bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of tart cherry on aromatase inhibitor-induced arthralgia (AIA) in nonmetastatic hormone-positive breast cancer patients: A randomized double-blind placebo-controlled trial.
Authors: Shenouda Mina , Tirona Maria R. B. Tria
Published: May 2019

525

Background: Aromatase inhibitors (AI) are the standard treatment for hormone receptor‐positive breast cancer in postmenopausal women. About half of patients (pts) taking AI suffer from AIA which can be severe enough to cause noncompliance. Suboptimal AI adherence is associated with decreased disease-free and overall survival, suggesting that improving adherence will lead to improved breast cancer outcomes. Effective interventions for AIA are still limited. In clinical trials, tart cherry (TC) showed beneficial effect on musculoskeletal pain associated with osteoarthritis, gout, and strenuous exercise. The flavonoids and anthocyanins in TC reportedly exert an anti-inflammatory effect that may lessen adverse effects of estrogen deficiency. This trial aimed to investigate whether TC can reduce AIA in non-metastatic hormone positive breast cancer (NMHPBC) pts. Methods: This is a randomized, placebo-controlled, double-blind trial. Eligible Pts with NMHPBC on AI for at least 4 weeks were randomized to TC concentrate (equivalent to 50 tart cherries) versus placebo (P) [syrup] in a 1:1 model. Pts were instructed to take 1 Oz of TC or P in 8 Oz water daily for 6 weeks, and to document their pain intensity at baseline, weekly and at study completion in a diary using a Visual Analog Scale (VAS), with 0 mm indicating no pain, and 100 mm indicating highest pain. Results: 60 pts were enrolled from May 2016 to August 2018. 2 pts did not complete the study due to diarrhea. 10 pts were non-compliant. 48 pts were included in the final analysis. TC group (23 pts) had 34.7% mean decrease in pain compared to 1.4% in P group (25 pts). This difference was statistically significant (Mann-Whitney U Test P = 0.034). Conclusions: Tart cherry can significantly improve AIA in non-metastatic breast cancer patients.
Breast cancer-specific survival outcomes among patients based on 21-gene recurrence score.
Authors: Swenson Wade T. , Mallick Shantanu
Published: May 2019

537

Background: The 21-gene recurrence assay predicts cancer recurrence rates and benefit from adjuvant chemotherapy among patients with hormone-receptor-positive breast cancer. The National Cancer Institute and Genomic Health collaborated to provide Recurrence Score (RS) results to complement data from 17 population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Program. Methods: Using the SEER database with linked RS results, a cohort of female breast cancer patients, age greater than 20 years, was identified by RS (low: < 18, intermediate: 18-30, high: > 30) diagnosed between the years 2004 and 2007. A retrospective analysis was conducted to determine eight-year breast cancer-specific survival rates based on RS and other variables. Results: 10,318 patients were identified in the cohort. 5,194 had a low risk RS; 4,282 had an intermediate risk RS; 872 had a high risk RS. Histologic subtypes were: 7,459 infiltrating ductal carcinoma, 941 mixed infiltrating and lobular carcinoma, 933 lobular carcinoma, 327 mixed infiltrating ductal and other histology, 244 mucinous adenocarcinoma, 101 tubular adenocarcinoma, 45 mixed lobular and other histology, 268 other histologies. 644 low risk RS patients received chemotherapy (12.4%); 1,608 intermediate risk RS patients received chemotherapy (37.8%); 593 high risk patients received chemotherapy (68.0%). The eight-year breast cancer-specific survival rates (with 95% confidence intervals) among low risk RS patients without known chemotherapy administration was 98.9% (98.5, 99.2), and 98.4% (97.0, 99.1) with chemotherapy; intermediate risk RS patients without known chemotherapy was 97.0% (96.2, 97.6), and 96.9% (95.9, 97.7) with chemotherapy; high risk RS patients without known chemotherapy was 89.7% (85.4, 92.8), and 92.9% (90.4, 94.7) with chemotherapy. Conclusions: Among a large cohort of patients identified in a population-based cancer registry between 2004 and 2007, there was no statistically significant difference in eight-year breast cancer-specific survival rates among those who received chemotherapy and those who did not, regardless of RS risk group.
Clinical behavior of recurrent hormone receptor-positive breast cancer by adjuvant endocrine therapy: A Breast International Group (BIG) 1-98 sub-analyses.
Authors: Leone Jose Pablo , Cole Bernard F. , Regan Meredith M. , Thurlimann Beat J. K. , Coates Alan S. , Goldhirsch Aron , Di Leo Angelo , Colleoni Marco , Luis Ines Maria Vaz Duarte , Lin Nancy U.
Published: May 2019

