bluuebunny/crossref_metadata_2025 huggingface dataset:
Socioeconomic disparities in supportive therapy use and tolerance of aromatase inhibitors in patients with early-stage, hormone-positive breast cancer.
Authors: Kier Melanie Wain , Li Zhiqiang , Casasanta Nicole , Patel Rima , Agarwal Parul , Zimmerman Brittney Shulman , Yang Yunchen , Fink Marc Y , Zhou Xiang , Newman Scott , Chen Rong , Schadt Eric , Oh William K. , Tiersten Amy
Published: June 2022

523

Background: Socioeconomic disparities impact breast cancer survival with significantly higher mortality among women of lower socioeconomic status. Little is known about how disparities affect patients with early-stage hormone receptor positive (HR+) breast cancer (BC) and patients’ tolerance and adherence to standard of care adjuvant aromatase inhibitor (AI) therapy. AI-related adverse effects are common and can cause therapy intolerance and early discontinuation. Supportive therapies have been shown to improve symptom tolerability when utilized by patients. This study assessed socioeconomic disparities in utilization of supportive therapies and adherence to initial AI therapy. Methods: We performed a retrospective chart review of all female patients at our academic institution with early-stage, HR+, BC who were initiated on adjuvant AI between 2011-2020. We collected information on side effects, duration of first AI and use of supportive therapies. We linked median family income with zip codes based on national census data and sorted them based on the Pew Research Center categorization. Primary endpoints were the rate of discontinuation of AI at 1-year and utilization of supportive therapies in relation to income, insurance coverage and primary language. The Fisher's exact test, Pearson's Chi-squared test, and Wald test methods were used to compare rates of discontinuation of front-line AI therapy and use of supportive therapies for each group. Results: We identified 1006 patients of whom 95% (n = 954) had AI related side effects yet only 31% (n = 311) received supportive therapies in the first year of AI treatment. The majority (59%) of patients were in the middle-income range ($52,200-$156,000), followed by upper (24%) and lower (17%) income. Upper-income was associated with higher use of supportive therapies (OR 1.46, p = 0.031) but was not associated with lower 1-year discontinuation rate. Medicare was the most common insurance coverage (45%), followed by Commercial (32%) and Medicaid (23%). English was the primary language for 86% of patients. Neither insurance coverage nor primary language was associated with either endpoint. In evaluating race, Black patients had the least use of supportive therapies (p < 0.001), yet this group had the lowest 1-year discontinuation rate (p = 0.005). Conclusions: Our results demonstrate that income and race were associated with use of crucial supportive therapies that are proven to help patients mitigate AI toxicities. The etiology of these disparities is likely multifactorial and requires further study to ensure equitable care and access for all patients.
Outcomes of patients with T1a,b N0 Her2-positive breast cancer treated with adjuvant trastuzumab in a prospective registry in Ontario, Canada.
Authors: Eisen Andrea , Gill Tripat , Habbous Steven , Beca Jaclyn M. , Arias Jessica , Chan Kelvin K. , Trudeau Maureen E.
Published: June 2022

533

Background: Multiple randomized trials of chemo +/- tras in early stage, Her 2 positive BrCa demonstrated improvement in survival, but patients (pts) with T1a,b N0 disease were mostly excluded. Given the uncertainty of benefit in this group and the toxicities of chemo + tras, treatment in Ontario was funded for these patients conditional upon data collection for toxicity and survival endpoints. We report the outcomes for 483 patients enrolled in this Evidence Building Program (EBP). Methods: Between 2011 and 2018, 483 eligible pts with Her 2 pos disease and adequate cardiac function were treated with chemo + tras in the EBP. Cardiac toxicity, febrile neutropenia (FN), event-free (EFS), and overall survival (OS) were determined for this cohort from administrative datasets, and compared retrospectively to controls of similar stage selected from the Ontario Cancer Registry who did not receive tras and/or chemo. For the EBP cohort, clinicians also reported changes in left ventricular ejection fraction (LVEF). Results: Pt characteristics are shown in the Table. EBP patients had improved OS when compared to controls who received no chemo or tras. The 3-year OS in the EBP pts was 99.1%, versus 96.9% in the controls [adjusted HR 0.59 (95% CI 0.29-1.20)]. Patients receiving EBP tras had a significantly longer EFS than controls with or without chemo [adjusted HR 0.54 (0.36-0.83), p=0.005]. Use of chemo + tras in EBP pts was associated with an increased risk of clinical congestive heart disease (CHD) and febrile neutropenia (FN). About 3.5% of pts experienced CHD during treatment with chemo + tras. About 6% of pts had an absolute reduction of LVEF >10% or reached LVEF <50%. In an adjusted analysis, the risk of CHD was higher in older pts [HR 1.06 (1.03-1.08) per 1-yr increase in age, p<0.0001) and for pts who received anthracyclines [HR 5.00 (1.71-14.7). In a matched analysis, the crude frequency of FN during treatment was 20% in EBP pts vs. 3% among controls who did not receive chemo or tras (p<0.001). Conclusions: Analysis of the Ontario EBP for pts with, T1a,b N0 HER2 pos BrCa revealed that the prognosis is excellent and is improved with the use of chemo + tras. The safety profile was expected and tolerable, especially when non anthracycline chemo was used. These results led to a funding policy change where prospective data collection has been discontinued and chemo + tras is now routinely funded in this population. [Table: see text]
Efficacy and safety of initial five years of adjuvant endocrine therapy in postmenopausal hormone receptor-positive breast cancer: A systematic review and network meta-analysis.
Authors: Liao Hao , Zhong Jianxin , Pei Wendi , Bin Shao , Liu Xiao-ran , Rugo Hope S. , Li Huiping
Published: June 2022

