Mahrus, Katherine E. Hutchinson, Patricia Luhn, Jennifer L. Schutzman. Utility of novel clinico-genomic data to understand patient characteristics, treatments, and outcomes according to PIK3CA mutation status among hormone receptor-positive metastatic breast cancer patients [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 29.

Risk of early progression according to circulating ESR1 mutation, CA-15.3 and cfDNA increases under first-line anti-aromatase treatment in metastatic breast cancer

BackgroundEndocrine therapy is recommended as a first-line treatment for hormone receptor-positive metastatic breast cancer (HR+MBC) patients. No biomarker has been validated to predict tumor progression in that setting. We aimed to prospectively compare the risk of early progression according to circulating ESR1 mutations, CA-15.3, and circulating cell-free DNA in MBC patients treated with a first-line aromatase inhibitor (AI).MethodsPatients with MBC treated with a first-line AI were prospectively included. Circulating biomarker assessment was performed every 3 months. The primary objective was to determine the risk of progression or death at the next follow-up visit (after 3 months) in case of circulating ESR1 mutation detection among patients treated with a first-line AI for HR+MBC.ResultsOverall, 103 patients were included, and 70 (68%) had progressive disease (PD). Circulating ESR1 mutations were detected in 22/70 patients with PD and in 0/33 patients without progression (p < 0.001). Among the ESR1-mutated patients, 18/22 had a detectable mutation prior to progression, with a median delay of 110 days from first detection to PD. The detection of circulating ESR1 mutations was associated with a 4.9-fold (95% CI 3.0–8.0) increase in the risk of PD at 3 months. Using a threshold value of 25% or 100%, a CA-15.3 increase was also correlated with progression (p < 0.001 and p = 0.003, respectively). In contrast to ESR1, the CA-15.3 increase occurred concomitantly with PD in most cases, in 27/47 (57%) with a 25% threshold and in 21/25 (84%) with a 100% threshold. Using a threshold value of either 25% or 100%, cfDNA increase was not correlated with progression.ConclusionThe emergence of circulating ESR1 mutations is associated with a 4.9-fold increase in the risk of early PD during AI treatment in HR+MBC. Our results also highlighted that tracking circulating ESR1 mutations is more relevant than tracking CA-15.3 or cfDNA increase to predict progression in this setting.Trial registrationClinicalTrials.gov, NCT02473120. Registered 16 June 2015—retrospectively registered after one inclusion (first inclusion 1 June 2015)

Abstract P4-01-06: Elacestrant (RAD1901) inhibits growth of ex vivo cultured circulating tumor cells derived from hormone receptor-positive metastatic breast cancer (mBC) patients including those harboring ESR1 mutations

Abstract Women with metastatic hormone receptor positive (HR+) breast cancer benefit from therapies targeting the Estrogen Receptor (ER), but the tumors eventually acquire resistance leading to disease progression. Endocrine resistance involves multiple mechanisms, including deregulation of ER signaling due to activating mutations in the ligand-binding domain of the ESR1 gene. In addition, recent reports describe specific contexts of ESR1 mutations in the preclinical setting where tamoxifen and fulvestrant have demonstrated limited activity. These data together with the frequency of ESR1 mutations (~20-60%) observed in mBC patients in the clinic suggest a need for more effective agents. The activity of elacestrant (RAD1901), an oral selective estrogen receptor degrader (SERD) with demonstrated activity against tumors harboring ESR1 mutations, both in preclinical models and in patients with previously treated advanced breast cancer, was assessed in ex vivo cultures of circulating tumor cells (CTCs) derived from women with metastatic HR+ breast cancer who had received multiple prior hormone therapies. Cultured breast CTCs underwent apoptosis following exposure to elacestrant, and CTCs harboring mutant ESR1 were significantly growth inhibited (IC50: 17.65 ± 3.32 nM) by elacestrant compared to the standard-of-care (SOC) agent fulvestrant. Furthermore, elacestrant eliminated the fulvestrant-resistant CTC populations in vitro. Elacestrant treatment led to significant suppression of ER target genes, PGR and GREB1. Elacestrant is currently being investigated versus standard of care endocrine monotherapy in a Phase 3 clinical trial (EMERALD) in patients with ER+/HER2- advanced/metastatic breast cancer. A co-primary endpoint of the EMERALD trial is evaluation of progression-free survival in patients whose tumors harbor ESR1 mutations. Citation Format: Taronish Dorab Dubash, Aditya Bardia, Brittany A Reeves, Brian Chirn, Annamaria Szabolcs, Ben S Wittner, John Iafrate, David Ting, Hitisha K Patel, Teeru Bihani, Mehmet Toner, Daniel A Haber, Shyamala Maheswaran. Elacestrant (RAD1901) inhibits growth of ex vivo cultured circulating tumor cells derived from hormone receptor-positive metastatic breast cancer (mBC) patients including those harboring ESR1 mutations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-01-06.