538

Background: Endocrine therapy resistance is a major cause of distant recurrence (DR) in HR+ breast cancer. Currently, no data exists evaluating differences in clinical behavior after DR between patients (pts) treated in the adjuvant setting with different endocrine therapy regimens. The aim of this study was to analyze post-DR survival of pts treated on BIG 1-98. Methods: BIG 1-98 compared 5 years of adjuvant treatment between 4 arms: tamoxifen (T), letrozole (L), T followed by L (TL) and L followed by T (LT). After 8.1 years median follow-up (follow-up through 2010), 911 (T n = 302, L n = 285, TL n = 170, LT n = 154) of 8010 pts had DR as site of first recurrence. Univariate and multivariable Cox analyses were performed to determine features associated with post-DR survival. With 661 total observed deaths, statistical power was 0.8 to detect a hazard ratio (HaR) > 1.24 at the 2-sided 0.05 level of significance. Results: Median follow up time after DR was 59 months (IQR: 29-88). Among all pts with DR, 38.1% were ≥ 65 years at study enrollment, 61.9% had tumor size > 2 cm, 69.7% were node positive. Neo/adjuvant chemotherapy was administered to 35.6% of pts. There was no difference in post-DR survival by treatment arm (median survival: T 20.8, L 17.9, TL 17.3, LT 20.8 months; p = 0.21). In multivariable analysis, older pts (HaR 1.36; p = 0.0002), tumors > 2cm (HaR 1.2; p = 0.04), ≥ 4 positive nodes (HaR 1.32; p = 0.05) and PR- tumors (HaR 1.28; p = 0.001) had significantly worse post-DR survival. Endocrine treatment arm, type of surgery, radiotherapy and neo/adjuvant chemotherapy were not associated with post-DR survival in the multivariate model. Conclusions: Treatment with adjuvant T, L or their sequence were not associated with differences in survival after DR. We observed significant differences in survival by primary tumor size, nodal and PR status, which suggest that traditional high-risk features remain prognostic in the metastatic setting. Clinical trial information: NCT00004205.
Distinct mutational landscape between HR+ and HR- HER2+ early-stage breast cancer patients.
Authors: Chen Bo , Liao Ning , Zhang Guo-Chun , Wang Yulei , Chen Xiaoqing , Guo Liping , Cao Li , Mok Hsiaopei , Ren Chong-Yang , Li Kai , Jia Minghan , Li Cheukfai , Wen Ling-Zhu , Lin Jiali , Wei Guangnan , Hou Ting , Lizaso Analyn , Liu Jing , Balch Charles M.
Published: May 2019

543

Background: HER2 targeted therapy has revolutionized the survival outcomes of early and advanced HER2+ breast cancer (BC). However, among HER2+ patients, the therapeutic response to HER2 inhibitors vary. To understand the molecular mechanism of the variability in therapeutic efficacies, the mutational landscape of HER2+ tumors need to be elucidated. Methods: 107 HER2+ Chinese stage I-III BC patients were included in the study, including 64 HR+ and 43 HR- patients. A majority of the patients were diagnosed with infiltrating ductal carcinoma (99/107). Capture-based targeted sequencing was performed using a panel consisting of 520 cancer-related genes spanning 1.64 MB of the human genome. Results: 1,119 alterations were detected, including 478 single nucleotide variants (SNVs), 14 insertions or deletions, 29 fusions, 593 copy number amplifications (CNA), 2 large genomic rearrangements and 3 CN deletions in 267 genes. Alterations in 99 genes were shared between HR+/HER2+ and HR-/HER2+ tumors; while 123 and 45 genes were only detected in either HR+/HER2+ or HR-/HER2+ tumors, respectively. CNA, splice site and frameshift mutations were significantly more in HR+/HER2+ patients ( p= 0.017). Specifically, CNA in SPOP, CCND1, FGF19, FGF3, FGF4, RNF43, RAD51C, ADGRA4 and MDM4 and various alterations in GATA3 were significantly more among HR+/HER2+ tumors ( p< 0.05). In addition to HER2 amplifications, concurrent fusions in ERBB2 (67%, 4/6), SNVs in ERBB3 (100%, 3/3) and ERBB4 (100%, 1/1) were more likely to be detected in HR+/HER2+ tumors, while concurrent EGFR amplifications were exclusively detected in HR-/HER2+ tumors. The trend of concurrent mutations was consistent with mutation types detected in HER2- tumors based on HR status, wherein EGFR amplifications were more frequent in HR-/HER2- tumors, while SNVs in EGFR, ERBB2, ERBB3 and ERBB4 were more predominant in HR+/HER2- tumors. Based on KEGG pathway analysis, HR+/HER2+ tumors had more frequent alterations in TGFb ( p= 0.007), WNT ( p= 0.002) and homologous recombination ( p= 0.004) pathways than HR-/HER2+ tumors. Furthermore, our data revealed that HR+/HER2+ and HR-/HER2+ patients had comparable TMB ( p= 0.24), with a median TMB of 4.0 mutations/Mb for both. Conclusions: Our study revealed genetic heterogeneity between HR+ and HR- HER2+ tumors. The distinct genetic alterations are potentially relevant in the development of optimal treatment strategies for such patients.
Effect of prophylaxis on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer: Phase II CONTROL trial.
Authors: Barcenas Carlos Hernando , Hurvitz Sara A. , Di Palma Jack A. , Bose Ron , Chan Arlene , Chien Amy Jo , Farrell Cindy , Hunt Daniel , McCulloch Leanne , Kupic Amy , Tripathy Debu , Rugo Hope S.
Published: May 2019

548

Background: CONTROL (clinicaltrials.gov: NCT02400476) is an open-label, sequential-cohort, phase II study investigating the effectiveness of prophylaxis or dose escalation in preventing diarrhea and improving tolerability of neratinib, an irreversible pan-HER tyrosine kinase inhibitor. Neratinib has demonstrated benefit as an extended adjuvant therapy for early-stage HER2+ breast cancer. Various prophylactic agents are being studied in adult patients treated with oral neratinib (240 mg/day for 1 year) after trastuzumab-based adjuvant therapy. Methods: Patients (n = 485) were enrolled into cohorts investigating antidiarrheal prophylaxis for 1–2 cycles (28 days) with the following agents: loperamide (n = 137); loperamide + budesonide (n = 64); loperamide + colestipol (n = 136); loperamide prn + colestipol (n = 104). An additional cohort assessing loperamide prn + neratinib dose escalation with no mandatory prophylaxis (n = 44) is ongoing. Adverse events were graded according to NCI-CTCAE v4.0. The primary endpoint was incidence of grade ≥3 diarrhea. Data cut-off: 14 Jan 2019. Results: As shown in the table, all prophylactic regimens reduce the incidence of Grade 3 diarrhea and drug discontinuation compared with the prior ExteNET trial [Martin et al. 2017]. The median cumulative duration of Grade 3 or higher diarrhea spanned from 2.0 to 3.5 days across regimens for the entire treatment period. No Grade 4 diarrhea was reported. Conclusions: The addition of budesonide or colestipol to loperamide prophylaxis given for 1–2 cycles reduces the severity and duration of diarrhea in patients treated with neratinib, thereby improving tolerability. Updated data for the dose-escalation cohort will be presented at the meeting. Clinical trial information: NCT02400476. [Table: see text]
Oncotype DX testing in early-stage node-positive breast cancer and impact on chemotherapy use at a comprehensive cancer center.
Authors: Losk Katya , Freedman Rachel A. , Mittendorf Elizabeth A. , Tan-Wasielewski Zhenying , Trippa Lorenzo , King Tari A.
Published: May 2019