535

Background: Endocrine therapy has greatly improved the clinical outcomes of hormone receptor-positive breast cancer patients. However, there was an unmet need to identify the potentially best regimen of initial adjuvant endocrine therapy. Therefore, in this network meta-analysis, we synthesized the latest evidence to indirectly compare the efficacy and safety among different 5 years of regimens of initial adjuvant endocrine therapy. Methods: We conducted a systematic search of the PubMed, Web of Science, and EMBASE in January 2022. Randomized clinical trials assessing the efficacy and safety of initial 5 years of adjuvant endocrine therapy were included. The primary outcomes were disease-free survival (DFS) and overall survival (OS) and the secondary outcome was severe adverse effects (SAEs). A Bayesian network meta-analysis was carried out to indirectly compare all regimens and the SUCRA values were used to obtain rankings. Results: Eleven studies with 49,987 subjects were included. For DFS, exemestane (EXE) (hazard ratio [HR] 0.91, 95% confidence interval [95%CI] 0.87-0.96), anastrozole (ANA) (0.94, 0.90-0.97), letrozole (LET) (0.93, 0.89-0.97), tamoxifen (TAM) followed by EXE (0.91, 0.87-0.96), and TAM followed by ANA (0.92, 0.87-0.98) were more favorable than TAM, with TAM followed by EXE ranking as the first of SUCRA. For OS, only TAM followed by ANA showed significant superiority than TAM (HR 0.91, 95%CI 0.86-0.97) and ranked as the first of SUCRA. For SAEs, EXE (HR 1.72, 95%CI 1.04-2.98), ANA (1.58, 1.03-2.43), and LET (1.63, 1.02-2.57) showed greater associations with bone fracture than TAM. However, no significant difference in the incidences of cardiac events, thromboembolic events, and cerebrovascular events was found among all comparisons. Conclusions: The sequential use of aromatase inhibitors may be the optimal treatment mode for hormone receptor-positive postmenopausal early breast cancer patients. In addition, the three kinds of aromatase inhibitors achieved roughly equal efficacy, but caused different types of SAEs.
The real-world experience of adjuvant docetaxel and cyclophosphamide (TC) chemotherapy in HER-2 negative breast cancer.
Authors: Giffoni M. M. Mata Danilo , Chan Kelvin K. , Eisen Andrea , Pezo Rossanna C. , Menjak Ines B. , Trudeau Maureen E.
Published: June 2022

538

Background: Adjuvant chemotherapy in breast cancer (BC) substantially improves overall survival (OS) and the risk of recurrence. The short and long-term side effects of anthracycline, and its modest benefits in the adjuvant setting, led to controversy about its role in comparison with TC. We aim to compare the OS of TC with anthracycline-based regimens in Ontario, the most populous province in Canada. Methods: We conducted a retrospective population-based cohort study using the Institute for Clinical Evaluative Sciences (ICES) database, involving females with stage I-III BC HER2-negative. Patients were treated with adjuvant chemotherapy between January 2009 to December 2017. The anthracycline regimens for comparison were as follows, FEC-D: Fluorouracil, Epirubicin, Cyclophosphamide, followed by Docetaxel; and ACT: Doxorubicin, Cyclophosphamide, followed by Docetaxel or Paclitaxel. Exclusion criteria included missing baseline characteristics, a prior history of malignancy or chemotherapy starting more than 120 days from breast surgery. The end of follow-up was March 31st, 2018. Adjusted analyses to compare OS by positive axillary lymph nodes (LN) and chemotherapy regimens were conducted with Cox proportional hazards models. Results: Of a total 10634 female patients with BC, 60% were ≥ 50 years-old, with 19.6% stage I, 61.1% stage II, and 19.3% stage III and 7130 (67%) women were classified as ER+ and 2379 (22.4%) as ER-. Among 5764 (54.2%) patients with positive LN, 4300 (40.4%) had LN 1-3 and 1464 (13.8%) had LN ≥ 4. There were 4945 (46.5%) high-grade cases. There were 2487 (23.5%) patients treated with TC, 2981 (28%) with ACT, and 5166 (48.5%) with FEC-D. With a median follow-up of 5.5 years, the OS comparison for the entire study population showed hazard ratio (HR) of TC vs ACT was 1.47 (95% CI 1.14 – 1.90), p = 0.0027 and TC vs FEC-D HR was 1.48 (95% CI 1.18 – 1.86), p = 0.0007. For ER+ patients treated with TC, the OS comparison of LN 1-3 and LN ≥ 4 vs. LN 0 showed HR 1.34 (95% CI 0.81 – 2.21), p = 0.26, and HR 4.29 (95% CI 2.09 – 8.79), p < 0.0001, respectively. For ER+ LN 0 patients, the OS HR of TC vs. ACT was 1.15 (95% CI 0.58 – 2.35), p = 0.67, and TC vs. FEC-D HR was 1.38 (95% CI 0.81 – 2.33), p = 0.23. For ER- patients treated with TC, the OS comparison of LN 1-3 and LN ≥ 4 vs. LN 0 showed HR 1.12 (95% CI 0.42 – 3.01), p = 0.82 and HR 4.41 (95% CI 1.33 – 14.59), p = 0.015, respectively. For ER- LN 0 patients, the OS HR for TC vs. ACT was 2.04 (95% CI 1.09 – 3.81), p = 0.025, and TC vs. FEC-D HR was 2.05 (95% CI 1.08 – 3.90), p = 0.028. Conclusions: Patients treated with adjuvant TC who had four or more axillary LN had significantly lower OS when compared to patients with LN 0. For women with ER- disease, TC demonstrated a significant unfavourable survival outcome when compared to anthracycline-based treatments.
Adherence to adjuvant endocrine therapy assessed by data from prescription renewals and medical records from tamoxifen in Swedish patients with cytochrome P450 2D6 (CYP2D6) genotyped early breast cancer.
Authors: Thoren Linda , Margolin Sara , Eliasson Erik , Bergh Jonas C. S. , Lindh Jonatan D.
Published: June 2022

