bluuebunny/crossref_metadata_2025 huggingface dataset:
Alpelisib (ALP) + endocrine therapy (ET) in patients (pts) with PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor-2-negative (HER2-) advanced breast cancer (ABC): First interim BYLieve study results.
Authors: Rugo Hope S. , Ruiz Borrego Manuel , Chia Stephen K. L. , Juric Dejan , Turner Nicholas C. , Drullinsky Pamela , Lerebours Florence , Bianchi Giulia Valeria , Nienstedt Carolyn C. , Ridolfi Antonia , Thuerigen Astrid , Ciruelos Eva
Published: May 2019

1040

Background: In the phase 3 SOLAR-1 study, ALP + fulvestrant (FUL) improved PFS in pts with HR+, HER2– ABC with a PIK3CA mutation overall and in the small group of pts with prior cyclin-dependent kinase 4/6 inhibitor (CDKi) use. We report interim data from the BYLieve study in pts with PIK3CA-mutated ABC and prior CDKi exposure. Methods: BYLieve is an ongoing, phase 2, open-label, non-comparative study of ALP 300 mg QD + ET in men and women with PIK3CA-mutated HR+, HER2– ABC whose disease progressed on/after CDKi + ET. Pts are permitted ≤2 prior anticancer therapies and ≤1 prior chemotherapy regimen for ABC. Pts with prior CDKi and AI ( FUL cohort) receive ALP and FUL 500 mg Q28d + C1d15 IM. Pts with prior CDKi and FUL ( LET cohort) receive ALP and letrozole (LET) 2.5 mg PO QD. In this preplanned interim analysis, conducted after ≥20 pts in FUL had ≥6 mo of follow-up, descriptive data are reported for preliminary safety and efficacy in the FUL and LET cohorts. Results: At data cutoff, 64 and 36 pts were enrolled in the FUL and LET cohorts, respectively; 39 pts ( FUL, n = 21; LET, n = 18) have safety and efficacy data with ≥6 mo follow-up and are reported here. Data on 100 pts enrolled at the time of data cutoff will be presented. In the 39 pts with ≥6 mo follow-up, median ALP duration was 5.3 and 5.5 mo in FUL and LET, respectively; median duration of FUL and LET was 5.6 mo. Median relative ALP dose intensity was 93% ( FUL) and 87% ( LET). Most common grade ≥3 adverse events were hyperglycemia (38.1% ( FUL) and 27.8% ( LET)) and rash (4.8% ( FUL) and 27.8% ( LET)). Only 2 pts (5%; 1 pt per cohort) discontinued due to an AE. In pts with centrally confirmed PIK3CA mutation (n = 20 ( FUL); n = 17 ( LET)), ORR was 20% ( FUL) and 18% ( LET), CBR was 40% ( FUL) and 35% ( LET). Efficacy and safety data for the 100 enrolled pts will be presented at the meeting. Conclusions: Pending further readout of the ongoing BYLieve trial, safety and tolerability of ALP and hormonal therapy in pts with prior CDKi are consistent with those of SOLAR-1; discontinuation due to toxicity was rare. NCT03056755. Clinical trial information: NCT02437318.
Efficacy and safety of talazoparib (TALA) or physician's choice of therapy (PCT) in United States patients (pts) with HER2- germline BRCA1/2-mutated (gBRCAm) locally advanced/metastatic breast cancer (LA/MBC) in the EMBRACA study.
Authors: Diab Sami , Rugo Hope S. , Mina Lida A. , Puhalla Shannon , Mahtani Reshma L. , Henry Norah Lynn , Denduluri Neelima , Yardley Denise A. , Wang Yao , Arruda Lillian Shahied , Tudor Iulia Cristina , Gauthier Eric Roland , Czibere Akos Gabor , Litton Jennifer Keating , Hurvitz Sara A.
Published: May 2019

1044

Background: TALA is a poly(ADP-ribose) polymerase (PARP) inhibitor approved in the US for HER2- g BRCAm LA/MBC. Approval was based on results from the Phase 3 EMBRACA trial comparing efficacy/safety of TALA (1 mg/d) to PCT (capecitabine, eribulin, gemcitabine, vinorelbine) in HER2- g BRCAm LA/MBC pts. This analysis describes outcomes in US pts included in the pivotal study. Methods: Clinical findings from US pts enrolled in EMBRACA were analyzed. Pt characteristics, progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), and safety/adverse events (AEs) were among the parameters assessed. Results: Of 431 randomized pts, 156 pts (36%) were from the US (TALA: 99; PCT: 57). Pt characteristics were balanced, although a higher percentage in the TALA arm had more poor prognostic features (eg, triple-negative breast cancer, disease-free interval < 12 mo, and more disease sites). TALA improved PFS, ORR, CBR, and duration of response (DOR) vs PCT (Table). 22% of pts in the TALA arm had a continued objective response at month 12 vs 0 pts in the PCT arm. The most common AEs in the TALA arm included anemia, neutropenia, thrombocytopenia, fatigue, nausea, alopecia, and headache; hematologic grade 3/4 AEs occurred more often than nonhematologic AEs. Conclusions: In US pts with HER2- g BRCAm LA/MBC, TALA demonstrated significant improvements in outcomes vs PCT with a manageable safety profile. Clinical trial information: NCT01945775. [Table: see text]
A phase II study of pembrolizumab in combination with palliative radiotherapy (RT) for hormone receptor-positive (HR+) metastatic breast cancer (MBC).
Authors: Barroso-Sousa Romualdo , Krop Ian E. , Trippa Lorenzo , Tan-Wasielewski Zhenying , Li Tianyu , Osmani Wafa , Andrews Chelsea , Dillon Deborah , Richardson Edward T. , Winer Eric P. , Mittendorf Elizabeth A. , Schoenfeld Jonathan Daniel , Tolaney Sara M.
Published: May 2019

