bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of BRCA alteration (alt) type with real-world (RW) outcomes to PARP inhibitors (PARPi) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Antonarakis Emmanuel S. , Madison Russell , Snider Jeremy , Snow Tamara , Sokol Ethan , Chung Jon , McCusker Margaret Elizabeth , Singal Gaurav , Alexander Brian Michael , Castellanos Emily , Venstrom Jeffrey , Schrock Alexa Betzig , Ross Jeffrey S.
Published: May 2020

5527

Background: Inactivating alts in BRCA1/2 result in homologous recombination deficiency and are predictive of PARPi response in mCRPC. BRCA reversion mutations, which restore the protein function, are frequently observed in acquired resistance to PARPi. In tumors harboring homozygous gene deletions ( BRCAdel) reversions cannot develop; thus, we hypothesize that BRCAdel pts may have prolonged benefit from PARPi compared to pts harboring other BRCA alterations. Methods: Pts were included from the Flatiron Health (FH)-Foundation Medicine (FMI) de-identified clinico-genomic database (CGDB). Inclusion criteria were diagnosis of mCRPC, treatment in the FH network and an FMI comprehensive genomic profiling result between 1/1/2011 - 9/30/2019. Time to therapy discontinuation (TTD) and overall survival (OS) from start of PARPi were estimated with Kaplan-Meier analysis and unadjusted/adjusted (age at PARPi initiation, line number, practice type) hazard ratios (HR/aHR) from Cox proportional hazards models adjusted for survival bias. Results: Out of 829 mCRPC cases, BRCA1/2 alts were detected in 15 (1.8%) and 71 (8.6%) respectively, with 2 cases included in both groups. 26% of BRCAalts were BRCAdel, 67% were coding mutations, and 7% were genomic rearrangements. 25 (28%) BRCAalt pts were treated with PARPi, 11/25 in the 1st or 2nd line setting including 43% of BRCAdel and 44% of other BRCAalt cohorts. Median age at PARPi initiation was 70 yrs and 88% were treated in community practices. TTD was significantly longer in the BRCAdel (n = 7) cohort vs. other BRCAalt cohort (n = 18) (22.7 vs. 9.2 months; HR: 0.16 [0.03-0.74]; aHR: 0.13 [0.02 – 0.92]) while a statistically nonsignificant difference in median OS was observed (31.5 vs. 11.9 months; HR: 0.20 [0.02-1.58]; aHR: 0.24 [0.02-3.15]). In comparison, no statistically significant difference in TTD was observed for BRCAdel (n= 7) vs. other BRCAalts (n=19) pts treated with 1st line hormonal therapies (abiraterone or enzalutamide) (3.4 vs. 5.7 months; HR: 1.16 [0.45-2.98]; aHR: 0.72 [0.25-2.10]). Follow up analysis with more pts and somatic/germline status and zygosity of BRCAalts will be presented. Conclusions: These data suggest a differential benefit from PARPi therapy across BRCAalt subgroups. This observation may in part be explained by the inability to develop reversion mutations to restore BRCA function in tumors with BRCAdel. Further studies are warranted to fully assess the association of BRCAalt type with outcomes to PARPi-based treatments.
Contrasting genomic profiles in post-systemic treatment metastatic sites (MET), pretreatment primary tumors (PT), and liquid biopsies (LB) of clinically advanced prostate cancer (PC).
Authors: Necchi Andrea , Grivas Petros , Bratslavsky Gennady , Shapiro Oleg , Jacob Joseph M , Sokol Ethan , Killian Jonathan Keith , Lin Douglas I. , Ramkissoon Shakti H. , Severson Eric Allan , Huang Richard , Alexander Brian Michael , Venstrom Jeffrey , Reddy Venkataprasanth P. , McGregor Kimberly , Elvin Julia Andrea , Schrock Alexa Betzig , Pavlick Dean , Danziger Natalie , Ross Jeffrey S.
Published: May 2020

5534

Background: Comprehensive genomic profiling (CGP) was done on pre-systemic treatment (pre) PT, post-treatment (post) MET sites and LB in PC to uncover differences in genomic alterations (GA) and potential impact on therapy selection. Methods: 1,294 PC tissues and 782 LB underwent hybrid-capture based CGP. PT biopsies and resections were compared with post-treatment MET biopsies from bone (BO), liver (LIV), lung (LU), brain (BN), lymph node (LN) and soft tissue (ST) sites and LB. TMB was determined on up to 1.1 Mbp of sequenced DNA for tumor samples. Tumor cell PD-L1 IHC was measured (Dako 22C3). Results: Differences in alteration frequencies between PT, MET and LB for selected genes are shown in the Table. TMPRSS2:ERG fusion frequencies were similar between PT and MET (35% vs 33%) but varied between MET sites (27% in BO and ST to 40% in LN). GA in AR were lowest in pre PT (2%) and highest in MET (24% in LU to 50% in LIV). BN had the highest GA/tumor (8) and the most PTEN GA. BRCA2 GA frequency varied from 0% in BN to 15% in LI. Potential predictors of IO response included CDK12 GA (16% in LU) and MSI high status (29% in BN). High PD-L1 expression was found in only two cases (LN) and low PD-L1 expression was relatively uncommon. ERBB2 amplifications were increased in MET compared with PT. RB1 GA were increased in LIV cases. LB GA had a similar increase in AR and TP53 GA to MET and appeared to be a blend of MET site biopsies across alteration frequencies. Conclusions: CGP of PT, MET and LB in PC demonstrates differences most likely associated with exposure to systemic therapies. Differences identified in the MET GA landscape suggest that liquid biopsies may capture a broader range of therapeutic opportunities for PC patients. [Table: see text]
Somatic and germline mutation profiles of Chinese breast cancer patients younger than 35.
Authors: Liao Ning , Zhang Guo-Chun , Chen Xiaoqing , Xiao Weikai , Lai Jianguo , Wang Yulei , Chen Bo , Ren Chong-Yang , Li XueRui , Li Kai , Wen Ling-Zhu , Cao Li , Jia Minghan , Wei Guangnan , Lin Jiali , Li Min , Lizaso Analyn , Han-Zhang Han , Liu Hao , Liu Jing
Published: May 2020