542

Background: Suboptimal adherence to adjuvant endocrine treatment (AET) is an important clinical concern. A correlation between CYP2D6 activity and tamoxifen discontinuation has been suggested. The main aim of this study was to investigate the consistency between prescription refill data and reports from medical records on adherence to AET in early breast cancer. We also studied if there was an association between menopausal status, CYP2D6 activity, estimated risk for recurrence and adherence to AET. Methods: 1235 pre-and postmenopausal Swedish breast cancer patients operated 2006 – 2014, genotyped for CYP2D6, who initiated adjuvant tamoxifen treatment, were included in the study. Information on AET was retrospectively collected from both medical records and the Swedish Prescribed Drug Registry. Consistency was defined as dispensed doses of AET divided by AET intake documented in medical records. Adherence was calculated for patients with at least 4.5 years of follow up and was defined as Medical Possession Rate (MPR) ≥ 80 %. Subgroup analyses were performed based on menopausal status, recurrence-risk and CYP2D6 activity. Results: In 84% of the patients the consistency of AET between the sources of information was within 80-125%. Consistency < 80% was most frequent in premenopausal/high risk patients and CYP2D6 Poor Metabolizers (PM). Among 899 patients with at least 4.5 years follow up, adherence to tamoxifen was 72% according to prescription refill data, compared to 77% as reported by medical records. When including aromatase inhibitors adherence increased to 82% and 88%. Adherence did not differ by menopausal status or risk for recurrence. CYP2D6 PM had poorer adherence (54%) to tamoxifen compared to patients with the highest CYP2D6 activity (83%). Conclusions: Consistency between medical records and dispensing data on adherence was better than anticipated. Adherence to AET was good, 82% when including switch to aromatase inhibitors. Surprisingly, CYP2D6 PMs had low adherence to tamoxifen, despite a reduced risk of side effects according to previous studies. Further work is needed to clarify the impact of CYP2D6 activity on adherence to tamoxifen.
Real-world effectiveness of first-line maintenance olaparib in women with BRCA-mutated advanced ovarian cancer: U.S. retrospective cohort study.
Authors: Eskander Ramez Nassef , Alam Naufil , Long Grainne H. , Ozgoren Ozan , Ambler Will , Volpe Stephanie , Moore Kathleen N.
Published: June 2022

5518

Background: Following cytoreductive surgery and first-line (1L) platinum based chemotherapy, 70% of patients (pts) with newly diagnosed advanced ovarian cancer (AOC) experience relapse within 3 years. 1L maintenance treatment (tx) with olaparib monotherapy, a poly (ADP-ribose) polymerase inhibitor, extended progression free survival in pts with BRCA mutated (BRCAm) AOC in the SOLO-1 (NCT01844986) randomized controlled trial (RCT). We aimed to describe real world characteristics, tx patterns, and clinical outcomes of pts with newly diagnosed, BRCAm AOC. Methods: Data were collected from 457 pts via electronic case report forms in the US. Pt eligibility criteria were positive BRCAm test result between Jan-June 2019 (6 months post 1L olaparib FDA approval), newly diagnosed AOC (no maintenance tx prior to index), aged ≥18 years, no RCT enrollment, no active neoplasia, no prior tx for metastatic/stage IV cancer. Pt follow up was until July 2021. Kaplan-Meier (KM) estimation was used for time to event analysis using progression proxies: Time to subsequent therapy and discontinuation (or death for both) from initiation of 1L maintenance olaparib monotherapy. Results: Pt mean age (±SD) at index was 62 (±10) years, 64% of pts were white and 18% African American; further clinical characteristics are in the table. 95% of pts received ≥1 pharmacological tx. At 1L, 36% of pts (156/433) received maintenance tx after chemotherapy, with 64% of pts (277/433) receiving routine surveillance (no maintenance tx). Olaparib was the most common maintenance tx (67%, 105/156), with 67% of pts (70/105) prescribed olaparib monotherapy. At 24 months, the KM model estimated 91% of pts (95% confidence interval: 82, 96) would not progress to their subsequent therapy, with a median discontinuation of olaparib monotherapy of 25.0 (interquartile range [IQR]: 21.0, not estimable) months, over a median follow-up of 22.0 (IQR: 20.6, 24.0) months. Conclusions: This real world study complements SOLO-1 RCT data by demonstrating prolonged benefit of 1L olaparib in newly diagnosed pts with BRCAm AOC in terms of lower likelihood of progression (tx switch/death). To assess real world tx effectiveness globally, data collection across further eight countries is due to be completed in 2022. [Table: see text]
Basket study of oral progesterone antagonist onapristone extended release (ONA-XR) in progesterone receptor positive (PR+) recurrent granulosa cell (GCT), low-grade serous ovarian (LGSOC), or endometrioid endometrial cancer (EEC).
Authors: Grisham Rachel N. , Li Karen , Zhou Qin , Iasonos Alexia , Girshman Jeffrey , Shah Pooja , Jang Dasom , Kyi Chrisann , Cohen Seth M. , O'Cearbhaill Roisin Eilish , Friedman Claire Frances , Makker Vicky , Sabbatini Paul , Hensley Martee Leigh , Zamarin Dmitriy , Aghajanian Carol
Published: June 2022