549

Background: The 21-gene Oncotype DX Recurrence Score (RS) is widely used to guide adjuvant chemotherapy decisions in hormone receptor positive (HR+), HER2-negtive (HER2-), lymph node negative (LN-) breast cancer. It’s adoption in lymph node positive (LN+) disease remains controversial. In 2016, we implemented ‘reflex’ RS testing for patients ≤65 years with HR+/HER2- breast cancer including T1/T2 N1 (grade 1 or 2) tumors. Providers can also order Oncotype DX outside of reflex criteria. We sought to assess RS distribution and factors associated with chemotherapy use in HR+/HER2-/LN+ breast cancer patients at our center. Methods: Patients with non-metastatic HR+/HER2-/LN+ breast cancer who underwent primary surgery at our center were identified from our prospective database. We examined the distribution of low (RS < 18), intermediate (RS 18-30) and high (RS > 30) RS and identified characteristics for those who did not meet reflex criteria. A multinomial logistic regression model was performed to identify factors associated with chemotherapy receipt among all LN+ patients. Results: From 1/2016-3/2018, we identified 296 consecutive patients with HR+/HER2-/LN+ breast cancer. 200 (68%) patients had RS testing and 128 (64%) met reflex criteria. Reasons for not meeting RS reflex criteria included age > 65 (n = 35), grade III disease (n = 35) and N2/N3 tumors (n = 10). Among the 200 patients with RS, 122 (61%) had RS < 18, 67 (34%) had RS 18-30, and 11 (6%) had RS > 30. Only 68/200 (34%) patients with RS received chemotherapy as compared to 54/96 (56%) patients without RS (p = 0.0004). Compared to patients without RS testing, the odds of receiving chemotherapy were less with RS < 18 (OR = 0.46). The odds of receiving chemotherapy were greater with ≥3 positive LNs versus 1 positive LN (OR = 3.40). Conclusions: The majority of HR+/HER2-/LN+ patients undergoing upfront surgery at our center receive RS testing (200/296), with 122 (61%) resulting in low risk RS. Patients with low risk scores (RS < 18) were less likely to receive chemotherapy. While nodal involvement remains a common driver of chemotherapy use, our study demonstrates that RS testing provides clinically useful information in this population.
Results of a phase 2 trial of ribociclib and letrozole in patients with either relapsed estrogen receptor (ER)-positive ovarian cancers or relapsed ER-positive endometrial cancers.
Authors: Colon-Otero Gerardo , Weroha S. John , Zanfagnin Valentina , Foster Nathan R. , Asmus Erik , Wahner Hendrickson Andrea Elisabeth , Jatoi Aminah , Block Matthew Stephen , Langstraat Carrie L , Glaser Gretchen Elizabeth , Dinh Tri , Robertson Matthew , Camoriano John Kelly , Butler Kristina , Copland John A.
Published: May 2019

5510

Background: Single agent aromatase inhibitor (AI) therapy is associated with limited clinical activity in ovarian cancer (OC) and endometrial cancers (EC). AI therapy was associated with a progression free survival (PFS) at 12 weeks of only 20% in relapsed OC (Bowman et al, 2002) and a median PFS of 1 month in relapsed EC (Rose et al, 2000). In Estrogen Receptor (ER) positive metastatic breast cancer, clinical studies had shown a significant prolongation of PFS with the addition of the cyclin kinase 4/6 inhibitor ribociclib to AI (Hortobagyi et al, 2016). Here, we report the results of a phase 2 clinical trial of the combination of ribociclib and letrozole in patients with relapsed ER positive OC or EC. Objectives: Primary endpoint was the proportion of patients with relapsed ER positive OC or EC alive and progression-free after 12 weeks of therapy (PFS12) with the combination of ribociclib given at a dose of 400 mg orally daily and letrozole 2.5 mg orally daily. A PFS of 45% was considered a favorable result based on the data referenced above from Bowman et al. Methods: Eligibility criteria included patients with relapsed ER positive OC or EC, with measurable disease, not previously treated with ribociclib or AIs. Xenografts were created from CT guided tumor biopsies at baseline to assess feasibility. Results: A total of 40 patients were enrolled (20 with OC and 20 with EC) ) with a median age of 61 years (range: 30-82) and 64.5 (range: 52-75) in the OC and EC groups respectively. Among the OC patients, 17 had high grade serous carcinomas and 3 had low grade serous carcinomas. 11 EC patients had endometrioid cancers (3 with grade 1 tumors) and 9 had high grade serous tumors. Ten out of 20 OC patients and 11/20 EC patients were alive and progression-free at 12 weeks (PFS12 of 50 and 55%, respectively). The most common grade 3 or higher adverse events (occurring in at least 5 pts) were leukopenia (18%), lymphopenia (18%), neutropenia (13%), and fatigue (13%). 34 tumor biopsies were suitable for injection into mice and 44% engrafted. ER expression persisted through multiple passages in mice. Two of three EC PDX models exhibited improved PFS with letrozole/ribociclib compared to letrozole alone. Conclusions: The combination of ribociclib and letrozole is associated with a promising 50% and 55% PFS12 in patients with ER positive relapsed OC or EC respectively. Creation of xenograft tumor models from CT guided biopsies of OC and EC tumors was feasible. Clinical trial information: NCT02657928.
Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-resistant ovarian cancer: Final findings from the FORWARD II study.
Authors: O'Malley David M. , Matulonis Ursula A. , Birrer Michael J. , Castro Cesar Martin , Vergote Ignace , Martin Lainie P. , Mantia-Smaldone Gina , Gilbert Lucy , González-Martín Antonio , Bratos Raquel , Esteves Brooke , Malek Karim S. , Moore Kathleen N.
Published: May 2019