554

Background: Limited studies have investigated the molecular underpinnings driving breast cancer development in Chinese younger women. Based from our previous data, more Chinese women are diagnosed with early-onset breast cancer than in the West. In our study, we aim to investigate the comprehensive mutational profile of Chinese women 35 years old and younger (≤35y) diagnosed with breast cancer. Methods: Targeted sequencing was performed on surgically-removed tumor tissues and blood samples collected from 589 women diagnosed with stage I-III breast cancer of various molecular subtypes at the Guangdong Provincial People’s Hospital (GPDH) using a gene panel interrogating 520 cancer-related genes. We compared the data of 53 women aged ≤35y from our cohort to the data from 33 breast cancer patients aged ≤35y included in The Cancer Genome Atlas (TCGA) dataset. Results: Among the women aged ≤35y with early-stage breast cancer from both cohorts, our cohort had more number of hormone receptor-positive (HR+) patients (GPDH, 72% vs. TCGA, 61%, P< 0.001). Analysis revealed an overall mutation detection rate of 98% in our cohort, with mutations affecting genes involved in the PI3K pathway (47%) and cell cycle pathway (23%). TP53 and PIK3CA were the most commonly mutated genes, with mutation rates of 51% and 25% from our cohort. No statistical difference in mutation profile was found between GPDH and TCGA cohorts. Moreover, germline mutations considered as pathogenic and likely pathogenic (P/LP) in breast cancer susceptibility genes including BRCA1 (n = 4), BRCA2 (n = 2), PALB2 (n = 1), PMS2 (n = 1), PTEN (n = 1), and ATM (n = 1) were detected from 18.9% (10/53) of the patients from our cohort. Women aged ≤35y had significantly more germline BRCA1 mutations than patients > 35y from our cohort (7.5%, 4/53 vs. 2.1%, 11/536 P= 0.049). Conclusions: Our study has identified the involvement of PI3K and cell cycle as the two key pathways in the early development of breast tumors in younger women. In addition, our results also support the role of P/LP germline mutations in breast oncogenesis in Chinese patients with early-onset breast cancer, indicating the need to include a more comprehensive germline mutation screening in our population.
Safety and overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 (Ra-223) plus subsequent taxane therapy.
Authors: Higano Celestia S. , Harshman Lauren C , Dizdarevic Sabina , Logue John , Richardson Timothy , George Saby , Song Danny , de Jong Igle J. , Tomaszewski Jeffrey , Saad Fred , Miller Kurt , Meltzer Jeffrey , Sandstrom Per , Tombal Bertrand F. , Sartor A. Oliver
Published: May 2020

5542

Background: Ra-223, a targeted alpha therapy, showed a survival benefit and favorable safety profile over 3 years’ (yrs) follow-up in mCRPC pts (ALSYMPCA trial). REASSURE (NCT02141438) is a global, prospective, single-arm, observational study of long-term Ra-223 safety in routine clinical practice in mCRPC pts (planned 7-yr follow-up). Methods: This analysis, based on the second prespecified interim analysis (data cutoff 3-20-2019) of REASSURE (N = 1465), evaluated safety/OS in the pt subset that was chemotherapy-naïve at Ra-223 administration but received subsequent taxane therapy any time after Ra-223 completion. Results: 182 pts received taxane therapy after Ra-223. Most (58%) had unresected primary tumors, 69% had ≥6 metastases, 99% received prior systemic anticancer therapy (Table). 143 (79%) completed 5 or 6 Ra-223 injections. Subsequent anticancer therapies included docetaxel (95%), enzalutamide (25%), cabazitaxel (24%), abiraterone (12%), lutetium-177-prostate-specific membrane antigen (4%), and sipuleucel-T (1%). During/up to 30 days after taxane therapy, 15 pts (8%) had grade 3/4 hematologic adverse events: anemia (erythropenia) (n = 11, 6%), neutropenia (n = 3, 2%), and thrombocytopenia (n = 2, 1%). Median OS was 24.3 (95% CI: 20.9–27.5) months from Ra-223 initiation and 11.8 (95% CI: 10.6–14.1) months from subsequent taxane initiation. Conclusions: In this cohort where Ra-223 was integrated prior to taxane therapy, most pts received multiple subsequent anticancer therapies. It appears that sequencing of multiple treatment modalities with different mechanisms of action may contribute to improved OS. Taxane therapy in routine clinical practice in pts previously treated with Ra-223 had acceptable hematologic safety/tolerability profiles. Clinical trial information: NCT02141438 . [Table: see text]
Pembrolizumab (pembro) plus olaparib in patients (pts) with docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 cohort A efficacy, safety, and biomarker results.
Authors: Yu Evan Y. , Piulats Rodriguez Jose Maria M. , Gravis Gwenaelle , Laguerre Brigitte , Arranz Arija Jose Angel , Oudard Stephane , Fong Peter C.C. , Kolinsky Michael Paul , Augustin Marinela , Todenhöfer Tilman , Kam Audrey E. , Gurney Howard , Tafreshi Ali , Retz Margitta , Berry William R. , Mar Nataliya , Wu Haiyan , Qiu Ping , Schloss Charles , De Bono Johann S.
Published: May 2020