Abstract PD8-02: Phylogenetic reconstruction of advanced breast cancer reveals two different routes of metastatic dissemination associated with distinct clinical outcome

Abstract Background: Local and regional lymph node metastases are associated with worse prognosis in a variety of cancers, including breast cancer. However, to date it still remains debated whether axillary lymph node metastases can seed distant metastases or whether they merely represent a surrogate marker for tumor aggressiveness. Here, using multiple matched samples from primary tumor, axillary lymph nodes and distant metastases from breast cancer patients, we explored to which extent lymph nodes are transit points for further dissemination events to distant organs and assessed their role in disease progression using copy number phylogenetic reconstruction. Samples and Methods: We retrospectively identified 30 estrogen receptor-positive lymph node-positive metastatic breast cancer patients with 238 formalin-fixed paraffin-embedded tissue samples available together with well-annotated clinico-pathological and outcome data. Eligible patients had at least one primary tumor, one axillary lymph node metastasis, one distant metastatic sample as well as histologically normal tissue sample as germline reference. Low coverage whole genome sequencing was performed to infer somatic copy number aberrations. After rigorous filtering of the raw data, copy number phylogenetic reconstruction was performed with Integer Linear Program for the Copy-Number Tree Problem algorithm. Bootstrapping of the samples and of the segmented copy number data was performed to assess the robustness of the phylogenetic tree classification. Results: Phylogenetic tree analyses revealed that two different routes of metastatic dissemination occur in breast cancer. Unexpectedly, in only 24% of the patients, lymph nodes and distant metastases shared a common origin implying that dissemination occurred via the axillary lymphatic system whereas in the majority of the cases (76%) lymph node and distant metastases showed a distinct origin suggesting a direct seeding from the primary tumor to a distant organ. Of note, histological grade was the only clinic-pathological feature significantly associated with the route of dissemination, low grade tumors being associated with the common origin dissemination route (p=0.04). Interestingly, the patients sharing a common origin dissemination route were found to have significantly worse prognosis than the remaining patients (p=5.3x10−4), despite being low grade. Bootstrapping analyses showed identical topology as the original phylogeny in about 80% of the cases demonstrating the robustness of our method. Conclusions: In this study, we showed for the first time that the predominant route of metastatic dissemination operating in estrogen receptor-positive breast cancer is the direct seeding of tumor cells from the primary tumor to distant organ, independently of lymph node metastasis. These findings shed light on the routes on which tumor cells metastasize and could potentially improve the clinical management of lymph node-positive breast cancer patients. Citation Format: David Venet, David Brown, Danai Fimereli, Bram Boeckx, Marion Maetens, Samira Majjaj, Ghizlane Rouas, Maria Capra, Giuseppina Bonizzi, Federica Contaldo, Christine Galant, Martine Piccart, Giancarlo Pruneri, Denis Larsimont, Diether Lambrechts, Françoise Rothé, Christine Desmedt, Christos Sotiriou. Phylogenetic reconstruction of advanced breast cancer reveals two different routes of metastatic dissemination associated with distinct clinical outcome [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD8-02.

Clinical significance of gene mutation in ctDNA analysis for hormone receptor-positive metastatic breast cancer.