5520

Background: Mirvetuximab soravtansine is an ADC comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. As part of the Phase 1b FORWARD II trial (NCT02606305), the combination of mirvetuximab soravtansine with bevacizumab (BEV) was evaluated in pts with FRα-positive, platinum-resistant ovarian cancer (recurrence within 6 months after last platinum). Methods: Pts received mirvetuximab soravtansine (6 mg/kg; adjusted ideal body weight) and BEV (15 mg/kg) on Day 1 of a 21-day cycle. Responses were assessed according to RECIST 1.1 and adverse events (AEs) evaluated by CTCAE v4.03. Results: In total, 66 pts received combination dosing at this level: 11 during escalation and 55 in expansion. The median age was 63 years, pts received a median of 3 prior lines of systemic therapy (range 1-8), and 62% had received prior therapy with BEV. The most common AEs were diarrhea (58%), nausea (50%), and blurred vision (48%), and were primarily low grade (≤ grade 2). Serious AEs were largely gastrointestinal in nature, with small intestinal obstruction the most frequent individual event (4 pts, 6%). Objective responses were seen in 27 pts for a confirmed overall response rate (ORR) of 41% (95% CI, 29, 54), median progression-free survival (mPFS) interval of 7.1 months (95% CI, 4.9, 9.5), and median duration of response (mDOR) of 8.6 months (95% CI, 4.9, 14.9). In a subset analysis of pts (n = 16) who were bevacizumab-naïve, had 1-2 prior therapies, and medium/high FRα levels (i.e., ≥ 50% of cells with at least moderate staining intensity) the ORR was 56% (95% CI, 30, 80), mPFS 9.9 months (95% CI, 4.1, 15.9), and mDOR 12 months (95% CI, 6.0, 14.9). Conclusions: The combination of mirvetuximab soravtansine with BEV exhibits favorable tolerability in pts with platinum-resistant ovarian cancer, characterized by a manageable side-effect profile. The encouraging efficacy compares favorably to reported outcomes for BEV and chemotherapy seen in similar patient populations. These data support continued exploration of the combination in ovarian cancer. Clinical trial information: NCT02606305.
Clinically significant discrepancy between clinical and pathologic stage of early-operable cervical cancer.
Authors: Gibbs Jennifer , Hastings Victoria , Malakhov Nikita , Economos Katherine , Kanis Margaux J
Published: May 2019

5526

Background: The cornerstone of the management of cervical cancer (CC) traditionally relies on clinical examination assessment (CE) of tumor size (TS) and local extension of disease. Previous reports demonstrate poor accuracy of CE, with the most common discrepancy being failure to identify parametrial involvement (PI). The goal of this study is to determine the accuracy of CE in comparison to final pathology (FP) in early operable CC. Methods: This is a multi-center retrospective review of patients with early CC (FIGO stage IB1, IIA1). Data on age, race, histology, stage, CE findings, FP report and receipt of adjuvant radiation therapy (RT) were collected. CE findings included TS, PI and vaginal involvement (VI). CE of TS, PI, and VI were compared to FP. Subanalysis was also conducted based on TS ( < or ≥ 2cm) and location of tumor (exophytic vs endophytic). Analysis was performed using paired-T and Cohen’s Kappa tests. Results: Final analysis included 135 patients. Mean age was 52.6 years. The majority of patients had squamous cell carcinoma (72.6%). Overall, there was a significant difference between CE of TS compared to FP; mean error of 1.22 cm (p < 0.0001). In those with tumors ≥ 2cm the mean error was 1.28 cm (p < 0.0001). No significant discrepancy was observed in tumors < 2 cm (mean error: 1.10cm; p = 0.5). CE of TS of endophytic tumors was poor (mean error 1.68cm; p = 0.004) compared to exophytic tumors (mean error: 1.12 cm; p = 0.693). There was no significant difference in the identification of VI between CE and FP (3.7% vs 8.89%; p = 0.067). No patients with PI on CE were included in this analysis. However, 14.07% of patients were found to have PI on FP (p < 0.0001). There was no difference in the accuracy CE of TS between non-obese ( < 30 kg/m2) and obese patients (≥30 kg/m2), mean error 1.13 and 1.3, respectively (p = 0.061). As a results of FP, 55 patients (40.7%) received adjuvant RT and 38 patients (28.14%) were upstaged from IB1 to IB2. Of these 38 patients, 36 (94.7%) went on to receive adjuvant RT. Conclusions: CE of TS and PI is inaccurate, especially in tumors ≥ 2cm and endophytic tumors. This suggests imaging should be strongly encouraged, particularly in the setting of the updated FIGO 2018 staging system and recent debate over surgical approach.
Feasibility of visual inspection with acetic acid (VIA) screening for cervical cancer in Tanzania with emphasis on special populations.
Authors: Chinn Justine , Runge Ava , Dinicu Andreea , Chang Jenny , Ziogas Argyrios , Maher Justine , Naaseh Ariana , Lucas Alexa , Zezoff Danielle , White Kayla , Bera Kevin , Crawford Elizabeth , Cooper Emma , Bernstein Megan , Hari Anjali , Tewari Sujata , Rutaisire Eugen , Forthal Donald , Pearre Diana , Tewari Krishnansu Sujata
Published: May 2019