1047

Background: RT is frequently used for palliation in MBC. In animal models its use has been reported to induce distant (abscopal) tumor responses when combined with immune checkpoint inhibitors. Here, we report the safety and efficacy of palliative RT plus pembrolizumab in a phase II single-arm study in patients (pts) with HR+/HER2- MBC. Methods: Eligible pts had HR+/HER2- MBC, ECOG PS <2, indication for palliative RT, and ≥1 measurable lesion outside of the RT field; there was no limit on prior lines of therapy. A total RT dose of 20 Gray was delivered over 5 daily fractions. Pembrolizumab was given at 200 mg IV 2-7 days before day 1 of RT, then every 3 weeks until disease progression. The primary endpoint was objective response rate (ORR) outside the field of radiation by RECIST v1.1. Using the Simons “optimal” method, if ≥ 1/8 pts responded during the first stage, 19 more would be enrolled. If ≥ 3/27 responded, the null hypothesis (ORR=3%) would be rejected in favor of a 20% ORR. Predefined secondary endpoints included progression free survival (PFS) and toxicity. Analyses associating PD-L1 expression, tumor-infiltrating lymphocytes (TIL), and neutrophil/lymphocyte ratio (NLR) with outcomes were exploratory. Results: Eight women were enrolled into the first stage of the trial; no objective responses were seen, and the study was closed to further accrual. The median age was 59y (37-68y), 6 (75%) had ECOG PS 1, all had bone and 5 (63%) had liver metastases. The median number of prior cytotoxic therapies for MBC was 2 (range 0 to 8). While one patient had a PR by RECIST criteria, this patient experienced concurrent clinical progression. Two pts had SD < 16 weeks and 5 had PD as best response. The median PFS was 1.4 months (95% CI 0.4 – 2.1). All-cause adverse events occurred in 87.5% of pts (G3-4, 12.5%). TIL were available for 6 pts: 4 had ≤10%, and 2 > 10%. Among 5 pts with PD-L1 status available, 2 were positive. Six pts had NLR > 4. Conclusions: Pembrolizumab combined with RT was well-tolerated, and no unexpected adverse events were observed; however, clinical benefit of the combination was not demonstrated in this heavily pretreated HR+ population. Clinical trial information: NCT03051672.
Dose-escalation study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), in postmenopausal women with ER+/HER2- metastatic breast cancer (mBC).
Authors: Bardia Aditya , Linden Hannah M. , Ulaner Gary A. , Chandarlapaty Sarat , Gosselin Alice , Doroumian Séverine , Celanovic Marina , Campone Mario
Published: May 2019

1054

Background: SERDs result in ER competitive antagonism and degradation and can block signaling in ER-dependent tumors resistant to other endocrine therapies. This study investigates SAR439859, a potent oral SERD, +/- palbociclib in ER+/HER2- mBC. Here are preliminary results, as of 28 Nov 2018, for single-agent SAR439859 dose escalation. Methods: Part A of this Phase 1/2 study (NCT03284957; TED14856) assessed SAR439859 dose escalation (dose range: 20–600 mg once daily [QD]; 3 + 3 design) in postmenopausal women with ER+/HER2- mBC treated for ≥ 6 months with prior endocrine therapy and ≤ 3 chemotherapies in the advanced setting. Endpoints: dose-limiting toxicities (DLTs); maximum tolerated dose (MTD); safety; pharmacokinetics (PK); tumor response (RECIST 1.1); pharmacodynamic (PD) inhibition of ER occupancy (18FES-PET scan). Results: Patients (pts; n = 16) had a median age of 59.5 years (range 40–79), ECOG performance status of 0 (62.5%) or 1 (37.5%) and a median of three prior anticancer therapies (range 1–8) in the advanced setting (endocrine therapy n = 16; chemo/targeted therapy n = 13). All pts had ≥ 1 treatment emergent adverse event (mostly grade 1–2); most frequent were asthenia/fatigue (43.8%), hot flushes (37.5%), nausea (37.5%), diarrhea (31.3%), constipation (31.3%), and decreased appetite (31.3%). There were no DLTs at any of the five dose levels (maximum administered dose: 600 mg QD); MTD was not reached. In 18FES-PET scans, signal inhibition > 87% occurred with plasma concentrations > 100 ng/mL. There was a dose proportional increase of exposure up to 400 mg after repeated QD doses. Average Ctrough was reached after repeated 400 mg QD allowing 90% of 18FES-PET signal inhibition. One pt (6.3%) had confirmed partial response (150 mg QD); eight (50%) had stable disease (SD) including three (18.8%) long-term SD (≥ 24 weeks); seven (43.8%) had progressive disease. Conclusions: SAR439859 had a favorable safety profile, high ER occupancy and encouraging antitumor activity (to be confirmed in dose expansion) in pretreated pts with ER+/HER2- mBC. With no DLTs and MTD, 400 mg QD was selected for expansion cohorts based on safety, PD and PK data. Funding: Sanofi. Clinical trial information: NCT03284957.
RIBECCA: A phase IIIb, multicenter, open label study for women with estrogen receptor-positive locally advanced or metastatic breast cancer treated with ribociclib (LEE011) in combination with letrozole—Results of the second interim analysis.
Authors: Nusch Arnd , Decker Thomas , Reinisch Mattea , Hartkopf Andreas D. , Heinrich Bernhard , Kurbacher Christian M. , Fuchs Roswitha Dorothea , Tesch Hans , Krabisch Petra , Brucker Sara , Fehm Tanja N. , Janni Wolfgang , Kümmel Sherko , Luftner Diana , Schneeweiss Andreas , Schuler Martin H. , Voges Claudia , Schubert Joerg , Fasching Peter A.
Published: May 2019

