bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of COVID-19 on breast cancer stage at diagnosis.
Authors: Lloyd Maxwell Roger , Stephens Sarah Jo , Hong Julian C. , James Ted A. , Mehta Tejas , Recht Abram , Spiegel Daphna
Published: June 2021

528

Background: During the SARS-CoV-2 pandemic, routine screening mammography (SM) was stopped and diagnostic mammography (DM) was limited for several months across the United States in order to reduce patient exposure and redeploy medical personnel. We hypothesized that this delay would result in patients presenting with later-stage disease following the initial shutdown. Methods: Patients diagnosed with invasive breast cancers from 2016-2020 were identified using the Beth Israel Deaconess Medical Center Cancer Registry. Baseline patient characteristics, demographics, and clinical information were gathered and cross-referenced with our electronic medical record. Late-stage disease was defined as initial anatomic stage III-IV disease in the AJCC 8th edition staging system. The control cohort consisted of patients diagnosed from 2016-2019; patients diagnosed in 2020 were the test cohort. Chi-squared analysis was used to compare monthly distributions in stage at diagnosis between the control and test cohorts. Multivariate analysis was performed using a logistic regression model. Results: There were 1597 patients diagnosed with invasive breast cancer between 2016-2019 and 333 in 2020. Median age at diagnosis was 60 years; 99% were female, and 69.1% were white. Mammography was limited from 3/16/20-6/8/20, with 90% reduction in volume during this time. The number of screening studies performed in March, April, May, and June of 2020 were 987, 1, 4, and 721 compared to 2042, 2141, 2241, and 2142 in 2019. The volume of new diagnoses per month decreased substantially during the shutdown (see table). The proportion of patients diagnosed with late-stage disease was 6.6% in the control cohort compared to 12.6% in the 2020 test cohort (p < 0.001); 92.9% of late-stage diagnoses in 2020 occurred from June to December following the shutdown period. On multivariate analysis, year of diagnosis (2020 vs 2016-2019; OR = 4.25 95% CI 0.035-0.095, p < 0.001), lower income (<200% of the federal poverty level; OR = 2.73 95% CI 0.016-0.099, p = 0.006) and increased Charlson Comorbidity Index (OR = 12.01 95% CI 0.037-0.052, p < 0.001) were associated with later stage at diagnosis. Conclusions: Patients were more likely to be diagnosed with late-stage breast cancer following the global shutdown due to the SARS-CoV-2 pandemic. Patients with lower income and medical comorbidities were disproportionately affected. These data raise significant concerns regarding the impact of SARS-CoV-2 on cancer diagnoses and long-term outcomes, especially in vulnerable patient populations.[Table: see text]
Chemotherapy induced profound neutropenia (PN) in patients (pt) with breast cancer (BC) after chemotherapy and plinabulin (Plin) plus pegfilgrastim (Peg) combination versus (vs) peg alone: Final phase 3 results from protective-2 (BPI-2358-106).
Authors: Shi Yuankai , Blayney Douglas W. , Adamchuk Hryhorii , Zhang Qingyuan , Du Lihua , Huang Lan , Mohanlal Ramon
Published: June 2021

546

Background: PN [absolute neutrophil count (ANC) of <0.1 cells x 10E9/L)] is the most severe form of chemotherapy (Chemo)-induced neutropenia (CIN), and is associated with severe adverse clinical outcome. According to literature, PN leads to 80% death in first week of infection1, 48% FN and 50% Infection2. Peg is standard of care for the prevention of CIN. Peg has a slow onset of action with absolute neutrophil count (ANC) recovery occurring in week 2 of the cycle (C), leaving patients (pts) vulnerable in the first week of the Cycle (C), which >75% of negative clinical consequences occur. Plin, which received breakthrough designation from FDA, is a novel, non-G-CSF small molecule agent for the prevention of CIN and has CIN protection in week 1 (Blayney JAMA Onc 2020), which is the rationale for adding Plin to Peg to achieve superior protection against CIN throughout the entire cycle vs Peg alone (Blayney, St Gallen 2019; ASCO 2019). Methods: Plin is given on Day (D)1 after the last Chemo, has a favorable safety profile, and also has anticancer activity. A phase 3 study evaluating Plin as an anticancer agent (DUBLIN-3; NCT02504489) in NSCLC pts, is fully enrolled, with anti-cancer OS results expected in 2021. In PROTECTIVE-2 (Study 106; NCT0329457), we compare the CIN preventive effects of Plin (on D1) added to Peg (on D2) vs Peg alone. Here we report on PN results. Study 106 is a global multicenter randomized (1:1) double-blind study to evaluate Plin 40 mg + Peg 6mg (Arm 1) versus Peg 6mg + Plac (Arm 2) in early-stage BC (node positive or node negative with a high risk of recurrence) pts (n=221) with ECOG status 0 or 1, receiving docetaxel (75 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) (TAC). Primary objective was to compare the prevention of severe (Gr 4) neutropenia between Plin+Peg and Peg+Plac. As an exploratory objective in C1, we evaluated PN between the Plin/Peg and Peg/Plac. ANC (Covance Central Laboratory) was assessed in Cycle 1 (C1) on D 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, and 15. Results: Shown in the table below. Conclusions: In conclusion, Peg still cannot protect patients with the most severe form of neutropenia, PN, at 46.4% in this study. Adding Plin to Peg offers superior protection for the prevention of profound neutropenia by reducing > 50% of PN, and its clinical sequelae in FN and hospitalization as compared to Peg alone. References: 1. Bodey et al. Ann Intern Med 64(2): 328 (1966); 2. Bodey et al. Cancer 41(4): 1610 (1978). Clinical trial information: NCT03531099. [Table: see text]
Validation of the RSClin risk calculator using the National Cancer Database (NCDB).
Authors: Howard Frederick , Pearson Alexander T. , Nanda Rita , Olopade Olufunmilayo I. , Huo Dezheng
Published: June 2021