5544

Background: Pembro + olaparib has shown antitumor activity and acceptable safety in docetaxel-pretreated pts with mCRPC enrolled in cohort A of the phase I/II KEYNOTE-365 study (NCT02861573). Updated results with new biomarker data are reported. Methods: Pts with docetaxel-pretreated mCRPC who progressed within 6 mo of screening received pembro 200 mg IV Q3W + olaparib 400-mg capsule or 300-mg tablet PO BID. Pts might have received 1 other chemotherapy and ≤2 second-generation androgen-receptor targeted therapies. Primary end points: PSA response rate (decrease ≥50% from baseline, confirmed by a second value ≥3 wks later), ORR per RECIST v1.1, and safety. Key secondary end points: DCR, DOR, rPFS, and OS. Biospecimens (eg, blood, tissue) were collected for biomarker analysis (tissue PD-L1 expression, androgen receptor variant 7 [AR-v7] expression in circulating tumor cells [CTCs], and a T-cell–inflamed gene expression profile [GEP]). ctDNA was analyzed by Guardant Health 360 (GH360) and Omni (GH Omni) assays. FFPE tissue was analyzed by FoundationOne CDx (F1CDx) assay. Results: 84 of 87 enrolled pts were treated; 48/84 (57.1%) had measurable disease. Median (range) time from enrollment to data cutoff was 3.6 mo (0.0-29.2) for all pts and 26.7 mo (21.2-29.2) for 41 pts with ≥27 wks’ follow-up. Confirmed PSA response rate was 9% (95% CI, 3.5-16.8) in 82 pts with a baseline PSA assessment. Median time to PSA progression: 3.8 mo (95% CI, 2.9-4.4). In 24 pts with measurable disease and ≥27 wks’ follow-up, ORR was 8.3% (95% CI, 1.0-27.0; 2 PRs) and DCR ≥6 mo was 20.8% (95% CI, 7.1-42.2). Median (range) DOR was NR (12.0+ to 21.4+ mo); 2 pts had DOR ≥12 mo. In all pts, median rPFS was 4.3 mo (95% CI, 3.4-7.7) and median OS was 14.4 mo (95% CI, 8.1-18.5). Grade ≥3 TRAEs occurred in 29 pts (35%); 2 pts died of TRAEs (1 myocardial infarction, 1 unknown). Overall, 26% had PD-L1+ tumors (combined positive score ≥1). Of 31 pts with CTC data, 12.9% were AR-v7+. No BRCA1/2 mutation was detected by GH360 (n=42). Of 57 pts analyzed by GH Omni, 2 had BRCA2 mutations, 1 had a BRCA1 mutation, 4 had ATM mutations, 1 had a CHEK1 mutation, and 6 had CDK12 mutations. Of 49 pts analyzed by F1CDx, 4 had BRCA mutations; 1 pt had a copy number loss mutation not detected by ctDNA analysis. GEP was not associated with ORR or PSA response. Conclusions: Pembro + olaparib continued to show activity and acceptable safety in pts with docetaxel-pretreated mCRPC. A phase III study of this combination is ongoing (KEYLYNK-010, NCT03834519). Clinical trial information: NCT02861573 .
Pembrolizumab (pembro) plus enzalutamide (enza) in patients (pts) with abiraterone acetate (abi)-pretreated metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 cohort C efficacy, safety, and biomarker results.
Authors: Conter Henry Jacob , Shore Neal D. , Berry William R. , Fong Peter C.C. , Piulats Rodriguez Jose Maria M. , Appleman Leonard Joseph , Todenhöfer Tilman , Gravis Gwenaelle , Laguerre Brigitte , Gurney Howard , Retz Margitta , Romano Emanuela , Mourey Loic , De Bono Johann S. , Kam Audrey E. , Emmenegger Urban , Wu Haiyan , Qiu Ping , Schloss Charles , Yu Evan Y.
Published: May 2020

5545

Background: Pembro + enza (cohort C) has shown antitumor activity and acceptable safety in abi-pretreated pts with mCRPC in the phase I/II KEYNOTE-365 study (NCT02861573). Updated results with new biomarker data from cohort C are reported. Methods: Pts who became intolerant to or for whom ≥4 weeks of abi failed in the prechemotherapy mCRPC state and who progressed within 6 mo of screening were enrolled. Pts received pembro 200 mg IV Q3W + enza 160 mg/day orally. Primary end points were PSA response rate (PSA decrease ≥50%; confirmed by a second value ≥3 weeks later), ORR per RECIST v1.1 by blinded independent central review, and safety. Key secondary end points were DCR per RECIST v1.1 (CR+PR+SD or non-CR/non-PD ≥6 mo), DOR per RECIST v1.1, radiographic PFS (rPFS) per PCWG-modified RECIST v1.1, and OS. Biospecimens (eg, blood, tissue) were collected at baseline and during the study for biomarker analysis, including tissue PD-L1 expression, androgen receptor variant 7 (AR-v7) expression in circulating tumor cells (CTCs), and a T-cell-inflamed gene expression profile (GEP). Results: Of 103 enrolled pts, 102 were treated; 39% of treated pts had measurable disease. Median (range) time from enrollment to data cutoff was 19.1 mo (1.1-28.8) for all pts and 21.4 mo (15.1-28.8) for pts with ≥27 wks’ follow-up (n=69). Confirmed PSA response rate was 22% in 101 pts with a baseline PSA assessment. Median time to PSA progression was 3.5 mo (95% CI, 2.9-4.0). In pts with measurable disease and ≥27 wks’ follow-up (n=25), confirmed ORR was 12% (2 CRs, 1 PR) and DCR was 32%. Median DOR was not reached (range, 0.0+ to 24.4+ mo); 2 pts had a response for ≥6 mo. In all pts, median (95% CI) rPFS was 6.1 mo (4.4-6.5) and median OS was 20.4 mo (15.5-NR). At 6 mo, rPFS rate was 55.1% and OS rate was 88.2%. Treatment-related AEs occurred in 92 pts (90%); most frequent (≥20%) were fatigue (38%), nausea (22%), and rash (20%). Grade 3-5 treatment-related AEs occurred in 40 pts (39%). Three pts died of AEs (1 AE was treatment related [cause unknown]). Of all pts, 29% had PD-L1+ tumors (combined positive score ≥1). Of 51 pts with AR-v7 data, 13.7% were AR-v7+ and 86.3% were AR-v7−. GEP was not significantly associated with ORR or PSA response. Conclusions: Pembro + enza continued to show activity in pts with abi-pretreated mCRPC. Safety of the combination was consistent with the known profiles of pembro and enza. A phase III study of this combination is ongoing (KEYNOTE-641, NCT03834493). Clinical trial information: NCT02861573 .
Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: Results of cohort 6 of the COSMIC-021 study.
Authors: Agarwal Neeraj , Loriot Yohann , McGregor Bradley Alexander , Dreicer Robert , Dorff Tanya B. , Maughan Benjamin Louis , Kelly William Kevin , Pagliaro Lance C. , Srinivas Sandy , Squillante Christian Michael , Vaishampayan Ulka N. , Wang Evelyn W. , Curran Dominic , Choueiri Toni K. , Pal Sumanta K.
Published: May 2020