5527

Background: Following the report that VIA screening reduced cervical cancer mortality by 31% in India (ASCO LBA2 2013; Shastri SS, et al JNCI 2014), the W.H.O. endorsed VIA guidelines for Africa, where the global disease burden is highest. In Tanzania, cervical cancer is a major source of morbidity and mortality, with nearly 10,000 new cases and 7,000 deaths annually. Due to lack of resources, therapies are limited and patient outcomes are further confounded by the relatively high prevalence of concurrent HIV infection. We report on the feasibility of VIA screening in Tanzania with emphasis on unique populations. Methods: Our two 5-day VIA screen-and-treat workshops in Buzuruga and Sangabuye Health Centres in Mwanza, Tanzania were approved by the University of California, Irvine IRB and local health authorities. Participants were recruited from surrounding communities and offered free cervical VIA screening, cryotherapy when indicated, and HIV rapid testing. Acetowhite lesions and/or abnormal vascular markings were VIA+. Chi-square and Fisher exact tests were performed with statistical significance assigned at 0.05. Results: During July 2018, 825 of 917 registered participants underwent VIA screening and 25.1% (n=207) were VIA+. 147 VIA+ non-pregnant women received same day cryotherapy and 15 (1.8%) with lesions suspicious for cancer were referred to Bugando Medical Center. In the subanalysis of 64 HIV+ patients (23 diagnosed at the workshops, 41 with prior diagnosis on ART), HIV infection was not associated with VIA positivity (p=0.497). Additionally, a non-significant trend of higher VIA+ screens among newly diagnosed untreated HIV patients (27.7%) vs patients with known HIV on ART (17.5%) was observed (p=0.556). Conclusions: VIA screening for cervical cancer, while feasible in Tanzania, will require follow-up and repetitive screening. Although cervical cancer is an AIDS-defining illness, lack of correlation between HIV infection and VIA-positivity may reflect the availability of W.H.O.-subsidized ART in sub-Saharan Africa to attenuate HPV-mediated neoplastic transformation, as previously reported by others. Further study of this phenomenon is warranted.
Safety and efficacy of nimotuzumab and concurrent intensity-modulated radiation therapy and chemotherapy for locally advanced cervical squamous cell cancer.
Authors: Qu Ang , Wang Junjie , Jiang Ping , Wang Panfeng , Zhang Muyi , Li Xu , Sun Haitao
Published: May 2019

5532

Background: To evaluate the safety and efficacy of nimotuzumab plus concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy for the treatment of locally advanced cervical squamous cell cancer (LACSCC). Methods: From December 2013 to March 2017, 31 patients with stage (FIGO 2009) IB2-IVA cervical squamous cell cancer were enrolled in this single-arm clinical trial at an academic medical center and received concurrent chemoradiotherapy plus nimotuzumab. All patients underwent at least 1 year of follow-up. The prescription radiation dose was 50.4 Gy/28 F on the pelvic field with or without extended-field radiation. An additional 30-36 Gy to Point A was delivered with high-dose-rate techniques. Cisplatin 40 mg/m2 and nimotuzumab 200 mg were infused intravenously once weekly during radiotherapy. The main and secondary outcome measures were toxicity evaluated using CTCAE 4.0., and the short-term outcome evaluated by RECIST 1.1. Results: The median follow-up duration was 29.7 months (13.3-61.2 months). All patients received external beam radiotherapy, brachytherapy, and nimotuzumab six times. Twenty-seven patients received six cycles of chemotherapy while four received only 4-5 cycles. There was no life-threatening toxicity. The incidence of acute grade 3 bone marrow depression was 51.6% (16/31) and grade 3 gastrointestinal tract reaction was 9.7% (3/31). The incidence of late toxicities was 22.6% (7/31), and these included vaginal-rectal fistula, intestinal obstruction, rectal hemorrhage, hematuria, and vaginal stenosis. Complete response was achieved in 30 cases (96.8%). The 1-year disease-free survival (DFS), local progression-free survival (LPFS), and overall survival (OS) rates were 87.1%, 90.3%, and 100%, respectively. The corresponding 3-year values were 74.8%, 90.3%, and 86.7%. Conclusions: Nimotuzumab plus concurrent IMRT and chemotherapy may represent a well-tolerated and effective treatment regimen in patients with LACSCC.
PD-L1 expression, DNA mismatch repair genes, and HPV types in cervical squamous cell carcinoma.
Authors: Haidary Tahmineh , Mendoza Rachelle Pacaanas , Zhou Yingyin , Lee Wen-Ching , Lee Yi-Chun , Gupta Raavi
Published: May 2019