1061

Background: RIBECCA is a national, multi-center, open-label, single-arm phase IIIb trial assessing the efficacy and safety of ribociclib in combination with letrozole in a patient population similar to the populations of MONALEESA-2, -3 and -7. Here we present the results of the second preplanned interim analysis. Methods: Main inclusion criteria allowed enrollment of men or women with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy, and histological or cytological confirmation of ER+, HER2- breast cancer, irrespective of their menopausal status. The primary objective is to assess the clinical benefit rate (CBR) after 6 months. Secondary objectives include: progression free survival (PFS), overall survival (OS), safety and changes in quality of life. Results: The cut-off date for this second interim analysis was 12 months after the last patient was enrolled in the pretreated and premenopausal cohort. Here we report a preliminary analysis on safety, efficacy and quality of life. We describe the baseline characteristics, safety data and the clinical benefit rate (CBR) at 24 weeks, of patients (pts) with at least 24 weeks follow up (n = 411). The median observation time for all patients in this analysis was 8.1 months. Baseline characteristics: of 411 pts, 409 were female and 2 male. Median age: 64 yrs; 46 pts pre-or perimenopausal, 363 postmenopausal; ECOG 0-1: 97.0%; median time since first recurrence: 1.6 months; 72.5 % pts had bone metastases (40.6% bone only), 30.7% liver, 27.3% lung and 29.2% other metastases. Median relative dose intensity was 0.905 for ribociclib and 1 for letrozole. The most common treatment emergent AEs (all grades) were neutropenia and/or neutrophil count decreased (54.5%), nausea (40.6%), fatigue (36.5%), alopecia (32.6%), leukopenia or WBC decreased (29%), nasopharyngitis (23.1%), diarrhea (21.4%), ALT increased (20.7%), AST increased (19%). The CBR by week 24 was 67.6%. Preliminary information on quality of life will be provided. Conclusions: The results of the second interim analysis in this additional patient population are in line with data published from the pivotal phase III studies MONALEESA-2, MONALEESA-3 and MONALEESA-7. Clinical trial information: NCT03096847.
IMpassion130: Expanded safety analysis from a P3 study of atezolizumab (A) + nab-paclitaxel (nP) in patients (pts) with treatment (tx)-naïve, locally advanced or metastatic triple-negative breast cancer (mTNBC).
Authors: Schneeweiss Andreas , Rugo Hope S. , Winer Eric P. , Barrios Carlos H. , Iwata Hiroji , Dieras Veronique , Loi Sherene , Maiya Vidya , Bond John , Lei Guiyuan , Chui Stephen Y. , Adams Sylvia , Emens Leisha A. , Schmid Peter
Published: May 2019

1068

Background: IMpassion130 showed PFS benefit with A + nP vs placebo (P) + nP as 1L tx for mTNBC in the ITT and PD-L1 IC+ pts. We report expanded safety data with 4.5-mo longer follow-up (FU), focusing on adverse events of special interest (AESI), potentially immune related. Methods: Pts with unresectable locally advanced or mTNBC received nP 100 mg/m2 IV (d1, 8 and 15 of a 28-d cycle) + A 840 mg IV q2w or P until PD or toxicity. Safety was a secondary endpoint. Results: With 15.6 mo of median FU, of 453 pts with A+nP and 437 pts with P+nP, 49% and 43% had Gr 3/4, 1% and <1% had Gr 5, 23% and 19% had serious AEs, and 58% and 42% had AESI, respectively. Most AESI (≥86%; either arm) were Gr 1/2. 14% (A+nP) vs 6% (P+nP) received systemic corticosteroids within 30 d of AESI onset. The only any-Gr AESI differing with A+nP vs P+nP were rash (34% vs 26%), hypo- (18% vs 5%) and hyperthyroidism (5% vs 1%) and pneumonitis (4% vs <1%). The leading cause of withdrawal was peripheral neuropathy, with Gr 3 affecting 6% (A+nP) vs 3% (P+nP). AESI median time to onset (TTO) was consistent with A monotherapy trials. Conclusions: A+nP had a tolerable safety profile, with no meaningful changes since the primary data cut. No cumulative toxicities or new or late-onset safety signals were seen with longer FU. Clinical trial information: NCT02425891. [Table: see text]
A phase II clinical trial of pembrolizumab and selective androgen receptor modulator GTx-024 in patients with advanced androgen receptor-positive triple-negative breast cancer.
Authors: Lee-Bitar Jin Sun , Frankel Paul Henry , Yost Susan Elaine , Synold Timothy W. , Martinez Norma , Tang Aileen , Schmolze Dan , Apple Sophia , Hurria Arti , Waisman James Ross , Somlo George , Patel Niki Tank , Sedrak Mina S. , Mortimer Joanne E. , Yuan Yuan
Published: May 2019

1069

Background: Androgen receptor (AR) targeting therapy has shown single agent activity in triple negative breast cancer (TNBC). GTx-024, a nonsteroidal selective androgen receptor modulator (SARM), demonstrated preclinical and clinical activity in AR+ breast cancer. The current study is designed to test the safety and efficacy of GTx-024 and pembrolizumab in patients with AR+ metastatic TNBC (mTNBC). Methods: This is an open-label phase 2 study for AR+ mTNBC. Eligible participants receive pembrolizumab 200mg IV every 3 weeks in combination with GTx-024 18mg po daily. Key eligibility criteria include patients with AR+ ( > 10%, 1+ by IHC); mTNBC; ECOG 0-1; measurable disease per RECIST 1.1. Patients are excluded if they had prior checkpoint inhibitors or AR targeted agents. The primary objective is to evaluate the tolerability of GTx-024 and pembrolizumab, and determine the response rate. Results: Seventeen patients were enrolled in the study. One patient was ineligible due to previously undiagnosed brain metastases. Ten of 16 patients had visceral metastasis (lung or liver), and 15% of patients had received ≥ 3 previous lines of therapy for mTNBC. Among 16 patients evaluable for response, 2 patients achieved a best response of partial response (PR), 2 patient had stable disease (SD, 18 and 19 weeks ), 11 patients had progressive disease (PD), and 1 patient is too early for restaging imaging. Durable response was found in 1 patient. Grade 3 toxicities include 1 diarrhea and 1 dry skin. Grade 2 adverse events include 3 elevated liver function, 1 adrenal insufficiency, 1 hyperthyroidism, 1 palpitation, 1 diarrhea, 1 hyperhydrosis, 1 hot flashes and 1 headache. Three patients had dose delay and two patients had dose reduction. Conclusions: AR targeted therapy GTx-024 combined with pembrolizumab is well tolerated with clinical activity. Clinical trial information: NCT02971761.
Effector T-cell cytolytic activity modules derived from CD3+ single cells from human primary triple-negative breast cancer (TNBC) in multiple solid tumors to predict response to immune checkpoint blockade therapy (ICB).
Authors: Acharya Chaitanya Ramanuj , Lyerly Herbert K
Published: May 2019