5564

Background: Cabozantinib (C) may enhance response to immune checkpoint inhibitors (ICIs) by promoting an immune-permissive microenvironment and has shown encouraging activity in combination with ICIs in tumor types including RCC and HCC. C and atezolizumab (A) have shown low objective response rates as monotherapy in metastatic castration-resistant prostate cancer (mCRPC) (Smith JCO 2012; Kim JCO 2018). COSMIC-021 (NCT03170960), a multinational phase 1b study, is evaluating the combination of C + A in various solid tumors. We report results for Cohort 6 in mCRPC. Methods: Eligible patients (pts) were required to have radiographic progression in soft tissue after enzalutamide and/or abiraterone, measurable disease, and an ECOG PS of 0 or 1. Prior chemotherapy for mCSPC was permitted. Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for the first year and Q12W thereafter. The primary endpoint is ORR per RECIST 1.1. Other endpoints include safety, ORR per irRECIST, duration of response (DOR), PFS, and OS. Results are presented for the first 44 pts enrolled. Results: Median follow-up as of Dec 20, 2019 was 12.6 mo (range 5, 20) for the 44 mCRPC pts. Median age was 70 y (range 49, 90), 50% had ECOG PS 1, 34% had visceral metastases, and 61% had extrapelvic lymph node metastases. 27% had prior docetaxel and 52% had 2 prior novel hormonal therapies. The most common any grade treatment-related adverse events (TRAEs) were fatigue (50%), nausea (43%), decreased appetite (39%), diarrhea (39%), dysgeusia (34%), and PPE (32%). One grade 5 TRAE of dehydration was reported in a 90 y/o. Median duration of treatment was 6.3 mo. ORR per RECIST 1.1 among all 44 pts was 32% (2 CRs [4.5%] and 12 PRs [27%]); 21 (48%) pts had SD resulting in a disease control rate of 80% in all pts. One pt with PD per RECIST 1.1 had an irPR per irRECIST. ORR per RECIST 1.1 was 33% in 36 pts with high-risk disease (visceral and/or extrapelvic lymph node metastases). Median DOR for all pts with response per RECIST 1.1 was 8.3 mo (range 2.8, 9.8+). 17 (50%) of 34 pts with post-baseline PSA evaluation had a decrease in PSA. In 12 responders with post-baseline PSA evaluation, 8 (67%) had a PSA decrease ≥50%. Tumor PD-L1 expression will also be reported. Conclusions: The combination of C + A had a tolerable safety profile and demonstrated clinically meaningful activity with durable responses in men with mCRPC. Given the encouraging activity in these pts, especially in those with high-risk disease, further evaluation of C + A in men with mCRPC is being pursued. Clinical trial information: NCT03170960 .
Oncological outcomes of 356 patients undergoing salvage focal ablative HIFU or cryotherapy following radiation failure.
Authors: Reddy Deepika , Shah Taimur T. , van Son Marieke , Guillaumier Stephanie , Hosking-Jervis Feargus , Dudderidge Tim , McCracken Stuart , Nigam Raj , Hindley Richard , McCartan Neil , Afzal Naveed , Lewi Henry , Persad Raj , Virdi Jaspal , Orczyk Clement , Moore Caroline , Arya Manit , Emberton Mark , Winkler Mathias , Ahmed Hashim Uddin
Published: May 2020

5582

Background: Patients that have previously failed radiotherapy for prostate cancer is usually limited to systemic therapy due to morbidity from salvage prostatectomy. We reviewed the outcomes following focal salvage ablative therapy with HIFU or cryotherapy within the UK’s HEAT and ICE registries. Methods: 356 consecutive patients underwent focal ablative treatment after initial radiation treatment failure (28/1/2004-1/10/2019, 194 (54.5%) underwent HIFU (posterior recurrence) and 162 (45.5%) underwent cryotherapy (mostly anterior or T3b). Primary outcome was failure-free survival (FFS) defined as no systemic therapy, whole-gland treatment, metastases or prostate cancer-specific death. Secondary outcomes were adverse events and overall survival. Results: Median (IQR) age was 69years (65-73) and PSA (IQR) was 4.0ng/ml (1-7-7.2). Overall median (IQR) follow-up was 41.3 months (21.4-58.5). Quadrant ablation was performed in 128 (36.0%), hemi-ablation performed in 64 (18.0%), hockey-stick in 5 (1.4%) and 159 (43.8%) had unknown ablative patterns. Due to histological or MRI proven recurrence/residual disease, 31 (8.7%) underwent further focal salvage re-treatment. FFS (95%CI) at 3 and 6 years were 81% (76-87%) and 75% (68-83%) respectively. Median (IQR) time to failure was 15.5 months (19.7). Overall survival (95%CI) at 3 and 6 years were 97% (95-100%) and 88% (81-96%) respectively. Prostate-specific mortality was 2.8%. Overall 3 (0.8%) patients were managed for fistula formation, 16 (4.5%) were treated for UTIs. Conclusions: Salvage focal ablative therapy for radio-recurrent prostate cancer is safe and provides good short to medium-term oncological control. The FORECAST study is awaited to further determine oncological outcomes in this cohort.
Impact of metastases directed radiation therapy on CDK4/6 inhibitors dose reduction and treatment discontinuation for metastatic HR+/HER2- breast cancer (MBC).
Authors: Meattini Icro , Scoccimarro Erika , Saieva Calogero , Desideri Isacco , Visani Luca , Dominici Luca , Cerbai Cecilia , Aquilano Michele , Ciccone Lucia Pia , Palmieri Valeria Emma , Scotti Vieri , Nori Jacopo , Bernini Marco , Orzalesi Lorenzo , Sanchez Luis , Dieci Maria Vittoria , Bianchi Simonetta , Livi Lorenzo
Published: May 2020