5533

Background: Previous studies observed low PD-L1 expression in cervical cancer, and that high PD-L1 expression is associated with deficient DNA mismatch repair genes and poor prognosis. No study has investigated the PD-L1 expression differences among HPV types in cervical cancer. We aim to determine PD-L1 expression in our patient population and its clinical significance. Methods: A total of 198 patients with SCC were identified and 60 had evaluable tumor specimens and clinical data. Immunohistochemistry on MMR genes and PD-L1 expression using tissue microarrays was performed. HPV analysis for 15 high-risk types was done by multiplex PCR and gel electrophoresis. Correlation between PD-L1 expression, MMR status, HPV types and other clinical parameters was analyzed using χ2 or Fisher's exact test. Cumulative 5-year survival was analyzed by Kaplan-Meier curves and log rank test. Results: Of the 60 patients, 90% were black, 55% between ages of 30-55 and 40% older than 55. 33 patients had poorly, 20 moderately, and 7 well-differentiated tumors. At 5-year follow up, 11 had recurrence, 14 patients died of disease and 7 lost to follow up. 93.3% of tumors had positive staining for PD-L1 with 56.7% showing high expression. Patients aged 30-55 showed a higher rate of PD-L1 expression. Majority had intact MMR (91.7%). High-risk HPV DNA was extracted in 41 specimens (68.3%), 11 of these were infected with ≥2 or more types, identifying 6 high-risk types not included in vaccine. Correlation analysis showed that there is significant correlation between age and PD-L1 expression on tumor cells (p = 0.047). No correlation between MMR status and PD-L1 expression. Mean disease free survival (DFS) was 43.7, 36.5, and 6.3 months for high, low and negative PD-L1 expression, respectively (p = 0.002). In patients with stage I-II disease, mean DFS was 52.2, 42.6 and 7.6 months for high, low and negative PD-L1 expression, respectively (p = 0.001). Similar direct relationship is observed with overall survival. Cases with mixed HPV infection are associated with late clinical stage at diagnosis (p = 0.037) and lower PD-L1 expression. Conclusions: Contrary to previous studies, our results showed remarkably high rate of PD-L1 expression in cervical SCC, which is associated with longer DFS and OS, especially in early stage tumors. Mixed HPV infection is associated with late clinical stage at diagnosis and lower PD-L1 expression.
Adverse events (AEs) with maintenance olaparib in newly diagnosed patients (pts) with advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): Phase III SOLO1 trial.
Authors: Colombo Nicoletta , Moore Kathleen N. , Scambia Giovanni , Oaknin Ana , Friedlander Michael , Lisyanskaya Alla Sergeevna , Floquet Anne , Leary Alexandra , Sonke Gabe S. , Gourley Charlie , Banerjee Susana N. , Oza Amit M. , González-Martín Antonio , Aghajanian Carol , Bradley William Hampton , Kim Jae-Weon , Lowe Elizabeth S. , Bloomfield Ralph , Disilvestro Paul
Published: May 2019

5539

Background: In SOLO1 (NCT01844986), maintenance olaparib provided a substantial progression-free survival benefit vs placebo in newly diagnosed pts with advanced OC, a BRCAm and clinical complete or partial response to platinum therapy (HR 0.30; 95% CI 0.23–0.41) and was well tolerated (Moore et al. NEJM 2018). We analysed the most common AEs and hematologic AEs in SOLO1. Methods: Pts received olaparib tablets 300 mg twice daily or placebo until progression unless they had no evidence of disease at 2 years, in which case treatment stopped. AEs were graded using CTCAE v4.0. Results: Of 391 pts randomized, 390 (olaparib, 260; placebo, 130) were treated and included in the safety analysis. Median treatment duration was approximately 25 months for olaparib vs 14 for placebo. Median time to first onset of the most common AEs (nausea, vomiting, fatigue/asthenia, anemia) and neutropenia and thrombocytopenia was < 3 months; the first event lasted a median of < 2 months, apart from fatigue/asthenia, which lasted a median of < 4 months (Table). AEs were usually managed with supportive therapy and/or dose modification; few pts discontinued. Conclusions: AEs in newly diagnosed pts with advanced OC treated with olaparib usually occurred early and were manageable, with few discontinuations. Clinical trial information: NCT01844986. [Table: see text]
Circulating tumor DNA analysis to reveal genomic profiles for epithelial ovarian cancer.
Authors: Xiang Yang , Zhu Shan , Wang Weiran , Cao Dongyan , Wan Xi-Run , Yang Junjun , Yang Jiaxin , Yu Mei , Gong Yuhua , Guan Yanfang , Wang Jing , Li Peiling , Yue Ying , Zhang Guo-Nan , Wang Ping , Wang Yongjun , Xia Xuefeng , Yang Ling , Yi Xin
Published: May 2019

5543

Background: Circulating tumor DNA (ctDNA) analysis in epithelial ovarian cancer (EOC) was previously reported, however with limited samples or limited genes. Here, we reported an analysis of ctDNA in EOC cohort using targeted sequencing with a 1021-gene panel. Methods: Patients with EOC were enrolled, and treatment-naïve tumor tissues and blood samples were collected. We utilized a 1021-gene NGS panel in matched tissue DNA and ctDNA to identify somatic mutations with white blood cell DNA as a germline control. Results: Mutations were identified in all of the 65 tissues and in 53 (81.5%) ctDNA. The median ctDNA mutation allelic frequency was 2.5%, ranging from 0.1% to 36.2%. A median of 66.7% (12.5%-100.0%) of tissue derived mutations were observed in ctDNA. Besides, there were 91 ctDNA private mutations, including TP53 gene mutations. The most frequently mutated genes were TP53 (55.4%), PIK3CA (13.8%) and ARID1A (12.3%) in ctDNA analysis, which were consistent with tissue analysis (60.0%, 26.2% and 20.0% of tissues with TP53, PIK3CA and ARID1A mutations, respectively). Mutations of TP53 (37/42) in high-grade serous ovarian carcinoma (HGSOC), PIK3CA (10/11) and ARID1A (8/11) in ovarian clear cell carcinoma, BRAF (4/5) in low-grade serous ovarian carcinoma and PIK3CA (3/5), ARID1A (2/5) and PTEN (2/5) in endometrioid carcinoma were observed as the most commonly genetic aberrations in ctDNA in different sub-types of EOC, which located in different signal pathways and suggested different pathogenesis. In total, 90.5% (38/42) of HGSOC were ctDNA positive, comparing with 65.2% (15/23) of other EOC subtypes (p = 0.012). In addition, 56.5% (13/23) of stage I~II EOC were ctDNA positive, comparing with 94.7% (36/38) of stage III (p = 0.002). No association between ctDNA positivity and other clinic characteristics was observed, including pathological differentiation, CA125, lesion density (solid vs. cystic-solid and cystic). Multivariable analysis suggested FIGO stage III (p = 0.008) as an independent predictor of ctDNA detection. Conclusions: In summary, genomic characterization of EOC may offer insights into tumorigenesis and identify potential therapeutic targets in this disease.
Bevacizumab beyond progression: Impact of subsequent bevacizumab retreatment in patients with ovarian, fallopian tube, and peritoneal cancer after progression.
Authors: Previs Rebecca Ann , Spinosa Daniel , Fellman Bryan M. , Lorenzo Amelia , Mulder Isabelle , Mahmoud May , Enbaya Ahmed , Hansen Jean M. , Cobb Lauren Patterson , Soliman Pamela T. , Coleman Robert L. , Secord Angeles Alvarez , Westin Shannon Neville
Published: May 2019