5521

Background: ONA-XR is a type I full progesterone antagonist that inhibits progesterone-mediated PR activation and stabilizes PR association with corepressors. GCT (98% of cases PR+), LGSOC (58% of cases PR+) and EEC (67% of cases PR+) are hormonally driven cancers that generally have poor responses to chemotherapy. Methods: This is an open-label, single-institution basket study of ONA-XR in patients with PR+ recurrent GCT (cohort 1), LGSOC (cohort 2), or EEC (cohort 3) (NCT03909152). Eligible patients required receipt of >1 prior line of chemotherapy, measurable disease by RECIST 1.1, and tumor tissue collected ≤3 years prior to enrollment with PR ≥ 1% by IHC. Patients received ONA-XR 50 mg PO BID until progression or intolerable toxicity. The study was designed as 3 parallel Simon 2-Stage studies. The primary objective was to evaluate efficacy, determined by RECIST 1.1, with at least 1/14 (cohort 1), 2/16 (cohort 2) or 4/19 (cohort 3) responses needed during stage 1 for advancement to stage 2. Secondary objectives included safety and tolerability, clinical benefit rate (CBR; stable disease lasting ≥ 16 weeks), and progression-free survival (PFS) as estimated by Kaplan Meier method. Results: The study enrolled patients to cohorts 1-3 from 5/2019 to 5/2020. Cohort 2 (LGSOC) enrolled 5 patients and cohort 3 (EEC) enrolled 1, both closed early due to slow accrual. Cohort 1 (GCT) enrolled 14 patients and completed Stage 1 accrual. There were no responses by RECIST 1.1 criteria observed in cohorts 1-3. In cohort 2 (LGSOC), 4/5 enrolled patients were evaluable, the median PFS was 4.4 months (1.8-NE) and CBR was 50% (6.8-93.2%). All 14 patients enrolled to cohort 1 (GCT) were evaluable with a median PFS of 3.5 months (1.6-8.8%), 6-month PFS rate of 30.1 % (8.4-56%), and 12-month PFS rate of 20.1% (3.5-46.4%). The CBR was 35.7% (12.8-64.9%). Two patients with GCT remain on active treatment for > 18 months. Grade 3 adverse events occurred in 5 patients: abdominal pain (2), small bowel obstruction (1), syncope (1), thromboembolism (1), urinary tract infection (1), and febrile neutropenia (1). Grade 3 laboratory toxicity occurred in 5 patients: anemia (2), neutropenia (1) and lymphopenia (2). Conclusions: ONA-XR was well tolerated and exhibited a 12-month PFS rate of 20.1% and a CBR of 35.7% in patients with GCT. No objective responses were observed. Cohorts 1-3 have closed to accrual, with 2 patients continuing active treatment for >18 months. Cohort 4, which combines ONA-XR with anastrozole, is currently enrolling patients with GCT. Clinical trial information: NCT03909152. [Table: see text]
Cytoreductive surgery plus HIPEC for advanced epithelial ovarian cancer: Analysis from a multicentric national Indian HIPEC registry of 1,470 patients—An ISPSM Collaborative study.
Authors: Somashekhar S.P. , Deo S.V.S. , Sekhon Rupinder , Rao Thammineedi Subramanyeshwar , Chaturvedi Harit , M S Ganesh , Joshi Rama , Kothari Kalpana , Gandhi Amit , Rajgopal Ashwin K. , Ray M D , Iyer R Rajagopalan , G N Hemanth , Kumar Rohit
Published: June 2022

5525

Background: Improved long-term results can be achieved in advanced epithelial ovarian cancer (EOC) patients using optimal cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Methods: Indian society of peritoneal surface malignancy (ISPSM) is a registered body which maintains prospective data of 26 centers across India who perform CRS –HIPEC. From February 2017 until January 2022, 1470 patients with advanced EOC were treated with CRS-HIPEC. He general practice patterns and the oncological outcomes in terms of progression free survival (PFS) and overall survival (OS) & post-operative morbidity and mortality is reported. Results: Upfront (n = 156), interval (n = 645) and recurrent (n = 669) cytoreductions were performed based on the timeline at presentation. Mean age 54.5±10.74, PCI 13. 6±5.2, duration of surgery 10.6±1.h hrs. 36.4% had total peritonectomy, 12.7% had multivisceral resection, 41.8%had bowel resections and stoma rate was 7.4%. 60.3% had semiopen HIPEC, 83.1% used cisplatin for HIPEC and 83.1 % had HIPEC for 90 minutes. Overall G3-G5 morbidity was 25.4% with major ones being post-operative intra-abdominal collection (21.8%), electrolyte imbalance (16.4%), pulmonary (16.4%) followed by hematological (12.7%). Surgical morbidity was more in upfront cytoreduction group compared to interval group (20% versus 13.5%) and recurrent group (20% versus 15%), respectively. The 30 day mortality was 3.8%. With a median follow-up of 46 months, median PFS was 33 months in primary (upfront plus interval) group and 16 months in recurrent cytoreduction group. Median OS was not achieved in both primary and recurrent groups (4 year OS rates: 60 and 55%, respectively). Conclusions: This prospective database provides a collation and audit of the management of advanced epithelial ovarian cancer with CRS HIPEC in multiple centers registered under ISPSM. In advanced EOC patients, CRS plus HIPEC offers potential benefits in PFS and OS rates, with acceptable rates of morbidity and mortality and can be practiced even in resource constrained setting.
Factors associated with receipt of second-line recurrent or metastatic cervical cancer treatment in the United States: A retrospective administrative claims analysis.
Authors: Sonawane Kalyani , Castellano Tara , Washington Christina , Ayer Turgay , Surinach Andy , Kirshner Carol , Ting Jie , Chhatwal Jagpreet , Moore Kathleen N.
Published: June 2022