1073

Background: The prognostic and predictive value of tumor infiltrating lymphocytes for ICB has been recognized in a variety of tumor types, including TNBC. Nonetheless, our understanding of the mechanistic aspects of T cell activation remains incomplete. We hypothesize that a specific effector phenotype of T cell cytolytic activity (ECA) is a consistent feature of epithelial tumors, possibly varying by tumor types with a range of inflammatory features. Methods: We evaluated 6,311 purified CD3+ single cells from human primary TNBC and computed sample set enrichment scores of a set of previously published immune metagenes. Following unsupervised clustering of the enrichment scores of the entire single cell population, two subgroups of cells with highest and lowest average enrichment score of T cell cytolytic activity formed a basis for detecting functional gene expression modules. Spectral decomposition and Jackstraw analysis estimated eight modules with overlapping sets of genes. Each gene expression module was then used to train a Random Forest classifier of ECA phenotype. Results: We discovered that our module-derived classifiers were prognostic not only in TNBC samples obtained from both TCGA (N = 150) and METABRIC (N = 320) datasets but also in 14 other tumor types encompassing 6,000 samples. For example, patient samples from TCGA dataset predicted to be in group ECA ‘High’ have better progression-free survival (p-value: 0.0098l; HR: 0.30) and better overall survival (p-value: 0.0066; HR: 0.17). In both breast datasets, gene within the classifier are relatively under-expressed in ER+ tumors as opposed to HER2+ and TNBC (p-value < 2.2e-16). In a dataset of normal, pure DCIS and mixed DCIS (GSE26304;N = 114), the same genes were relatively under-expressed in DCIS samples relative to invasive tumors (p-value < 2.2e-16). Additionally, in a pre-therapy tumor dataset of fifty-one advanced melanoma patients treated with Nivolumab, who previously either progressed on ipilimumab or were ipilimumab-naïve, our module-derived classifier was able to classify responders and non-responders with 77% accuracy (p-value = 0.02) and was associated with progression-free survival (p-value = 0.03; HR: 0.28). Conclusions: Our study highlights one important application of single-cell genomics in our understanding of immune microenvironment and potentially identify new immunotherapy targets.
First results of a prospective registry in unresectable locally advanced or metastatic breast cancer patients: GEICAM/2014-03 (RegistEM).
Authors: Jara Carlos , Alvarez Isabel , Vila Mireia Margeli , Rodriguez Cesar Augusto , Martinez Purificacion , Batista J. Norberto , Alonso Romero Jose Luis , Antolín Novoa Silvia , Ruíz Sofía , Guerrero Angel , Tusquets Ignasi , Anton Antonio , Chacon Jose Ignacio , Rodríguez-Lescure Álvaro , Tibau Martorell Ariadna , Varela Ferreiro Silvia , Miralles Juan José , Bezares Susana , Rojo Federico , López-Tarruella Sara
Published: May 2019

1077

Background: In Spain there is limited prospective data for unresectable locally advanced breast cancer (ULABC) or metastatic breast cancer (MBC) patients (pts) treated as per clinical practice. RegistEM study will provide epidemiological, pathological and clinical data, including treatments given for different disease stages. Understanding the real distribution of the different BC subtypes is the primary objective. Methods: This is a non-interventional cohort study enrolling approximately 1,400 pts with advanced disease diagnosed from January 2016 to December 2018, either after recurrence or as first diagnosis, in 38 Spanish sites. Biological samples (primary tumor, metastatic lesions, blood) are currently being collected. In this first analysis, we include 489 pts who met study criteria before October 31, 2017. All data are described in two subgroups: on the most recent tumor lesion or on the primary breast tumor. Results: At first diagnosis, 67.9%, 31.5% and 0.6% of pts had early BC (EBC), MBC and ULABC, respectively. In the total analysis population, median age at diagnosis of advanced disease was 59.6 years, most of pts were white (98.2%), female (99.4%) and postmenopausal (70%). Family history of BC and ovarian cancer was reported in 5.7% pts. In ~390 pts BC clinical subtypes distribution was luminal B(HER2-)-like (~55%), luminal B(HER2+)-like (~16%), luminal A-like or triple negative (TN) (~10% each) and HER2 enriched-like (~8%). Median time to recurrence (years) in EBC pts was: luminal A-like 5.8, luminal B(HER2-)-like 5.1, luminal B(HER2+)-like 3.9, HER2 enriched-like 2.7 and TN 1.7. Bone (59%), visceral (58%) and lymph node (27%) lesions were the most frequent metastatic locations. The two most frequent therapies in first line consisted in: endocrine therapy (ET) (47%) and ET+biological therapy (BT) (29%) for luminal A-like; ET (32%) and ET+BT (32%) for luminal B(HER2-)-like; chemotherapy (CT)+ET+BT (43%) and CT+BT (24%) for luminal B(HER2+)-like; CT+BT (68%) and CT (16%) for HER2 enriched-like; CT (59%) and CT+BT (34%) for TN. Conclusions: These first data confirm that luminal B (HER2-)-like subtype is the most predominant in MBC.
Association of secondary somatic mutations in BRCA1/2 with clinical resistance to PARP inhibitors and chemotherapy.
Authors: Zhu Lingjun , Zhang Yan , Dai Pingping , Zhou Ping , Li Hui , Xu Chunwei , Wang Wen xian , Zhang Chi , Guan Yan-Fang , Xia Xuefeng , Yang Ling , Yi Xin
Published: May 2019