In this study, we aim to investigate the mutation spectrum of circulating tumor DNA among hormone receptor-positive metastatic breast cancer (HR-MBC) patients using ultradeep targeted resequencing. In addition, we also evaluate the correlation of mutations detected from this study with progression-free survival (PFS). A total of 56 HR-MBC patients were enrolled. Cell-free DNA (cfDNA) was extracted from plasma and sequenced by using Oncomine Breast cancer cfDNA assay in this study. Concentration of cfDNA is correlated with a number of metastatic organs and serum CEA levels (Spearman's rank correlation p = 0.0018, p = 0.0015 respectively). Cases with high cfDNA levels (≥ 2.6ng/μl of plasma) showed worse progression-free survival (PFS) and overall survival compared with cases with low cfDNA levels (p = 0.043 and 0.046, respectively). Among these patients, 29 patients (51.7%) have TP53 mutations, 12 patients (30.3%) have PIK3CA mutations, and 9 patients (16.0%) have ESR1 mutations. Acquisition of ESR1 mutation increased according to the lines of hormone therapy. In addition, patients with ESR1 mutation showed shorter PFS than those without mutation (log-rank p = 0.047). In the multivariate analysis, ESR1 mutation and cfDNA concentration were significant for PFS (p = 0.027 and 0.006, respectively). In conclusion, assessment of ESR1 mutation and cfDNA concentration could be useful in predicting prognosis for HR-MBCs.

Clinical Significance of Circulating Tumor Cells in Hormone Receptor–positive Metastatic Breast Cancer Patients who Received Letrozole with or without Bevacizumab

Clinical Significance of Circulating Tumor Cells in Hormone Receptor–positive Metastatic Breast Cancer Patients who Received Letrozole with or without Bevacizumab

Targeted deep sequencing revealed variants in cell-free DNA of hormone receptor-positive metastatic breast cancer patients

Cell-free DNA (cfDNA) is described to mirror intratumoral heterogeneity and gives insight about clonal evolution for improved therapeutic decisions. We sequenced cfDNA of a hormone receptor-positive, HER2-negative metastatic breast cancer (MBC) cohort with a high coverage to examine the prevalence and relevance of any detected variant. cfDNA of 44 MBC patients was isolated, followed by library construction using a customized targeted DNA panel with integrated unique molecular indices analyzing AKT1, AR, BRCA1, BRCA2, EGFR, ERCC4, ERBB2, ERBB3, ESR1, FGFR1, KRAS, MUC16, PIK3CA, PIK3R1, PTEN, PTGFR, and TGFB1. CfDNA was sequenced on the NextSeq® 550 platform (Illumina) and variants were analyzed with Ingenuity Variant Analysis (QIAGEN). We evaluated cfDNA variants in 40 of the 44 hormone receptor-positive and HER2-negative patients with a high mean coverage of 22,000×, resulting in MUC16, BRCA2, ERBB3, and AR variant calling in > 90% of the patients. 47% of all AR variants were pathogenic and at least one pathogenic or likely pathogenic variant was detected in each patient. A specific BRCA1 variant and > 3.5 pathogenic variants significantly associated with a reduced survival after diagnosis of metastasis. Longitudinal monitoring revealed an increase of pathogenic and likely pathogenic PIK3CA and ESR1 variant allele frequency under everolimus and exemestane, 8 months before proof of therapy failure by visual staging in one exemplary case. The identification of new variants with high prevalence, prognostic value, and dynamics under treatment by deep sequencing of cfDNA might empower sensitive monitoring and personalized therapeutic decisions.

Influence of patient and tumor characteristics on therapy persistence with letrozole in postmenopausal women with advanced breast cancer: results of the prospective observational EvAluate-TM study

BackgroundTreatment of postmenopausal, hormone receptor-positive metastatic breast cancer (MBC) patients varies despite clear therapy guidelines, favoring endocrine treatment (ET). Aim of this study was to analyze persistence of palliative aromatase inhibitor (AI) monotherapy in MBC patients.MethodsEvAluate-TM is a prospective, multicenter, noninterventional study to evaluate treatment with letrozole in postmenopausal women with hormone receptor–positive breast cancer. To assess therapy persistence, defined as the time from therapy start to the end of the therapy (TTEOT), two pre-specified study visits took place after 6 and 12 months. Competing risk survival analyses were performed to identify patient and tumor characteristics that predict TTEOT.ResultsOut of 200 patients, 66 patients terminated treatment prematurely, 26 (13%) of them due to causes other than disease progression. Persistence rate for reasons other than progression at 12 months was 77.7%. Persistence was lower in patients who reported any adverse event (AE) in the first 30 days of ET (89.5% with no AE and 56% with AE). Furthermore, patients had a lower persistence if they reported compliance problems in the past before letrozole treatment.ConclusionsDespite suffering from a life-threatening disease, AEs of an AI will result in a relevant number of treatment terminations that are not related to progression. Some subgroups of patients have very low persistence rates. Especially with regard to novel endocrine combination therapies, these data imply that some groups of patients will need special attention to guide them through the therapy process.Trial registrationClinical Trials Number: CFEM345DDE19

Clinical significance of circulating tumor cells (CTCs) in hormone receptor-positive (HR+) metastatic breast cancer (MBC) patients (pts) receiving letrozole (Let) or Let plus bevacizumab (Bev): CALGB 40503 (Alliance).