562

Background: Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) represent the standard I-II line for hormonal receptors positive/human epidermal growth factor receptor 2 negative metastatic breast cancer (MBC) patients. Metastases directed radiotherapy (RT) for these patients is commonly used with palliative or radical schedules during systemic treatment. Although encouraging preliminary results were published, there is still a lack of robust data on the safety concerning RT during CDK4/6i treatment. Methods: we analyzed at Our Institution 85 consecutive patients treated in I (n=47) and II line (n=38) for MBC with CDK4/6i between April 2017 and September 2019 (22 ribociclib, 63 palbociclib). Overall, 25 (29.4%) patients received metastases directed RT during CDK4/6i treatment, including 14 concomitant (16.5%) and 11 sequential (12.9%). Estimated CDK4/6i half-life is 26 and 30 hours for palbociclib and ribociclib, respectively. Five half-lives are required to reduce drug concentration by 95-97%; thus, we also analyzed CDK4/6i treatment as non-concomitant or sequential to RT. Main endpoints of our analysis were impact of RT on CDK4/6i dose reduction and discontinuation, overall adverse events rate (any grade and grade ≥2), and neutropenia grade ≥2 as per CTCAE scale version 5.0. Results: at a median follow up of 12 months (range 3-29), we observed a CDK4/6i dose reduction in 35 patients (41.2%) and 5 patients (5.9%) discontinued treatment due to adverse events; 82 patients (96.5%) experienced any grade of toxicity, 72 (84.7%) a grade ≥2 and 70 patients (82.4%) neutropenia grade ≥2. We did not observe significant difference in terms of CDK4/6i dose reduction or discontinuation, any grade or grade ≥2 toxicity, neutropenia grade ≥2 in the comparison between patients receiving RT versus no RT and between patients receiving concomitant RT versus sequential RT versus no-RT (Table). Conclusions: our results showed that the prescription of a metastases directed RT during treatment with a CDK4/6i as I-II line for MBC did not significantly impact on dose reduction or discontinuation caused by an exceeding in adverse event rate. Although these promising results, caution should be used and cooperative initiatives strongly encouraged. [Table: see text]
Breast cancer patient reported outcomes, depression, and objective measures of breast cosmesis.
Authors: McManus Shauna , Lin Jolinta Y , Bhave Manali A. , Brown Gabrielle , Green India , Yang Xiaofeng , Liu Tian , Miller Andrew H. , Torres Mylin Ann
Published: May 2020

569

Background: Patient-reported outcomes (PROs) of cosmesis after breast-conserving therapy (BCT) are increasingly emphasized as meaningful treatment endpoints but little is known about the relationship between objective measures, mood, and PROs following radiation (XRT). We hypothesized that pre-XRT depression, assessed by Inventory of Depressive Symptomatology Self-Report (IDS-SR), would influence PROs of breast cosmesis 1-year post-XRT independent of objective measures of breast asymmetry. Methods: 98 women were enrolled on two prospective longitudinal studies of breast cosmesis. Percentage breast retraction assessment (pBRA) was used as an objective measure of breast asymmetry pre- and 1 year post-XRT. At the same time points, pBRA was measured and compared with two different PRO ratings of cosmetic outcome (0-10 scale): 1) happiness with cosmesis and 2) perceived differences in treated vs. untreated breast. We performed univariate and multivariate analysis to evaluate the relationship between PROs, pBRA, IDS-SR scores, clinical, tumor, and treatment characteristics. Results: Among subjects, 50% were African American. Mean age was 56.45 years. At 1 year, 65.3% of patients were happy with their cosmetic outcome (Score > 8) although 59.5% noted moderate to severe differences in the treated vs. untreated breast (Score < 6). Mean pBRA increased from 7.20 (SD 3.88) pre-XRT to 9.69 (SD 6.22) confirming more breast asymmetry 1-year post-XRT. Prior to XRT, 23% of patients had moderate-to-severe depression (IDS-SR scores > 26). In multivariate analyses, 1 year PROs of happiness with cosmetic outcome did not correlate with pBRA (p = 0.3) but were strongly correlated with pre and post-XRT depression (all p < 0.05). Patients were more likely to perceive differences in breast texture or asymmetry (i.e. lower PRO ratings of asymmetry) if they had higher pBRA measurements at 1 year (all p = 0.004). Neither pre- nor post- XRT depression were associated with specific PRO ratings of breast asymmetry in multivariate analysis. Conclusions: Our study suggests that PROs may not always reflect the effects of cancer treatment. For patients treated with BCT, baseline depression strongly influenced patient reported happiness with overall cosmetic outcome 1 year post-XRT. Perceived differences in the treated vs. untreated breast correlated with objective measures of breast asymmetry. Our data suggests that this PRO may be more indicative of treatment-related toxicities than patient ratings of overall satisfaction and happiness with cosmetic outcome. Clinical trial information: NCT03167359 .
Predicting nodal positivity in women with hormone receptor-positive (HR+), early stage breast cancer (ESBC).
Authors: Ray Emily Miller , Strassle Paula D. , Gaber Charles E. , Muss Hyman B. , Downs-Canner Stephanie M.
Published: May 2020

574

Background: Omission of axillary surgery is appropriate in some patients with clinically node-negative (cN0), HR+ ESBC; however, there are no pre-operative tools to predict pathologic node positivity (pN+) in these women. We propose a clinically validated predictive model to inform treatment decisions regarding axillary evaluation. Methods: We constructed a cohort of adult women with ESBC (clinical T1/T2, N0, M0) diagnosed 2012-2016, who underwent lumpectomy or mastectomy and lymph node surgery without neoadjuvant therapy using the National Cancer Database breast cancer dataset. The dataset was non-randomly split into training (2012-2015) and testing (2016) for development and validation. Stepwise logistic regression was used to identify predictors of pathologic node positivity (pN0 vs pN+) in the training dataset. Potential predictors included: age, race, ethnicity, comorbidity score, histologic type, clinical T, ER positivity, PR positivity, HER2 positivity, and grade. Predictor variables required a bivariate p-value <0.30 to be entered into model, and an adjusted p-value <0.35 to stay in model. A partial score method was used to develop a lymph node prediction score (LNPS) by assigning a weighted value to each strong predictor variable (OR >1.5) and adding together the values for each included variable. LNPS was treated as a linear variable for prediction in validation dataset. Results: 423,068 women were included (2012-2015: 334,778; 2016: 88,290). Pathologic node positivity was 17% in 2012-2015 and 2016. All variables were included in the final stepwise model. Strong predictors were age, histologic type, clinical T, and grade. Scores ranged from 0-11. In the validation dataset, predicted pN+ by LNPS was very similar to actual pN+ (Table). A 1-point increase in LNPS was associated with a 3.3% increase in absolute risk of pN+. Conclusions: A novel lymph node prediction score can be used in HR+ cT1-T2 cN0 breast cancers to estimate the probability of pN+ and guide decisions regarding axillary surgical evaluation. [Table: see text]
Gls-010, a novel anti-PD-1 mAb in Chinese patients with recurrent or metastatic cervical cancer: Results from a multicenter, open-label and single-arm phase II trial.
Authors: Wu Xiaohua , Xia Lingfang , Zhou Qi , Zhu Jianqing , Wang Ke , Chen Jie , Huang Yi , Kurb Gulina , Chang Baoping , Zhao Weidong , Wang Xia , Yang Yingjie , Lin Zhongqiu , Luo Xiaoyong , Lou Ge , Wang Chunyan , Wang Jing , Meng Haijin
Published: May 2020