1087

Background: Somatic reversion mutations in either BRCA1/2 has been reported to lead to the resistance of platinum-based chemotherapy or PARPi. In this study we try to analyze the secondary somatic mutations in BRCA1/2 in patients with germline mutations. Methods: Using gene-panel target-captore next generation sequencing, we analyzed the secondary somatic mutations from 86 patients with BRCA1/2 germline mutations. Results: Eighty-six cases with BRCA1/2 gremline mutations were identified. Secondary somatic mutations restoring BRCA1/2 were identified in 7 patients, including 2 breast cancer, 3 ovarian cancer, 1 prostate cancer and 1cholangiocarcinoma patient. For these seven patients, five had been treated with platinum-based chemotherapy without PARPi and the other two (patient 1 and 2) with PARPi (olaparib). Patient 1 and 2 both received targeting therapy of PARP inhibitor olaparib after the germline BRCA1/2 mutation was detected. About six months later, plasma ctDNA was sequenced. Result showed that the germline mutations remained and additional larger deletions was detected. These secondary somatic mutations are not predicted to significantly affect the BRCA1/2 protein, and are likely to cause resistance to platinum-based chemotherapy or PARPi therapy by restoring BRCA1/2 ORF and DNA repair function. Conclusions: Secondary somatic mutations that restore BRCA1/2 in carcinomas with germline BRCA1/2 mutations predict resistance to platinum-based chemotherapy and PARP inhibitors, some strategies to reverse this type of drug resistance need further investigation. [Table: see text]
Detection of subthreshold microsatellite instability in breast cancer: An ongoing investigation.
Authors: Drago Joshua Z. , Latham Alicia , Modi Shanu , Razavi Pedram , Stadler Zsofia Kinga , Robson Mark E.
Published: May 2019

1089

Background: Microsatellite instability (MSI) and mismatch repair deficiency (MMRd) can occur sporadically in solid tumors across histologic subtype and predict clinical response to immune checkpoint blockade (ICB). MSIsensor uses next generation sequencing to report the percentage of unstable microsatellites in a given tumor sample as a score. While scores of ≥10 and < 3 have excellent sensitivity/specificity for MSI/MMRd, intermediate scores of 3-10 are of unknown clinical significance, and may include patients with MSI-like genomic signatures who would be overlooked by historical assays. Methods: MSIsensor testing was performed on primary or metastatic tumor specimens from 2,371 patients with breast cancer. Scores of 3-10 were considered MSI-Indeterminate (MSI-I). Concurrent somatic mutations were determined using the MSK-IMPACT assay. Results: Of the 2,371 patients tested, 147 were found to have MSI-I tumors. Ninety-nine (67.3%) were metastatic specimens, and 48 (32.7%) were primary specimens. Of the MSI-I patients, 64 (43.5%) were estrogen receptor positive, 57 (38.8%) were triple negative, and 24 (16.3%) were HER-2 amplified. Somatic TP53 mutations were detected in 109 (74.1%) MSI-I patients, including 54 (94.7%) triple negative patients. Fourteen MSI-I patients were found to have somatic mutations in MMR genes ( MLH1, MSH2, MSH6, PMS2 or EPCAM), but no germline mutations were found. Of the 99 patients with MSI-I metastatic disease, 15 received ICB as part of their clinical care, exhibiting a median progression-free-survival (PFS) of 3 months. Of the 4 patients who demonstrated a PFS of > 6 months on ICB, 2 were found to have somatic mutations in MMR genes. Conclusions: We introduce a subpopulation of breast cancer patients whose tumors exhibit genomic signs of microsatellite instability without meeting the classic criteria for MSI/MMRd as previously defined in colon and endometrial cancers. A subset of these patients may exhibit the properties of MSI/MMRd at the epigenetic and protein-expression levels, and thus potentially benefit from ICB.
Gaps in metastatic breast cancer patient knowledge and understanding in Mexico.
Authors: Villarreal-Garza Cynthia , Fonseca Alan , Pineda Claudia , Platas Ana , Rivera Fernanda , Mesa-Chavez Fernanda , García-García Marisol , Jasqui Ariel , de la Rosa-Pacheco Sylvia , Platas Alejandra
Published: May 2019

1090

Background: Among patients with metastatic breast cancer (MBC), there is paucity of data regarding knowledge and understanding about disease stage and goals of treatment. The limited evidence shows that up to 40% of MBC patients ignore their stage and reports inadequate educational resources and support. Aim: To assess MBC patients’ knowledge of their disease and satisfaction with the medical information received. Methods: 185 patients diagnosed with MBC who attended follow-up medical appointments at INCan from June to December 2018 were asked to complete a survey to assess their knowledge on MBC curability, subtype, topics reviewed with the oncologist, need of additional information regarding MBC and satisfaction with the quality of the information they received. Clinical data was obtained from the medical records. Descriptive statistics were applied, and the association between qualitative and quantitative variables was assessed with the Chi square test and the Mann Whitney U test, respectively. This study was supported by the SPARC mBC Challenge. Results: Only 52% of patients knew that their disease is not curable, while 31% were not sure and 17% thought it was curable. 82% ignored their MBC subtype and 81% reported to want more information about their cancer. 64% scored their satisfaction with the provided information ≥9 (out of 10), and 74% stated that their most helpful source of information was the medical staff. A statistically significant association was found between the perception of the impossibility of curing MBC and better patient satisfaction (p = 0.038). Likewise, better patients’ satisfaction was associated with older age (p = 0.002), longer time since initial diagnosis (p = 0.018) and since diagnosis of MBC (p = 0.014). Conclusions: Our results dramatically illustrate the lack of understanding patients have regarding their cancer, even when reporting high satisfaction with the received information, and identify a critical need for improvement of healthcare providers’ communication skills. Directed efforts should be implemented to enhance patients’ comprehension to promote their participation in decision-making processes, adherence and, ultimately, outcomes.
TAKTIC: A prospective, multicenter, uncontrolled, phase IB/II study of LY2780301 (LY) in combination with weekly paclitaxel (wP) in HER2-negative locally advanced (LA) or metastatic breast cancer (MBC) patients.
Authors: Vicier Cecile , Isambert Nicolas , Dalenc Florence , Campone Mario , Levy Christelle , Rezai Keyvan , Provansal Magali , Adelaide José , Garnier Séverine , Guille Arnaud , Chaffanet Max , Popovici Cornel , Charafe-Jauffret Emmanuelle , Pakradouni Jihane , Autret Aurelie , Goncalves Anthony
Published: May 2019