5532

Background: There is limited real-world data on the proportion of eligible patients who received second-line (2L) treatment following progression on first-line (1L) systemic therapy for recurrent or metastatic cervical cancer (r/mCC). In addition, factors impacting selection of 2L are not well-understood. The objective of this study was to determine the prevalence and predictors of subsequent therapy among patients with 1L-treated r/mCC. Methods: We conducted a retrospective analysis of the 2015-2020 MarketScan claims database. Women ≥18 years of age with at least one inpatient claim or two outpatient claims with a diagnosis for malignant neoplasm of the cervix followed by 1L therapy codes were identified. The last recorded date of 1L treatment was assigned as the index date for each woman. Continuous enrollment criteria of minimum 3-month pre-index and 12-month post-index were applied. Women with claims for a new therapy after 60 days but no later than 365 days from the end of 1L treatment were identified as those who continued r/mCC treatment. We used descriptive statistics to examine the baseline characteristics of the final analytical cohort. A multivariable logistic regression model examined the factors associated with treatment discontinuation. All analyses were performed using SAS, Cary, NC. P-value was tested at 0.05. Results: A total of 1,080 patients with 1L-treated r/mCC were identified, of whom 384 met the study criteria. Post-1L treatment, 196 (51.0%) patients received a new therapy within a median duration of 122 days. A total 188 (49.0%) patients did not receive subsequent therapy. The geographic location of patient (identified based on census region as Northeast, Midwest, South, or West) and prior bevacizumab exposure were significant predictors of receiving subsequent therapy. Specifically, patients from the Midwest (odds ratio [OR] = 0.43; 95% CI: 0.23-0.84) and Southern (OR = 0.53; 95% CI: 0.29-0.96) regions had lower likelihood of receiving 2L treatment after 1L, compared to those living in the Northeast. Women without prior bevacizumab treatment were also less likely to receive subsequent therapy (OR = 0.65; 95% CI: 0.42-0.99). Age, type of health plan, and comorbidities were not associated with the likelihood of receiving subsequent treatment. Conclusions: Overall, nearly half of the 1L-treated r/mCC patients did not continue to 2L therapy, with findings showing treatment drop-off differing significantly by geographic region and prior treatment. Additional research and targeted outreach efforts are needed to understand geography-, population-, or practice-specific barriers impacting access to therapy among r/mCC patients.
Immunological correlatives of durable responses and survival benefit for patients with cervical cancer in a trial of combined chemotherapy and immune therapy.
Authors: Honan Amanda M , Castillo Rosa P , Castillo Melissa N , Saigh Shannon J , Cai Xiaodong , Chen Zhibin , Huang Marilyn
Published: June 2022

5537

Background: Recurrent, metastatic, or persistent cervical cancer is largely an incurable disease due to lack of effective therapies. New treatment strategies are needed to provide long-term anti-tumor responses. We sought to gain insight into the immune pathways contributing to treatment response to immunotherapy. Methods: Fourteen patients with recurrent, persistent, or metastatic cervical cancer were enrolled in a single-arm phase II clinical trial (NCT03367871) with the combination of chemotherapy, bevacizumab and pembrolizumab regardless of tumor PD-L1 status. We designed a 40-color full spectrum flow cytometry panel to profile the protein markers of immune cells in peripheral blood mononuclear cells (PBMCs) at the single cell level to assess immunological correlates in blood with patients' anti-tumor responses. Results: In this trial with a cohort of predominantly Black and Hispanic patients (93%), 50% had durable responses to a combination therapy, and no difference was observed in the combined PD-L1 score (CPS) between responders and non-responders. With 40-color flow cytometry multiplex assays, we detected several differences between the non-responders and responders within the B and T cell populations. Within the B cell population, we observed a significant increase in the HLA+CD200hi B cells, a potentially suppressive cell subset, within the non-responders while among the responders we observed an increase in the number of HLA+CD200lo B cells. This HLA+CD200lo subset was mainly composed of IgD-CD27- memory B cells, a population suggested to have effector function. Moreover, the HLA+CD200hi B cell population contained a higher percentage of PD-L1 expressing cells than the HLA+CD200lo population, further supporting the suggestion that the HLA+CD200hi population may be an immunosuppressive subset. Within the T cell compartment, we observed an increase in the number of CD4+CD69+ T cells, which represent an activated CD4 T cell population, in the responder group compared to the non-responder group. The number of activated CD4+ T cells was observed to correlate (r = 0.5) with the HLA+CD200hi B cell subset. Conclusions: This study identified novel immunological correlates in peripheral blood that were associated with durable antitumor responses and survival benefit for cervical cancer patients. These results suggest a role for T-B collaboration in effective antitumor immunity induced by combination of chemotherapy and immune therapy against cervical cancer. Clinical trial information: NCT03367871.
Detection of early-stage breast cancer in women by plasma lipidomic profiling.
Authors: Kehelpannala Cheka , Pascovici Dana , Li Desmond , Heffernan Kerry , Lamoury Gillian , Batarseh Amani M.
Published: June 2022

554

Background: Early detection of breast cancer provides the best opportunity for cure. Mammography is the benchmark for screening, but suffers technical, logistic, and diagnostic limitations. An effective and accurate blood test to detect early stages of the disease should increase the screening detection rate for breast cancer. We conducted a series of lipidomic studies in early-stage breast cancer patients and combined the datasets via a machine learning driven analysis to test if plasma lipidomic profiles can detect breast cancer. Methods: Blood samples were collected from women with stage 0-IV breast cancer (4 separate cohorts) with age and BMI matched breast cancer-free controls. Lipids from plasma enriched extracellular vesicles were extracted and analysed by high resolution accurate mass LC-MS. A commercially available software was used to annotate and quantify >400 manually curated lipid species. Following variable selection, a lipid signature was identified capable of distinguishing breast cancer samples from control. Results: Plasma samples from women with breast cancer were distinguished from controls with an average cross-validated accuracy of 0.81, and average AUC of 0.84 across 4 cohorts (Table 1). An optimised cross-cohort subset of early-stage IDC, DCIS and ILC were differentiated from controls with a cross-validated AUC of 0.90, sensitivity of 0.88 and specificity of 0.82 (201 early-stage breast cancer, 199 controls) (Table 1). For this optimised cohort our test achieved a sensitivity of 0.71 at a prescribed specificity of 0.90, or equivalently a sensitivity of 0.89 at a prescribed specificity of 0.80. Conclusions: Our study demonstrates the high sensitivity and specificity of a lipid biomarker signature with potential for early detection of breast cancer. Ongoing studies will prospectively compare the lipid-biomarker based test against mammographic and pathological diagnosis. [Table: see text]
Efficacy and safety of pembrolizumab in combination with anlotinib in the treatment of refractory or recurrent high-grade serous ovarian cancer: A phase 2 nonrandomized clinical trial.
Authors: Jiang Man , Li Tianjun , Wang Guanqun , Zhang Xiaochun
Published: June 2022