1049 Background: CALGB 40503 randomized HR+ MBC postmenopausal pts to Let alone or Let+Bev as first-line therapy. Adding Bev to Let prolonged progression-free survival (PFS) but not overall survival (OS) (Dickler JCO 2016). We performed a correlative study to assess prognostic and predictive value of CTCs in this population. Methods: Blood was collected prior to initiation of treatment. CTCs were enumerated using US FDA-cleared CellSearch assay; samples with ≥5 CTCs per 7.5 mLs of blood were considered CTC-positive (CTC+). Correlation of CTCs with PFS and OS was assessed using Cox regression analysis. Median follow-up was 39 months (mo). Results: Of 343 pts treated, 294 had CTC data and were included in this analysis. Original study results that showed improved PFS (HR = 0.75; 95% CI: 0.59-0.96) but not OS (HR = 0.87; 95% CI: 0.65-1.18) in pts receiving Let+Bev compared to Let were recapitulated in this subset. In multivariable analysis, CTC+ pts (31%) had significantly reduced PFS (HR = 1.49; 95% CI: 1.12-1.97) and OS (HR = 2.08; 95% CI: 1.49-2.93) compared to CTC- pts. Moreover, CTC+ pts who did not receive Bev had worse PFS (HR = 2.31; 95% CI: 1.54-3.47) and OS (HR = 2.64; 95% CI: 1.59-4.40) (Table). CTC+ pts who received Bev had numerically longer median PFS (18.0 vs. 7.0 mo) and OS (33.6 vs. 27.1 mo) compared to CTC+ pts with no Bev; however, tests for interaction between CTC status and Bev (yes vs. no) were not statistically significant for PFS (p=0.70) or OS (p=0.84). Conclusions: CTCs were highly prognostic in this study involving addition of Bev to first-line Let in postmenopausal HR+ MBC. Further research to determine the potential predictive value of CTCs in the setting of both metastatic disease and early breast cancer is warranted. Support: U10CA180821, U10CA180882; Genentech; https://acknowledgments.alliancefound.org ; NCT00601900. Survival in HR+ MBC pts receiving Let or Let+Bev stratified by CTC status. Clinical trial information: NCT00601900. [Table: see text]

Chemotherapy Modulates Endocrine Therapy-Related Resistance Mutations in Metastatic Breast Cancer

PURPOSE: Accumulation of PIK3CA, ESR1, and GATA3 mutations results in resistance to endocrine therapy in breast cancer patients; however, the response of these genes to chemotherapy is unclear. Therefore, we sought to evaluate the genetic response of circulating tumor DNA (ctDNA) to chemotherapy in metastatic breast cancer patients. METHODS: The mutation frequency of 1021 genes was examined prior to chemotherapy in ctDNA of 44 estrogen receptor–positive metastatic breast cancer patients. These genes were evaluated again in a subset of patients (n=24) following chemotherapy. Mutation frequency was defined as the percentage of mutations found in ctDNA compared to total cell-free DNA. RESULTS: Prior to chemotherapy, PIK3CA was the most commonly mutated gene, with mutation found in 22 of the metastatic breast cancer patients. Following chemotherapy, 16 patients exhibited progressive disease (PD), and 8 patients experienced no progression (non-PD). PIK3CA mutation frequency increased in 56.25% (9/16) of the PD patients but decreased in 62.5% (5/8) of the non-PD patients. As a result, more PD patients exhibited increased PIK3CA mutation frequency than non-PD patients (56.25% vs 0%, P=.002). Further, ESR1 and GATA3 mutations correlated with PIK3CA mutation. Interestingly, patients receiving the mTOR inhibitor everolimus exhibited a lower progression rate (0% vs 62.5%, P=.001), and the combination of everolimus and chemotherapy effectively suppressed PIK3CA, ESR1, and GATA3 gene mutations. CONCLUSION: Together, these results suggest that mTOR inhibition may be a useful chemotherapy adjuvant to suppress chemotherapy-induced gene mutations that render tumors resistant to endocrine therapy in metastatic breast cancer patients with PD.