1091

Background: Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-pathway is frequently activated in HER2-negative breast cancer and may play a role in taxane-resistance. LY is a dual inhibitor of p70 S6 kinase and AKT. TAKTIC study aimed to determine the recommended phase II dose (RP2D) of the combination of LY with wP (phase Ib) and to estimate overall response rate (ORR) of this regimen (phase II) in HER2-negative LA or MBC patients, both in the overall patient population and in patients with activation of PI3K/AKT pathway (PI3KAKT+). Methods: HER2-negative inoperable LA or MBC patients (pts), with (phase Ib) or without (phase II) previous cytotoxic treatment for advanced disease were eligible. Oral LY (400 or 500mg) was administered daily in combination with intravenous wP (70 or 80mg/m2). A modified CRM using an adaptive Bayesian model guided the dose escalation of both agents. PI3KAKT+ was defined as activating mutation of PIK3CA and/or AKT by targeted NGS or homozygous loss of PTEN by array comparative genomic hybridization (aCGH) or loss of PTEN by immunohistochemistry, as evaluated on available fresh tumor tissue. Results: A total of 12 and 35 patients (pts) were included in the phase Ib and II, respectively. In phase Ib, only 1 dose-limiting toxicity (confusion) was observed at the last dose level (LY, 500 + wP, 80), which was determined as RP2D. Main drug-related adverse events (AE) in phase Ib were skin toxicity (92% of pts, G3-4 in 33%), and paresthesia (50% of pts, G3-4 in 8%). In the phase II study, ORR was 62.9 % [44.9,78.5] including 1 CR and 21 PR in the overall population and 55.6 % [30.8,78.5] in PI3KAKT+ pts (10 PR in 18 pts). Median progression-free survival was 12.4 months [7.9,17.9] and 6-month clinical benefit rate was 82.9% [66.4,93.4]. AEs in phase II were similar to phase I part, except that 17% of pts experienced pneumonia (G3-4 in 9%). Conclusions: Combining LY and wP in HER2-negative LA or MBC was feasible with preliminary evidences of efficacy, independently of PI3K/AKT activation. Clinical trial information: NCT01980277.
Development and validation of novel microenvironment-based immune molecular subtypes of breast cancer: Implications for immunotherapy.
Authors: Yu Yunfang , Zhang Wenda , Ou Qiyun , Li Anlin , Chen Yongjian , Wang Ying , Zhao Jianli , Tan Yujie , Yao Herui
Published: May 2019

1094

Background: Breast cancer treatment with immunotherapy can improve clinical benefits, but the majority of patients did not respond to the treatment. To understand tumor–immune interactions in breast cancer, we identified novel microenvironment-based immune molecular subtypes. Methods: A training cohort of 1,394 breast cancer patients from the Molecular Taxonomy of Breast Cancer International Consortium profiled by RNA and DNA sequencing data were analyzed to calculate immune-related gene biomarkers and to assign prognostic categories using LASSO Cox regression model. Additionally, 969 patients from The Cancer Genome Atlas data set was used as an independent validation cohort. We further compared tumor mutation burden (TMB) and cytolytic activity (CYT) levels between different immune molecular subtypes. Results: Using the LASSO model, we established an immune molecular classifier based on following 5 features: IFN-γ signature, ICOSLG, TNFRSF14, Mast.cells.resting, and T.cells. CD4.memory.resting. Then we found that it contained two distinct microenvironment-based subtypes (immune class and non-immune class), characterized by significant differences in overall survival in the training cohort (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.61 to 0.81; P < 0.001) and in the validation cohort (HR 0.34; 95% CI 0.22 to 0.54; P < 0.001). We found an inverse association between immune gene expression and TMB levels (ρ = 0.096, P < 0.001). Immune class subtype patients with good prognosis had significantly lower TMB and higher CYT than did non-immune class subtype patients with poor prognosis (all, P < 0.05). The clinical use of the immune molecular subtypes showed a closer association with survival than did IFN-γ signature or PD-L1 expression (all, P < 0.05). The robustness of the immune molecular subtypes was confirmed in the validation cohort. Conclusions: We revealed novel immune molecular subtypes, which represented better utility in predicting breast cancer patients’ survival compared with IFN-γ signature or PD-L1, and could be an important guide for precision immunotherapy.
Clinical characteristics and outcome of metaplastic breast cancer: A retrospective tertiary care center experience.
Authors: Thapa Bicky , Arobelidze Salome , Jia Xuefei , Awada Hassan , Kewan Tariq Zuheir , Covut Fahrettin , Patel Mita , Daw Hamed , Spiro Timothy Peter , Haddad Abdo S.
Published: May 2019