5543

Background: Anlotinib, an oral multi-targeted receptor tyrosine kinase inhibitor (TKI), exhibits good safety and efficacy in many advanced refractory solid tumors. Previous studies have indicated that anlotinib has synergistic effects with anti–programmed death-1 antibodies via modulation of the tumor microenvironment. Our study aims to examine the efficacy and safety of anlotinib-pembrolizumab combination therapy as a treatment for refractory or recurrent High-Grade Serous Ovarian Cancer. Methods: Patients with refractory or recurrent High-Grade Serous Ovarian Cancer received pembrolizumab (200 mg, intravenously over 60 minutes, once every 3 weeks) plus anlotinib (12 mg/day, orally, 2 weeks on and 1 week off, every 3 weeks) therapy or pembrolizumab (200 mg, intravenously over 60 minutes, once every 3 weeks) monotherapy, respectively. Primary end points were progression-free survival (PFS) and overall survival (OS). The relationships of potential biomarkers with clinical efficacy were also evaluated. Results: A total of 33 patients were enrolled, with 15 participants received the anlotinib-pembrolizumab combination regime and 18 with pembrolizumab monotherapy, respectively. Grade 3 treatment-related adverse events (TRAEs) were recorded in 3 participants (20%) receive the combination treatment and 3 (16.7%) in the pembrolizumab monotherpay group, respectively. The PFS were 13.0 months and 8.0 months to anlotinib-pembrolizumab combination regime and pembrolizumab mono-treatment, respectively. And the OS of the two groups were equal as 31 months. In the anlotinib-pembrolizumab combination treatment group, patients with ARID1A mutation indicated a significantly survival benefit compared patient with the wide type (PFS: 12.5 VS. 7.0, P = 0.004 ). Conclusions: The anlotinib-pembrolizumab combination showed promising efficacy and favorable safety as treatment for refractory or recurrent High-Grade Serous Ovarian Cancer. The ARID1A are potential biomarkers for predicting the efficacy of this novel regimen.
OReO/ENGOT Ov-38 trial: Impact of maintenance olaparib rechallenge according to ovarian cancer patient prognosis—An exploratory joint analysis of the BRCA and non-BRCA cohorts.
Authors: Selle Frederic , Asselain Bernard , Montestruc François , Bazan Fernando , Pardo Beatriz , Salutari Vanda , Marmé Frederik , Ør Knudsen Anja , Bologna Alessandra , Madry Radoslaw , Glasspool Rosalind , Henry Stéphanie , Korach Jacob , Lheureux Stephanie , Shaw Bob , Santaballa Ana , Cioffi Raffaella , Canzler Ulrich , Lortholary Alain , Pujade-Lauraine Eric
Published: June 2022

5558

Background: In the Phase IIIb OReO/ENGOT Ov-38 trial (NCT03106987), maintenance olaparib (O) rechallenge significantly improved progression-free survival (PFS) vs placebo in patients (pts) with platinum-sensitive relapsed ovarian cancer (PSROC) regardless of their BRCA status (Pujade-Lauraine, ESMO 2021). The impact of prognostic factors on this PFS benefit were unknown. Methods: Pts had PSROC, one prior line of PARP inhibitor (PARPi) maintenance and were in response to platinum-based chemotherapy (Cx). Pts were enrolled into two cohorts – BRCA mutated (BRCAm) and non-BRCAm – and randomized to receive maintenance O (300 mg bid) or placebo. Primary endpoint was PFS. Post-hoc individual patient data meta-analysis was used to combine both cohorts using fixed and random effect models, interaction, and stratified tests in the Cox model. Stepwise Cox multivariate model for PFS and logistic regression models were used for late relapse, defined as disease progression occurring >24 weeks after randomization. Randomization stratification criteria and cohort effect were included in all models. Results: This study included 220 pts from the BRCAm (n=112) and non-BRCAm (n=108) cohorts recruited between October 3, 2017 and February 10, 2021. No heterogeneity was detected between cohorts: Cochran’s Q test P=0.53 (fixed and random); interaction test P=0.63. The O effect was consistent, and no significant interactions were observed between subgroups. In the multivariate PFS analyses, the main independent factors for prognosis were CA-125 level, visceral disease (liver, lung, pleura, brain), and treatment arm. These factors were independent predictive factors for late relapse among the 181 evaluable pts with the opportunity of at least 6 months of follow-up (Table). Conclusions: In the OReO/ENGOT Ov-38 trial, CA-125 level and presence of visceral disease at baseline were the best predictors of patient outcome. Maintenance olaparib rechallenge was effective overall regardless of prognostic subgroup. Clinical trial information: NCT03106987. [Table: see text]
Whole transcriptome analysis of tumors with discordant oncotype and MammaPrint results in the FLEX trial.
Authors: Socoteanu Matei P. , O'Shaughnessy Joyce , Hoskins Kent , Brufsky Adam , Graham Cathy Lynne , Vukelja Svetislava J. , Misleh Jamal Ghazi , Tedesco Karen L. , Layeequr Rahman Rakhshanda , Lee June , Berrocal Julian , Sharma Kamal , Begas Albert , Crozier Jennifer , Grady Ian , D'Abreo Nina , Kuilman Midas M. , Nguyen Holly , Blumencranz Lisa Eileen , Audeh M. William ,   FLEX Investigators Group
Published: June 2022