6032

Background: GLS-010 is a novel fully human anti-PD-1 mAb. Previous Phase I study exhibited favorable result of tolerance, preliminary efficacy and 240mg fixed dose q2w was selected as Recommended Phase II Dose (RP2D). This Phase II clinical trial is aimed to further evaluate the safety and anti-tumor activity of GLS-010 in patients with recurrent or metastatic cervical cancer. Methods: PD-L1 positive (combined positive score (CPS) ≥1) patients with recurrent or metastatic cervical cancer who had received one or more lines of chemotherapy were enrolled and received GLS-010 240mg every 2 weeks. Primary endpoint was the objective response rate (ORR) per RECIST 1.1, secondary endpoints included duration of response (DoR) and safety. Results: From May 16th 2019 to December 24th 2019, 44 pts were enrolled and treated in the study. As of December 24th 2019,the median line of prior systemic chemotherapy was 2(range: 1~4), and 59% (26/44) of pts had received ≥2 previous lines of chemotherapy. The median number of GLS-010 doses was 1.5(range: 1~4). 25 pts received response evaluation per investigator review. With a median follow-up of 2.9 months, 7 of 25 evaluable pts achieved a partial response (PR). The ORR was 28% (95% CI, 12.07-49.39), with 7 pts achieving a PR ( 3 of 7 confirmed), 3 pts achieving stable disease (SD) and 15 pts with progressive disease (PD), 1 of which was assessed as dissociated response with treatment ongoing. Median duration of response had not been reached yet. 33 of 44 patients (75%) experienced one or more treatment-related adverse events (TRAEs) per NCI CTCAE v4.03, most of which were grade 1 or 2. The most common TRAEs were Anaemia (15/44), and 73.3% of them were grade 1 or 2. The most common ≥grade 3 TRAE included Anaemia (4/44). As data cut off, only 1 pt discontinued treatment due to adverse event. Conclusions: GLS-010 showed impressive therapeutic activity and manageable safety profile in Chinese recurrent or metastatic cervical cancer patients. Current evidence support further development of GLS-010 in this and more indications. This trial is still ongoing, and we are looking forward to further results. Clinical trial information: NCT03972722.
Anlotinib in patients with recurrent advanced cervical cancer: A prospective single-arm, open-label, phase Ⅱ trial.
Authors: Wu Xiaohua , Zhu Jun
Published: May 2020

6034

Background: Anlotinib is a novel multi-target tyrosine kinase inhibitor that has previously shown clinical antitumor activity in various cancers, including the phase I study on female genital tumors. This phase II study (ChiCTR1800020116) aims to further evaluate the safety and efficacy of anlotinib, in those patients with recurrent advanced cervical cancer. Methods: Eligible patients were advanced cervical cancer who had received at least two previous lines of chemotherapy. Patients were given anlotinib (12 mg/day) from day 1 to day 14 in a 21-day cycle until disease progression or had unacceptable toxic effects. The primary endpoint of this study was objective response rate (ORR) and the secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: Between 2018 December and 2019 October, 41 patients (female) were enrolled. As of January 15, 2020, median follow-up duration, from randomization to data cutoff, was 2.6 months (range, 0.7-10.3). Therapeutic evaluation showed the ORR was 32.1% (95%CI, 13.7%-50.6%) and the median PFS was 3.9 months (95% CI, 1.3%-6.5%). The most frequently reported adverse events were lymphocyte count decreased, anemia, hand-foot syndrome, blood uric acid increased, blood creatinine increased, blood thyroid stimulating hormone increased. All frequently occurring AEs were grade 1 or 2. High grade AE was only observed in 1 patient with white blood cells urine positive of grade 3. Neither unexpected safety signals nor treatment related death occurred. Conclusions: Anlotinib showed a promising activity with an acceptable safety profile for patients with recurrent advanced cervical cancer. Clinical trial information: ChiCTR1800020116.
Low expression of gamma-glutamyl transpeptidase 1 is an independent poor prognostic factor in ovarian clear cell carcinoma, in relation to up-regulation of immune suppressive genes and EMT-related genes.
Authors: Asano Hiroshi , Matsuoka Ryosuke , Hatanaka Kanako C , Endo Daisuke , Nozaki Ayako , Ihira Kei , Mitamura Takashi , Kato Tatsuya , Konno Yosuke , Matsuno Yoshihiro , Hatanaka Yutaka , Watari Hidemichi
Published: May 2020