1095

Background: Metaplastic breast cancer (MBC) is a rare neoplasm which accounts for less than 1% of all breast cancers. MBC is associated with worse prognosis and there is a paucity of literature on management. We evaluated the clinical characteristic and outcomes of MBC patients at our institution. Methods: After IRB approval, 136 patients diagnosed with MBC were reviewed from the Cleveland Clinic tumor registry from 2000-2017. Patients were evaluated for overall survival (OS) and progression free survival (PFS) using univariable analysis. Time to event variables were estimated by Kaplan-Meier method. Results: A total of 136 pathologically proven MBC patients were included in the study. Median age at diagnosis was 60 years (27-92). Eighty two percent (n = 112) had nuclear grade III, 7% (n = 10) had high grade dysplasia, 2% (n = 3) had nuclear grade I, and 4% (n = 5) had nuclear grade II; 60% (n = 82) patients were diagnosed at stage II, 21% (n = 28) at stage I, 14% (n = 19) at stage III, and 5% (n = 7) at stage IV. Estrogen receptor, progesterone receptor and Her2 expression were positive in 16% (n = 22), 9% (n = 12), and 10% (n = 14) respectively. Only 37% (n = 50) patient had lumpectomy, 18% (n = 25) received hormonal therapy, 56% (n = 76) received radiation, 51% (n = 70) received anthracycline chemotherapy and 26% (n = 36) received non-anthracycline chemotherapy; 37% (n = 50) had chemotherapy after 4 weeks of surgery and 35% (n = 48) patients had chemotherapy within 4 weeks of surgery. On univariable analysis, the 5-year OS for stage III was 30% (14% - 64%), hazard ration (HR) of 4.53 (95% CI, 1.71 - 12.01) (p = 0.002), for stage IV HR of 43.26 (95% CI, 12.34 - 151.64) (p = 0.001); chemotherapy within 4 weeks of surgery was associated with a higher risk of death, HR of 0.30 (95% CI, 0.12 - 0.74) (p = 0.009). Hormonal therapy, radiation therapy, surgery and type of chemotherapy was not associated with significant change in OS and PFS. In our cohort, 2-year OS was 79 % (73 % - 87 %) and 5-year OS was 69 % (61 % - 77 %); 2-year PFS was 61 % (52 % - 70 %) and 5-year PFS was 72 % (65 % - 81 %). Conclusions: Stage of MBC and chemotherapy within 4 weeks of surgery was associated with statistically significant OS and PFS on univariable analysis. Randomized clinical trials are warranted to improve outcomes in MBC patients.
Effect of germline ATM mutations on clonal hematopoiesis.
Authors: Slavin Thomas Paul , Tsang Kar Wing Kevin , Longmate Jeffrey , Castillo Danielle , Herzog Josef , Qin Hanjun , Wang Jinhui , Neuhausen Susan L. , Mejia Rosa , King Elisabeth , Telatar Milhan , Marcum Catherine A , Hendricks Carolyn B. , Hake Christopher R. , Seewaldt Victoria Louise , Geradts Joseph , Stark Jeremy , Marcucci Guido , Weitzel Jeffrey N.
Published: May 2019

1509

Background: Clonal hematopoiesis (CH) in myeloid related-genes is associated with development of primary and secondary leukemia and atherosclerotic disease, as well as, decreased overall survival. Identification of factors beyond age and cytotoxic exposures that predispose to CH may be useful to both recognize individuals at increased risk for CH and to better understand how CH develops. We have previously shown that germline mutations in the DNA repair gene ATM may predispose to CH. We hypothesized here that heterozygous ATM germline mutation carriers would have higher rates of CH in myeloid genes compared to controls. Methods: Germline DNA samples from 34 heterozygous ATM germline mutation carriers (cases) and 22 controls without ATM germline mutations were sequenced on an Illumina 2500 using a custom 79-gene-myeloid-CH-coding-exon-amplicon-based Qiaseq panel. Read depth averaged 130x. Pathogenic and likely pathogenic CH variants (PV) above an allele fraction of 2% were used for analyses. Cases and controls were compared using a rank-sum test. Results: Cases had a higher median age (56 years, range 30-82) than controls (48 years, range 5-72). Cases and controls were similar in solid tumor cancer history and known exposure to cancer cytotoxic therapy; 73.5% vs 86.4%, and 18.1 vs 20.6%, respectively. The number of CH PV was similarly associated with age in both cases and controls (cor = 0.31, p = 0.01). Cases displayed more CH PVs than controls (total 62 vs 3 PVs, median 2 PVs vs 0, p = 10-6). Of note, cases frequently had a concomitant second (n = 10; 29% of cases) or third (n = 4; 11.8% of cases) unique ATM CH PV, whereas no ATM CH PVs were seen in controls. Even after excluding ATM CH PVs, CH PVs were more frequent in cases (p = 0.00003). After ATM CH PVs, the most frequent CH PVs in cases were in NF1 (5 PVs), BCORL1 (4 PVs), and DMNT3A (4 PVs). Conclusions: Our study supports ATM as a strong predisposition locus for myeloid gene CH. CH in ATM germline mutation carriers frequently involved unique low allele fraction PVs in ATM, suggesting ATM germline PVs are driving production of likely bi-allelic ATM inactivation in white blood cells, or complete ATM loss. Complete ATM loss may be a nidus particularly for lymphocytic leukemia, as bi-allelic ATM inactivation is a frequent somatic finding.
Prevalence and penetrance of breast cancer-associated mutations identified by multiple-gene sequencing in the Women’s Health Initiative.
Authors: Kurian Allison W. , Hughes Elisha , Bernhisel Ryan , Larson Katie , Caswell-Jin Jennifer Lee , Shadyab Aladdin H. , Ochs-Balcom Heather , Pan Kathy , Qi Lihong , Reding Kerryn , Hartman Anne-Renee , Lancaster Johnathan M. , Tang Jean Y. , Stefanick Marcia L.
Published: May 2019