5557

Background: The Food and Drug Administration approved the use of bevacizumab for treatment of recurrent epithelial ovarian, fallopian tube, and primary peritoneal carcinoma (OC) in combination with chemotherapy. This study evaluates whether patients immediately retreated with bevacizumab derive benefit after progressing on a bevacizumab-containing regimen. Methods: This multi-institutional, retrospective study compared patients with high grade non-mucinous epithelial OC who received bevacizumab followed directly by another bevacizumab-containing treatment regimen to patients who received bevacizumab followed by a regimen that did not contain bevacizumab (or received no further treatment). All patient retreated with bevacizumab had stable or progressive disease on prior bevacizumab containing regimen. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan and Meier product-limit estimator and modeled via Cox proportional hazards regression. PFS was measured from the date of first bevacizumab treatment to the date of first progression, date of death or date of last clinic visit. OS was measured from the date of first bevacizumab treatment after progression to the date of death or date of last contact/clinic visit. Statistical significance was defined at the 0.05 level. Results: 275 patients received bevacizumab, of which 226 were evaluable; 102 received sequential treatment with bevacizumab and 124 received a bevacizumab containing regimen followed by a non-bevacizumab containing regimen at the time of progression. There was no significant difference between tumor grade, stage, or BRCA mutation. Median follow-up for all subjects was 17 months (range: 1.2-138.2 months). Median PFS was 10.21 months (95%CI: 8.05 - 11.79) and median OS was 22.14 months (95%CI: 17.1 – 27.4). Median PFS for patients who received bevacizumab without retreatment was 5.1 months (95%CI: 4.3 – 6.3) and 17.6 months (95%CI: 14.3 – 21.3) for patients who received sequential bevacizumab retreatment (p < 0.001). Median OS for patients who received bevacizumab without retreatment was 12.9 months (95%CI: 9.3 – 16.7) and 30.1 months (95%CI: 26.1 – 35.4) for patients who received sequential bevacizumab retreatment (p < 0.001). Conclusions: Our study shows OC patients treated with bevacizumab-containing regimens sequentially at the time of progression have significantly prolonged survival outcomes compared to those patients who received no re-treatment with bevacizumab.
Real-life data: Women with recurrent platinum-sensitive ovarian cancer and BCARGEM treatment.
Authors: van der Scheun Frederique C. , Bruijnen Cheryl P. , Witteveen Petronella , Suelmann Britt B.M.
Published: May 2019

5566

Background: Ovarian cancer is still the most mortal gynaecological cancer in the world. Even after achieving a good clinical response after initial treatment, the cancer will relapse in 80% of the patients. Treatments that improves progression-free survival (PFS) are necessary. In 2012, the OCEANS trial showed an improved PFS (12.4 months) for patients with platinum-sensitive recurrent ovarian, primary peritoneal, or fallopian cancer (ROC) treated with carboplatin, gemcitabine plus the monoclonal antibody bevacuzimab followed by maintenance therapy of bevacuzimab (BV) till progression (BCARGEM). Based on this trial, bevacizumab was incorporated in the second line treatment protocol of various European countries for patients with platinum-sensitive ROC. However, there is no real life information yet available on the effectivity and tolerance of this one randomized clinical trial (RCT) in clinical practise. Therefore, the aim of this study was to assess what the real time efficacy and tolerance of treatment with BCARGEM was in patients with platinum-sensitive ROC. Methods: All patients with platinum-sensitive ROC and treated with BCARGEM in the UMC Utrecht Cancer Center were retrospectively selected for analysis. All data such as baseline information, assessments and adverse events during cycles were obtained from medical records. The primary outcome was PFS; secondary outcomes were relative dose intensity (RDI), adverse events (AE) leading to dose modifications, and overall survival (OS). Results: Overall, the median PFS of the 39 patients with platinum-sensitive ROC and treated with BCARGEM was 9.4 months (95% CI 4.6 - 14.2). The median OS was 20.9 months (95% CI 15.0-26.7). The average RDI for BCARGEM was 67%. None of the patients reached a RDI of 100%. In most patients (69%) neutropenia grade ≥ 3 led to dose modifications or discontinuance of BCARGEM. After treatment with BCARGEM, 34 patients started treatment with BV till progression. The median number of cycles of BV was 5. In 26 of the cases the BV was ended due to progression. Conclusions: In our retrospective study, the PFS of real life patients treated with BCARGEM is lower compared to the study patients in the OCEANS trial; 9.4 versus 12.4 months. In addition, the RDI of BCARGEM is very low reflecting the many AEs leading to dose modifications or discontinuation. Therefore, this study underlines the fact that results of RCTs with strict in- and exclusion criteria do not represent actual outcomes in clinical care, because the selected study patient does not match the patient we face in real time.
Association of Ki67 expression levels and therapy outcome in low-grade serous ovarian cancer.
Authors: Grabowski J.P. P. , Martinez-Vila Clara , Richter Rolf , Taube Eliane T , Braicu Elena Ioana , Sehouli Jalid
Published: May 2019