6042

Background: Ovarian clear cell carcinoma (OCCC) is a distinct entity from other epithelial ovarian cancers such as the most prevalent high-grade serous cancer (HGSC), and often exhibit less sensitivity to platinum-based chemotherapy. Several studies using cell lines have reported that glutathione (GSH) metabolism plays an important role in chemo-resistance of OCCC. Here, we aimed to correlate the prognosis of OCCC and the expression of gamma-glutamyltransferase 1 (GGT1), one of the key enzymes in GSH metabolism. Methods: We prepared a FFPE-tissue microarray, and analyzed 56 OCCC patients with the follow-up periods over 3 years. Expression level of GGT1 was evaluated by immunohistochemistry (IHC) using H-score (0-300), and was correlated with clinical outcomes. The prognostic significance was assessed by multivariate analysis using Cox regression model. To investigate the possible related pathways, we performed transcriptome analysis using Ion AmpliSeq Transcriptome Human Gene Expression Kit (Thermo Fisher Scientific) from the frozen tissue specimens collected from 33 ovarian cancer patients including 15 OCCC patients and 18 HGSC patients. Results: The OCCC patients were divided into two populations in the histogram of H-score in IHC staining, and the cut-off value was 90; 44 cases showed GGT1-high, and remaining 12 cases were GGT1-low. Follow-up periods, FIGO stage, and optimal surgery rate were not significantly different between two groups. However, platinum-resistant recurrent rate was significantly higher (42% vs. 14%, p=0.027), and overall survival (OS) was significantly shorter (5-year OS; 42% vs. 72%, p=0.0226) in GGT1-low OCCC. Multivariate analysis revealed that low expression of GGT1 was one of the independent poor prognostic factors as well as platinum-drug resistance. In enrichment analysis, the genes related to GSH metabolism, such as SLC3A1, GGT1, CSE, and GPX3 were up-regulated and positively correlated with HNF1B expression in OCCC. The expression level of GGT1 was inversely correlated with that of immune suppressive genes (TGF-b, IFNG, IL10, FOXP3, PD-L1, CTLA4) and epithelial-mesenchymal transition (EMT)-related genes (CDH2, VIM, TWIST1, ZEB1, ZEB2) in OCCC samples. Conclusions: Low expression of GGT1 is an independent poor prognostic factor probably in part due to suppression of tumor immunity and induction of EMT in OCCC.
A clinical study of tremelimumab alone or in combination with olaparib in patients with advanced epithelial ovarian cancer.
Authors: Gaillard Stephanie , Berg Maureen , Harrison Jeanne , Huang Peng , Leatherman James M. , Doucet Michele , Sen Rupashree , Suru Aditya , Cai Hongyan , Durham Jennifer N. , Jelovac Danijela , Cimino-Mathews Ashley , Ganguly Sudipto , Emens Leisha A.
Published: May 2020

6045

Background: Single agent immunotherapy (IO) has shown only modest clinical activity for the treatment of ovarian cancer. The combination of anti-programmed death-1 and PARP inhibitors showed promising activity in early trials. Here, we report the results of an open-label, parallel arm, dose escalation study of tremelimumab (T) alone or in combination with olaparib (O) in patients (pts) with advanced epithelial ovarian cancer (EOC). Methods: Pts with recurrent/persistent EOC who had progression < 12 months from last platinum exposure were enrolled. Prior therapy with IO (except anti-CTLA-4) or PARP inhibitor was allowed. Pts were randomized to either T 10mg/kg every 4 weeks (wks) x 7 then every 12 wks (Arm A) or T with O twice daily at three planned dose levels (Arm B). The primary objectives were safety, pharmacodynamic (PD) change in CD4+ICOShi peripheral T cells by flow cytometry, and identification of the optimal dose combination of T with O. Secondary objectives included 6-month progression-free survival (PFS6) and objective response rate (ORR). Results: A total of 24 pts were treated, 12 on Arm A, and 12 on two Arm B dose levels. Pts had a median age of 60 years (range 44-81). Histologic subtypes included high-grade serous EOC (20 pts, 83%), clear cell (3 pts, 13%), and moderately-differentiated adenocarcinoma (1 pt, 4%). BRCA1 mutation (mt) was present in 2 cases, BRCA2 mt in 1. Median number of prior regimens was 3.5 (range 1-9). Most adverse events (AEs) were attributable to T, the most common grade 3 toxicities were rash (13%), immune-mediated hepatitis (8%), and colitis (8%). No grade ≥4 toxicities were identified. Immune-mediated AEs also included acute kidney injury, hypophysitis, and hypothyroidism. No dose limiting toxicities were identified on Arm B. Two pts in Arm B had >PFS6. Of 20 pts evaluable for response, there was 1 partial response (Arm B), and 9 pts had stable disease (6 on Arm A, 3 on Arm B). Mean percentage of CD4+ICOShi T cells was significantly increased on Days 15 and 22 compared to Day 1 at both T dose levels (Table).T at 3 mg/kg with O at 150mg is the optimal dose of those tested. Conclusions: T and T with O was tolerable, with modest clinical activity in this pt population. AEs were as expected, and peripheral CD4+ICOShi T cells increased on therapy. Clinical trial information: 02485990. [Table: see text]
Population-adjusted indirect treatment comparison (PAITC) of maintenance PARP inhibitor (PARPi) with or without bevacizumab versus bevacizumab in women with newly diagnosed ovarian cancer (OC).
Authors: Hettle Robert , McCrea Charles , Lee Chee Khoon , Davidson Richard
Published: May 2020

6052

Background: In patients (pts) with newly diagnosed OC, bevacizumab (B), PARPi, and PARPi + B have shown benefit as maintenance treatment options after platinum chemotherapy response. Phase III trials have demonstrated longer median progression-free survival (PFS) with PARPi + B (PAOLA-1, olaparib [O]; NCT02477644) vs placebo (P) + B and with PARPi alone (PRIMA, niraparib [N]; NCT02655016) vs P. As there are no randomized head-to-head trials comparing PARPi + B vs PARPi, or PARPi vs B, we performed indirect treatment comparison across these regimens. Methods: Unanchored PAITC was performed with individual pt data (IPD) from a PAOLA-1 subset comprising pts with stage IV disease, stage III with residual disease after primary surgery, inoperable stage III disease, or any patient who received neoadjuvant chemotherapy. Propensity weights were used to match the baseline (BL) characteristics of the PRIMA population. PRIMA dataset was reconstructed using published PFS curves. Both datasets were pooled; treatment efficacy was assessed by weighted Cox regression and Kaplan–Meier methods. PAITC was performed in all pts (biomarker unselected) and the homologous recombination repair deficiency positive (HRD+; cut-off 42) subgroup. Results: 595/806 (266/387 HRD+) PAOLA-1 pts were included. After matching, the effective sample size (ESS) for PAOLA-1 was 532 (242 HRD+; weights 0.241–2.37). Weighted BL data were balanced across cohorts. Conclusions: In biomarker-unselected and HRD+ pts, PAITC suggests that adding O to B significantly improved PFS vs. N or B alone. In biomarker-unselected pts, PAITC results show no significant difference in PFS between N and B. In HRD+, improved efficacy with N appears to translate into improved PFS vs. B alone, although follow-up was <2 years (14 vs 22 months, respectively). Results are hypothesis generating and could guide randomized trial design. Clinical trial information: NCT02477644 and NCT02655016. [Table: see text]
Hypersensitivity to platinum salts according to BRCA status in ovarian cancer: Retrospective analysis of clinical outcomes.
Authors: Giannone Gaia , Scotto Giulia , De Giorgi Ugo , Farolfi Alberto , Katsaros Dionyssios , Borella Fulvio , Ferrero Annamaria , Villa Michela , Tuninetti Valentina , Ghisoni Eleonora , Turinetto Margherita , Zavallone Laura , Aglietta Massimo , Pasini Barbara , Di Maio Massimo , Valabrega Giorgio
Published: May 2020