556

Background: Genomic tests, such as MammaPrint (MP) and Oncotype DX Breast Recurrence Score (RS), assess risk of recurrence in patients with early breast cancer (EBC). Using both assays may yield discordant results which leads to uncertainty in treatment recommendations. The assays differ in technology and genes analyzed. RS relies on RT-PCR to query 16 cancer-related genes and 5 controls. MP uses a microarray to query 70 cancer-related genes and 465 normalization controls. Here we explore the genetic basis for discordance by using the FLEX whole transcriptome database to examine differentially expressed genes among patients who received discordant RS and MP results. Methods: Patients with EBC enrolled in the FLEX study (NCT03053193) undergo standard of care MP and BluePrint (BP) tests, and consent to clinically annotated whole transcriptome data collection. MP stratifies risk of recurrence as Low risk and High. RS classifies patients as Low Risk (RS 0-10), Intermediate (RS 11-25), and High Risk (RS 26-100). Due to low representation of BP Basal and BP HER2-type tumors in this data set, we only examined BP Luminal-type tumors (N = 705). We used full genome transcriptomes to compare gene expression among discordant cases. Gene expression data were quantile normalized and analyzed using R package ‘limma’. Genes were considered differentially expressed at a fold change of at least 1.7 and an adjusted p-value of lower than 0.05. To keep the analysis as unbiased as possible, comparisons between RS categories only included tumors within the same MP score range and similarly comparisons of MP categories only contained tumors within the same RS score range. Results: The comparisons between discordant cases, their numbers and the amount of differentially expressed genes (DEGs) are shown below. Sample sizes are shown in parentheses. Of the 49 DEGs found in the RS Intermediate group, several are associated with increased proliferation or increased metastatic potential. SCUBE2 and MMP9 were among the 49 genes and are among the 70-genes assayed by MP. Conclusions: The comparisons highlight the genomic diversity of the RS Intermediate (RS11-25) group, as seen with the high number of DEGs. MP separates cases into more genomically distinct categories, as reflected by fewer DEGs. Clinical trial information: NCT03053193. [Table: see text]
Potential indicators in circulating cell-free DNA for monitoring PARP inhibitor resistance in high-grade serous ovarian cancer.
Authors: Chen Gang , Hu Dianxing , Guo Ensong , Yang Bin , Qin Xu , Fu Yu , Fan Junpeng , Zang Rongyu , Zhou Qi , Zhao Weidong , Sun Chaoyang
Published: June 2022

5564

Background: Although the clinical application of PARP inhibitors (PARPis) has brought great survival benefits to patients with high-grade serous ovarian carcinoma (HGSOC), its resistance has gradually become a major challenge for clinicians with the widespread use of PARPis. Unfortunately, there are no effective, non-invasive means for monitoring PARPis resistance in time during maintain therapy. Methods: We collected peripheral blood samples (n = 37) from 37 healthy subjects and a series of longitudinal peripheral blood samples (n = 61) of 25 platinum-sensitive HGSOC patients undergoing Olaparib maintenance therapy. The genome of white blood cell and cfDNA in plasma was extracted for germline and somatic mutation detection by Circular Ligation Amplification and sequencing (CLAmp-seq) based on a targeted 42-gene panel, respectively. Before cfDNA mutation analysis, background noise introduced by random NGS error was removed and clonal hematopoietic mutations were filtered. Variant-supporting reads > 2 and without germline mutations were defined as the criterion for somatic mutations. Progression-free survival (PFS) was collected through regular follow-up. We analyzed the dynamic changes of cfDNA mutation profiles, the correlation between cfDNA mutations and the prognosis of patients, and screened specific mutation sites that closely associated with Olaparib resistance. Results: The elevation of maximum mutant allele frequency (Max MAF) in cfDNA during Olaparib maintenance therapy predicted a poor prognosis of patients ( P = 0.0043). Pathogenic germline mutations in BRCA1/2 or RAD51 were strongly associated with longer PFS ( P = 0.0229) and acquired new MRE11A mutations significantly shortened the PFS in patients ( P = 0.0005). Dynamic fluctuations of somatic mutation sites in CHEK2:p.K373E ( P = 0.0091) and CHEK2:p.R406H ( P = 0.0002) can be used to evaluate the therapeutic efficacy of patients. Remarkably, MRE11A:p.K464R may be a vital driving factor of Olaparib resistance and all patients who acquired new MRE11A:p.K464R in post-treatment cfDNA developed resistance to Olaparib and had significantly shorter PFS than those without it ( P = 0.0005). Besides, the combination of CHEK2:p.R406H and acquired new MRE11A:p.K464R in post-treatment improved the predictive efficiency of patients’ prognosis compared with them alone ( P < 0.0001). Conclusions: Olaparib resistance was robustly associated with the mutation load of tumor cells, and analysis of mutation profiles in cfDNA can be accurately monitor the status of Olaparib resistance in patients with HGSOC. Acquired new MRE11A:p.K464R may be a vital driver of Olaparib resistance and is expected to be a target for anti-tumor drug development.
Clinicopathologic and molecular features associated with response to anti-HER2 therapy in endometrial cancer.
Authors: Shen Sherry , Ma Weining , Zhou Qin , Iasonos Alexia , Zhang Yanming , Ross Dara S. , Makker Vicky , Chui Michael Herman
Published: June 2022