A comparison of fulvestrant plus a targeted agent with fulvestrant alone in hormone receptor-positive advanced breast cancer that progressed on prior endocrine therapy: a meta-analysis.

Fulvestrant is recommended for the hormone receptor-positive metastatic breast cancer (MBC) patients progressed during or after prior endocrine therapy. Notably, recent evidence has also demonstrated that adding a targeted agent to fulvestrant conferred a significantly clinical benefit in these patients. Since these results were inconsistent among the studies, this meta-analysis herein was conducted to compare the efficacy and toxicities of the fulvestrant-based combination therapy with fulvestrant monotherapy. Thus, a systemic research was performed in PubMed, Embase, and Cochrane library to identify relevant Phase II or Phase III randomized controlled trials. The progression-free survival (PFS), overall response rate (ORR), and toxicities were evaluated. And HR, risk ratio (RR), and their 95% CIs were employed to complete the pooled analyses. In total, 13 studies with 3,910-hour positive MBC patients progressed on prior endocrine therapy were included in our meta-analysis. Improvements of doublet-agents group were proven in terms of PFS (HR 0.73, 95% CI =0.63–0.86, P=0.000) and ORR (RR 2.07, 95% CI =1.67–2.58, P=0.000). And the further subgroup analysis also demonstrated that fulvestrant in combination with a cyclin-dependent kinase (CDK4/6) inhibitor or a PI3K/mTOR inhibitor was associated with a superior efficacy (RR 2.72, 95% CI =1.93–3.83, P=0.000 and RR 1.60, 95% CI =1.15–2.23, P=0.005, respectively). However, the efficacy was comparable between the other combination strategies and fulvestrant alone. With respect to the adverse effects, adding a targeted agent to fulvestrant also produced more frequent grade 3/4 toxicities (RR 3.86, 95% CI =2.66–5.61, P=0.000). Taken together, combination of fulvestrant with a targeted agent, especially inhibitors targeting CDK4/6 or PI3K/mTOR pathway, may open a new avenue for more effective therapies in relapse or metastatic hormone receptor-positive breast cancer after prior aromatase inhibitors or tamoxifen treatment. In addition, identifying reliable biomarkers to delineate which subgroup of patients will specially benefit from fulvestrant-based combination therapy is warranted.

Real-World Experience of Palbociclib-Induced Adverse Events and Compliance With Complete Blood Count Monitoring in Women With Hormone Receptor–Positive/HER2-Negative Metastatic Breast Cancer

BackgroundThe cyclin-dependent kinase 4/6 inhibitor palbociclib has emerged as a novel therapeutic agent in metastatic breast cancer. Neutropenia is commonly observed, and thus stringent treatment guidelines regarding complete blood count (CBC) monitoring have been developed. The aim of this study was to provide a real-world experience of the toxicities associated with palbociclib therapy and to evaluate compliance with CBC monitoring. Patients and MethodsWe performed a retrospective single-center audit of hormone receptor–positive metastatic breast cancer patients treated with palbociclib over a 6-month period in an Irish tertiary referral hospital. ResultsA total of 64 patients were included in the analysis. Palbociclib was most commonly used in combination with letrozole (n = 40). A total of 28 patients (44%; 95% confidence interval, 31.2-56.2) had treatment deferrals due to neutropenia, with a median time to first deferral of 4 weeks. Fifteen patients (23%; 95% confidence interval, 15.4-37.7) required dose adjustments; however, there was no association with an increased risk of progressive disease (P = .56). Only 3 patients discontinued treatment as a result of poor tolerance. Adverse events were as expected; however, 7 venous thromboembolic events were reported. ConclusionCompliance was good with existing CBC monitoring guidelines. We observed an 11% incidence of venous thromboembolic events, a significant increase from 2% reported in the PALOMA-3 trial. Further studies are recommended to determine if prophylactic anticoagulation may benefit these patients.