6053

Background: Hypersensitivity reactions (HSRs) to platinum salts are an important issue in the treatment of ovarian cancer (OC) patients (pts). Few data suggest that, along with number of previous cycles, germline BRCA mutations could be a risk factor. We aimed at evaluating the incidence and severity of HSRs to platinum salts in a large group of OC pts with known BRCA status and correlated them with drug exposure time. Methods: Between March 2003 and September 2019, 432 pts with a diagnosis of OC and a known BRCA status, were recorded in our 5 Institutions and retrospectively analyzed. The following data were collected: histology, BRCA status, type of surgery and first line therapy, number of total lines and cycles received, line and cycle of HSR onset, symptoms, history of other allergies and if desensitization was attempted. We graded the severity of HSRs according to CTCAE v5.0. We calculated the total duration of exposure to platinum salts, summing up the duration of all platinum lines received by the pts. Results: Four hundred nine of 432 (94.7%) pts were treated with at least one platinum-based line of therapy and were eligible for the analysis. Among them, 314 pts were BRCA wild type (BRCAwt) (76.8%) and 95 were BRCA mutated (BRCAmut) (23.2%). There was no statistical difference in number of prior lines of therapy [median 1 (2-6) for BRCA wt and 2 (1-6) for BRCAmut pts (p = 0.194)] and duration of exposure to platinum [median 126 (42 – 893) and 197 (42 – 896) days for BRCAwt and BRCAmut pts, respectively (p = 0.145)]. Incidence of any grade HSRs was 29 / 314 (9.2%) among BRCAwt pts vs. 17/ 95 (17.9%) among BRCAmut pts (Odds ratio [OR] 0.47, 95% CI 0.24 – 0.89, p= 0.019). All recorded HSRs to platinum salts were related to carboplatin. We observed a numerically higher incidence of Grade 3-4 HSRs in BRCAmut pts (5.1% in BRCAwt vs. 10.5% in BRCAmut cohort, OR 0.46, 95% CI 0.20 – 1.04, p = 0.057). The risk to develop HSRs increases with duration of exposure to platinum, particularly in BRCAmut pts. The cumulative incidence of any grade HSRs was 20.6% vs. 23.3% after 12 months and 38.4% vs. 59.7% after 18 months in BRCAwt and BRCAmut pts, respectively (Hazard Ratio [HR] 1.72, 95% CI 0.94 – 3.12, p = 0.073). The cumulative incidence of severe HSRs was 10.9% vs. 15.7% after 12 months and 26.5% vs. 41.0% after 18 months in BRCAwt and BRCAmut pts, respectively (HR 1.88, 95% CI 0.85 – 4.16, p = 0.11). Conclusions: In BRCAmut OC pts, there is a significantly higher incidence of HSRs to carboplatin, that seems not justified by longer drug exposure only.
Whole transcriptome changes correlate to exceptional ovarian cancer responders: A sub-analysis of a HIPEC Phase I trial.
Authors: Dellinger Thanh Hue , Wu Xiwei , Cho Hyejin , Liang Winnie S. , Han Ernest Soyoung , Wakabayashi Mark Tsuneo , Lee Stephen , Lin Wei-Chien , Kebria Mehdi , Cristea Mihaela C. , Ruel Nora , Stewart Daphne B. , Wang Edward Wenge , Raoof Mustafa , Lee Byrne , Rodriguez-Rodriguez Lorna
Published: May 2020

6060

Background: Advanced stage ovarian cancer patients benefit from hyperthermic intraperitoneal chemotherapy (HIPEC), prolonging overall survival by nearly 12 months. However, molecular changes triggered by HIPEC are not well characterized, and no molecular signatures of response are known. We analyzed early gene expression changes after HIPEC treatment in ovarian tumors. Methods: This is an interval subgroup analysis of a single institution Phase I trial using HIPEC with cisplatin 75 mg/m2 at time of optimal cytoreduction. Snap-frozen biopsies from tumor and normal peritoneum from 20 patients with ovarian cancer before and after HIPEC underwent whole-transcriptome sequencing using Illumina’s NovaSeq 6000 for paired 100 base-pair reads. Differential expression analysis comparing post and pre-samples was done to identify significantly changed genes, and pathway analysis was conducted using GSEA. Results: Sixty-three genes were differentially expressed (P < 0.05, fold change ≥2) between pre- and post-HIPEC tumors. Hierarchical clustering analysis of these genes confirmed that all tumors and normal tissues clustered based on pre-HIPEC versus post-HIPEC status, and not based on their patient source. Gene set enrichment analysis using a collection of 50 “hallmark” gene sets revealed that post-HIPEC tumors demonstrate significant upregulation in immune pathways (TNFA signaling via NFKB, coagulation, complement), followed by epithelial-mesenchymal transition, inflammation, apoptosis, hypoxia, angiogenesis, KRAS signaling and JAK/STAT3 signaling. In contrast, post-HIPEC normal tissues exhibited upregulation in cell cycle pathways (Myc targets V2, G2M checkpoint). As expected, both post-HIPEC tumor and normal samples shared upregulation of genes related to inflammatory response. Lastly, post-HIPEC normal samples revealed downregulation of growth and metabolism pathways; in contrast, cell cycle or DNA repair pathways were downregulated in post-HIPEC tumors. Two exceptional-responders with recurrent platinum-sensitive disease (ongoing PFS 47 and 12+ months) demonstrated the most substantial changes in gene expression. Conclusions: Exceptional ovarian cancer responders to HIPEC are characterized by extensive gene expression changes; specifically, early HIPEC-induced molecular changes are strongly associated with immune pathways changes, implicating a role for immunotherapy after HIPEC in ovarian cancer. Clinical trial information: NCT01970722.