5584

Background: Endometrial cancer (EC) is the most common gynecologic malignancy in the United States. Human epidermal growth factor 2 (HER2) overexpression or gene amplification occurs in 10-60% of EC. The addition of trastuzumab to carboplatin-paclitaxel chemotherapy improves survival in women with HER2-positive serous EC. However, criteria for assessment of HER2 status in EC are not standardized, and furthermore, intratumor heterogeneity may impact therapeutic efficacy. We aimed to identify factors associated with treatment response and survival outcomes in a retrospective cohort of ECs treated with anti-HER2 therapy. Methods: Patients with advanced/recurrent EC treated with trastuzumab or trastuzumab emtansine alone or in combination with chemotherapy from 2013-2021 at our institution were identified. Clinical and treatment information were retrieved from medical records. Central pathology review, HER2 immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) were performed. HER2 IHC was scored using modified ASCO/CAP 2007 guidelines for breast cancer. HER2 expression heterogeneity was defined as a 2-degree difference in staining intensity in ≥5% of tumor cells or discordant IHC score on different specimens. HER2 amplification (tumor/normal fold change) was also estimated from targeted next-generation sequencing (NGS). Best response was assessed by RECIST v1.1 as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), with clinical benefit defined as CR/PR/SD. Results: Among 39 patients included, median age was 69. Histologic subtypes included serous (n = 18, 46%), carcinosarcoma (n = 7, 18%), high-grade EC with ambiguous features (n = 13, 33%) and low-grade endometrioid carcinoma (n = 1, 3%). HER2 IHC results were 0 or 1+ (n = 2, 5%), 2+ (n = 17, 46%), 3+ (n = 18, 49%), with HER2 heterogeneity in 15 cases. By FISH, the HER2/CEP17 ratio was ≥2.0 in 34 (92%) and < 2.0 in 3 (8%); HER2 copy number (CN) was ≥6.0 in 25 (68%) and < 6.0 in 12 (32%). HER2 copy number ≥6.0 was significantly correlated with HER2 amplification by NGS ( p< 0.001). 18 (49%) patients had a co-existing somatic PIK3CA mutation. Amongst parameters assessed, only higher level of HER2 amplification by NGS was significantly associated with clinical benefit ( p= 0.036). None of these features were associated with progression-free survival. Notably, 2 patients with IHC 0/1+ had PD and 1 patient with IHC 3+, but non-amplified by FISH, achieved PR. Conclusions: In our cohort of EC patients treated with anti-HER2 therapy, higher level of HER2 amplification was associated with clinical benefit. Further studies with larger sample sizes are needed to determine whether any additional characteristics are associated with treatment response and survival.
Outcomes of recurrent and metastatic endometrial cancer (RMEC) treated with systemic progestins.
Authors: Kulkarni Anjali , Andrews Wright Natalie , Forget Alyssa N , Mallick Ranjeeta , Ramsay Tim O , Weberpals Johanne I
Published: June 2022

5585

Background: Recurrent endometrial cancer has a poor prognosis with limited treatment options. Systemic therapy for RMEC includes chemotherapy, immunotherapy and hormonal therapy. Although studies on hormonal therapy have described modest results, agents such as megestrol acetate (megace) continue to be used mainly for low grade, ER+/PR+ve tumors in the advanced and recurrent setting. Overall response rates have been reported in the range of 20-25% with responses up to 25-35% in ER+/PR+ve tumors. Despite comparative response rates to chemotherapy, the use of hormonal therapy in clinical trials in RMEC is hampered by a lack of clear progression-free survival (PFS) data. The primary objective of this study is to determine the PFS in RMEC patients treated with progestins. Methods: A retrospective chart review on RMEC was conducted at The Ottawa Hospital with data sourced from medical records. Main inclusion criteria were a diagnosis of RMEC between 2000 and 2019, endometrioid histology, and ≥1 one line of progestin treatment. PFS was the time from initiation of progestin therapy until progression of disease (PD) by imaging, biopsy or death. Overall survival (OS) was the time from initiation of progestins until death. Median time to PFS and OS were estimated using the Kaplan-Meier method and compared using a Log-rank Test with 95% confidence interval (CI). Results: Of 2342 cases reviewed, 75 met inclusion criteria. The mean age at the time of primary diagnosis was 66.7 years and the range of follow-up was 1-199 months (mo). Sixty-six (88.0%) patients received megestrol acetate and 9 (12.0%) received a progestin alternative. The distribution of all patients by grade was: 1: 25 (33.3%), 2: 30 (40.0%) and 3: 20 (26.7%). The median PFS for all patients with grade 1 and 2 RMEC was 15.7 mo (95% CI: 8.0, 19.5), compared to 5.0 mo (3.0, 23.0) for grade 3 disease (p=0.28). The median OS for all patients with grade 1 and 2 versus grade 3 RMEC, was 25.9 mo (15.3, 40.3) versus 12.5 mo (5.7, 35.9), respectively (p=0.12). The number of patients treated with 0 and ≥1 line of chemotherapy was 34 (45.3%) and 41 (54.7%). The median PFS for patients who were naïve to chemotherapy was 17.9 mo (14.3, 27.0), compared to 6.2 mo (3.9, 14.8) for patients who had received ≥1 prior lines of treatment (p=0.09). The median OS was 29.1 mo (17.9, 61.1) for patients who were naïve to chemotherapy, versus 23.0 mo (10.5, 37.6) for patients who were previously exposed (p=0.64). Conclusions: This real-world data suggests that progestins for RMEC have comparable outcomes to other systemic therapies in chemotherapy-exposed patients. Progestins such as megestrol acetate may be considered in the design of RMEC clinical trials.