1513

Background: Next-generation sequencing enables rapid analysis of many inherited cancer susceptibility genes. Little is known about the prevalence and penetrance of pathogenic variants (PVs) in such genes among post-menopausal women with breast cancer, who comprise the majority of all breast cancer patients. Methods: The Women’s Health Initiative enrolled post-menopausal women from 1993-1998. We conducted a nested case-control study using banked DNA samples of 2,195 women who subsequently developed invasive breast cancer (cases) and 2,322 cancer-free controls. Sequenced genes were APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A (p16INK4a and p14ARF) , CHEK2, EPCAM, GREM1, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, POLD1, POLE, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53. PV were defined using American College of Medical Genetics criteria. PV prevalence is reported as proportions and penetrance as the odds ratio (OR) and 95% confidence interval (CI) of PV versus none among cases versus controls. Results: Among cases, the median age at diagnosis was 73 years; 66% were White, 18% Black, 6% Hispanic, 6% Asian and 4% other. The prevalence of PVs in any gene was significantly higher in cases (6.61%, 95% CI 5.57-7.65%) versus controls (4.09%, 95% CI 3.29-4.90%). The prevalence of BRCA1/2 PVs was 1.2% in cases and 0.22% in controls. Among cases, the prevalence of PVs in other breast cancer-risk genes was 2.3% ( ATM, CDH1, BARD1, BRIP1, CHEK2, NBN, and PALB2 collectively), two-fold higher than PVs in BRCA1/2. Prevalence of BRCA1/2 PVs decreased with age among cases, while prevalence of ATM, CHEK2 and PALB2 PVs did not. Statistically significant ORs for breast cancer penetrance were observed for BRCA1 (5.43, 95% CI 1.19-51.52), BRCA2 (4.71, 95% CI 1.84-15.08), BARD1 (9.78, 95% CI 1.04-1295.87) and PALB2 (6.30, 95% CI 1.93-31.94). Conclusions: Approximately 7% of women diagnosed with post-menopausal breast cancer carry a PV in a cancer susceptibility gene. In contrast to studies of younger breast cancer patients, PVs in other breast cancer-related genes were two times more common than in BRCA1/2. Results may guide genetic testing of women with post-menopausal breast cancer.
Genome-wide association study using whole-genome sequencing to identify a novel locus associated with cardiomyopathy risk in adult survivors of childhood cancer: Utility of a two-stage analytic approach.
Authors: Sapkota Yadav , Liu Qi , Shelton Kyla C. , Wang Xuexia , Wilson Carmen Louise , Wang Zhaoming , Mulrooney Daniel A. , Jefferies John L , Oeffinger Kevin C. , Morton Lindsay M. , Zhang Jinghui , Armstrong Gregory T. , Bhatia Smita , Hudson Melissa M. , Robison Leslie L. , Yasui Yutaka
Published: May 2019

1516

Background: Survivors of childhood cancer are at increased risk of treatment-related cardiomyopathy, found to be modified by genetic factors. To further investigate genetic risks of cardiomyopathy, we utilized whole-genome sequencing (WGS) in a clinically phenotyped cohort of long-term survivors of pediatric cancer. Methods: Utilizing a novel 2-stage analytic approach, we first performed association analysis for ejection fraction (EF) using WGS data in European-descent childhood cancer survivors from the St. Jude Lifetime Cohort (SJLIFE). EF was analyzed as a continuous variable to increase statistical power for genetic discovery. Common variants (minor allele frequency (MAF) > 0.05) were analyzed using linear regression, adjusting for age at diagnosis, sex, age at follow-up, doses of anthracycline and average radiation dose to the heart, and eigenvectors. Rare/low-frequency variants were aggregated by different functional annotations and agnostic 4-kb sliding windows, testing jointly using Burden/SKAT test. In the second stage, only the variant showing genome-wide significance with EF was tested for its association with cardiomyopathy risk. Results: Among the 2,015 SJLIFE survivors with WGS data, a locus on 6p21.2 near KCNK17achieved genome-wide significance with EF (rs2815063; MAF = 0.13; per allele beta = -0.016; P = 2.10´10-8), which replicated in 320 SJLIFE African survivors (MAF = 0.48; beta = -0.015; P = 0.004). In SJLIFE Europeans, 282 had a CTCAE Grade 2-5 cardiomyopathy. rs2815063 was significantly associated with increased risk of cardiomyopathy [per allele odds ratio (OR) = 1.38; P = 0.02], which replicated in 3,957 European survivors from the Childhood Cancer Survivor Study (163 CTCAE Grade 3-5 self-reported cases; per allele OR = 1.39; P = 0.038). rs2815063 alters DNA binding motif of EWSR1-FLI1, whose expression was found to lead to cardiomyopathy and death due to chronic cardiac failure in mice. Conclusions: Using a 2-stage approach, we report a novel locus for cardiomyopathy in childhood cancer survivors, which warrants additional work to gain mechanistic insights.
Preimplantation genetic diagnosis: What do BRCA mutation carriers think?
Authors: Khouri Olivia R , Gerber Deanna , Smith Julia Anne , Boyd Leslie R.
Published: May 2019

1526

Background: The use of pre-implantation genetic diagnosis (PGD) to select against BRCA mutated embryos for in-vitro fertilization (IVF), introduces complex choices for patients with pathogenic BRCA mutations. We sought to describe the uptake of and attitudes toward this technology in this patient population. Methods: We conducted a prospective survey study at a single institution in New York City affiliated with both a Cancer Center and Fertility Center, to assess attitudes and utilization of PGD. Cancer Center staff distributed surveys to patients with known BRCA mutations between April and August 2018. Survey participation was voluntary and anonymous. Survey data were analyzed using descriptive statistics and two-tailed t tests. Results: 80 survey responses were collected. A majority of the patient population identified as Caucasian (87.5%, 70) and Jewish (52.5%, 42). The survey was distributed to all age groups; however 81% (65) were between 26 and 45 years of age. 63.8% (51) had heard of PGD prior to completing the survey, while 36.3% (29) had not. Only 40% of respondents (32) felt sufficiently educated regarding PGD. 35% (28) patients met with an REI, of whom 6.3% (5) utilized IVF with PGD, and 21.3% (17) plan to use IVF with PGD in the future. 11.3% (9) wish they had known about this technology prior to starting a family, 20% (16) would not have used PGD had they known about it prior to childbearing. Reasons respondents were unlikely to pursue PGD included: cost (38.8%, 31), completed childbearing (25%, 20), medical risk (18.8%, 15), and ethical concerns (16.2%, 13). Patients gave cost estimates for PGD ranging from $500 - $120,000. There was no statistically significant correlation between likelihood of pursuing PGD and parity (p = 0.45), religion (p = 0.78), education level (p = 0.13), number of family members affected by BRCA mutations (p = 0.20) or by cancer (p = 0.11). Conclusions: Overall, a small number of patients with pathogenic BRCA mutations utilize PGD. A minority of survey respondents felt adequately educated about PGD. Reported barriers to uptake were varied, and there was a wide range of cost estimates reported. Our results suggest that increased patient education regarding PGD in BRCA mutation carriers is warranted.