5577

Background: Low-grade serous ovarian cancers (LGSOC) characterize different clinical pattern and lower chemotherapy responsiveness. The expression level of Ki67 is associated with prognosis differences in this patient group. However, Ki67 has not been evaluated as prognostic marker and a predictor of therapy outcome until now. Methods: Patients with LGSOC and Ki67 expression results were identified in institutional database. Receiver-operator characteristics (ROC) curve analysis was performed to find cut off values of Ki67% to discriminate patients with residual tumor mass after surgery from maximal debulked patients, and platinum sensitive patients from platinum resistant patients. Odd ratios (OR) and 95% confidence intervals (95% CI) were calculated using univariate and multivariate logistic regression analysis. Two-sided tests p < 0.05 and are considered statistically significant at a 95% confidence interval. The statistical analysis was performed with the IBM SPSS Statistics 25.0. Results: A total of 68 patients with LGSOC were included. All patients underwent surgery and 15 (22.1%) patients had residual mass ( > 0 mm) after cytoreduction. Sixty-one (89.7%) patients received platinum based first-line chemotherapy. Forty-three patients revealed a recurrence ≥6 months and eleven < 6 months. Patients with Ki67 < 3.6% had significantly higher therapy-free interval (TFI≥6 months), (OR = 13.9, 95%CI 1.62-118.40, p = 0.016). In the multivariate analysis of TFI over 6 months including CA 125, age at diagnosis, peritoneal carcinomatosis and ascites ( > 500ml) Ki67 < 3.6% remained significant (OR = 17.6, 95%CI 1.56-197.52, p = 0.020). Moreover, Ki67% > 3.6% were associated with higher risk of residual mass after surgery (OR = 6.75, 95%CI 1.39-32.87, p = 0.018). Conclusions: It is the first study showing association between Ki67% expression and duration of TFI to platinum-based chemotherapy as well as outcome of the surgery in LGSOC. Further prospective trials should be planned to develop predictive models in this patients.
Glutaminase (GLS) expression in primary breast cancer (BC): Correlations with clinical and tumor characteristics.
Authors: Vidula Neelima , Yau Christina , Rugo Hope S.
Published: May 2019

558

Background: Tumor cells rely on glutamine for growth. GLS is a mitochondrial enzyme that is necessary for glutamine catabolism, and is present as isoforms GLS1 and GLS2. A GLS1 inhibitor is being studied in triple-negative (TN) BC. We studied GLS1 expression in primary BC to understand associations with clinical and tumor characteristics in publically available databases. Methods: GLS1 mRNA levels were evaluated using expression data from the TCGA (n = 817) dataset, with confirmation in METABRIC (n = 1992). Associations between GLS1 levels and tumor subtype were assessed using ANOVA, followed by the post-hoc Tukey test for pairwise comparisons. Pearson correlations were used to study associations between GLS1 and selected genes. Correlations with overall survival (OS) were studied with Cox proportional hazard model. For all analyses, p < 0.05 was considered significant. Results: In TCGA, the expression of GLS1 and its isoform GLS2 were significantly inversely correlated (r = -0.32). GLS1 expression was highest in TN compared to hormone receptor (HR)+ and HER2+ BC (p < 0.001). In addition, GLS1 expression was higher in basal vs luminal A, luminal B, and HER2 enriched BC (p < 0.001). GLS1 expression was significantly inversely correlated with ER (r = -0.45), PR (r = -0.34), and AR (r = -0.34), and these inverse correlations remained significant when restricted to TNBC (ER: r = -0.25, PR: r = -0.25, AR: r = -0.30). Consistent with previous reports of MYC upregulation of GLS1, GLS1 expression was significantly positively correlated with MYC (r = 0.26). Similarly, in METABRIC, GLS1 was most highly expressed in basal and TNBC, significantly inversely correlated with the expression of GLS2, ER, PR, and AR, and positively correlated with MYC expression. In METABRIC, higher GLS1 expression was associated with better OS (HR 0.91, p = 0.005); this association remained significant in the TN subset (HR 0.83, p = 0.03). Correlations between GLS1 and genes involved in metabolism and immune activation will be presented at the meeting. Conclusions: GLS1 expression is highest in basal and TNBC, is associated with MYC expression, and may have prognostic implications. These findings support ongoing trials of GLS1 inhibition in TNBC.
Tumor stroma proportion to predict platinum chemoresistance in primary ovarian carcinomas: A prospective study.
Authors: Lou Emil , Vogel Rachel Isaksson , Hoostal Spencer , Grad Aaron , Monu Minnu , Lukaszewski Tomasz , Deshpande Jaai , Linden Michael , Klein Molly , Teoh Deanna Gek Koon , Geller Melissa Ann
Published: May 2019

5581

Background: Platinum chemotherapy resistance occurs in approximately 25% of patients with ovarian carcinoma and represents a major barrier to effective care of this patient population. To date there are no effective nor validate predictive biomarkers of chemoresistance of ovarian carcinomas. We performed a prospective trial designed to enroll patients with ovarian masses suspicious for ovarian cancer, with the goal of identifying tumor-based predictive biomarkers of platinum resistance. Methods: 60 women were enrolled on the study. Tumor specimens were collected from 49 of these women with newly diagnosed pelvic masses, of which 29 were found to have histopathologically proven primary ovarian carcinoma. Of these primary malignant cases, 24 had specimens accessible for assessment of tumor-stroma proportion and data available regarding chemosensitive vs chemoresistance status via review of the medical record using a UMN IRB-approved protocol. Tumor slices were stained with H&E and also for antibodies against two microRNAs (29b and 199a) differentially expressed in ovarian cancer cell lines. Tumor-stroma proportions were assessed by two experienced pathologists blinded to chemoresistance status, with <50% stroma scored as low proportion, >50% scored as high proportion. Results: The average age of assessed patients with malignant tumors was 62. 87.5% had high-grade epithelial carcinomas. Baseline median CA-125 was 416 (range 32-2782). 80% of ovarian cancer patients with chemoresistance had tumor stroma proportions >50%; 73.7% of cancer patients with chemosensitive tumors had proportions <50% (p-value: 0.047). Expression of miR29b or 199a did not significantly correlate with chemoresistance. Conclusions: Tumor-stroma proportion is a useful predictive biomarker of platinum chemoresistance. If validated in larger datasets, it would be a relatively inexpensive and helpful tool for tailoring treatment strategies and clinical decision-making in women with ovarian cancer.