549

Background: Clinical practice guidelines recommend the use of genomic assays to aid decision making regarding the use of adjuvant chemotherapy (CT) for hormone receptor-positive, HER2-negative (HR+/HER2-) early breast cancer (EBC). Recently, the RSClin clinical tool, which integrates the 21-gene recurrence score (RS) and clinicopathologic features, was developed using data from the TAILORx trial. By integrating clinical and genomic risk, RSClin demonstrated greater precision in guiding adjuvant CT use in HR+/HER2- EBC than the 21-gene RS alone. As outcomes differed by race and ethnicity in TAILORx, further validation in real world datasets of diverse populations is needed. Methods: This study includes patients (pts) from the NCDB who were diagnosed with HR+/HER2- EBC from 2010-2017 and received adjuvant endocrine therapy (ET) with or without CT. RSClin provides a predicted absolute reduction in distant recurrence at 10 years with CT, while the NCDB database only provides overall survival (OS) metrics. While OS underestimates distant recurrence, we correlated RSClin predictions with survival differences between pts receiving ET versus those who received ET plus CT. Inverse probability of treatment weighting was used to correct for differences in age, comorbidity index, insurance, and race/ethnicity. OS benefit of CT was assessed in pts with low (< 2%), intermediate (2-5%), and high (>5%) absolute CT benefit (ACB) per RSClin using the log-rank test. Results: 150,268 pts with EBC were included. Average (avg) age was 59 yrs; 84% were white, 8% black, 4% Hispanic, and 4% Asian/Pacific Islander. Avg tumor size was 1.7 cm, avg RS 17, and 82% had lymph node (LN) negative disease. A significant OS benefit with CT was seen in the intermediate (HR 0.70) and high (HR 0.66) RSClin predicted ACB in the LN negative pts. When analyzed by racial / ethnic subgroup, all pts with a high RSClin ACB had improvement in survival with CT; in pts with an intermediate RSClin ACB, only white pts demonstrated significantly higher OS with CT (HR 0.72). Conclusions: Although developed to predict distant recurrence rates, the RSClin tool also correlates with OS in pts receiving ET with or without CT, which can aid in clinical decision making in pts with HR+/HER2- EBC. Predictive accuracy of RSClin differs by race/ethnicity. Accurate risk stratification in diverse populations is essential in ensuring equitable treatment and mitigating disparities in breast cancer outcomes in different racial/ethnic groups.
Maintenance vigil immunotherapy in newly diagnosed advanced ovarian cancer: Efficacy assessment of homologous recombination proficient (HRP) patients in the phase IIb VITAL trial.
Authors: Rocconi Rodney Paul , Ghamande Sharad A. , Barve Minal A. , Stevens Erin E. , Aaron Phylicia , Stanbery Laura , Bognar Ernest , Manning Luisa , Nemunaitis John J. , O'Malley David M. , Herzog Thomas J. , Monk Bradley J. , Coleman Robert L. ,   The Vigil Team
Published: June 2021

5502

Background: In the VITAL (NCT02346747) trial, maintenance therapy with Vigil, an autologous tumor cell vaccine transfected with a DNA plasmid encoding GMCSF and bi-shRNA-furin for TGFβ expression control, following frontline platinum-based chemotherapy led to a recurrence-free survival (RFS) benefit in patients with advanced high-grade ovarian cancer (HR=0.69, 90% CI 0.44–1.07, p=0.078) and significantly in BRCA-wt patients (HR=0.51, 90% CI 0.30-0.88, p=0.020) ( Rocconi et al. Lancet Oncol. 2020). Here we report post-hoc HR deficiency (HRD) subgroup analysis and identification of an additional molecular subgroup sensitive to Vigil therapy involving STRING analysis. Methods: This double-blind, placebo-controlled, Phase 2b study randomized 92 patients with newly diagnosed stage III/IV ovarian cancer with a complete clinical response (CR) to frontline surgery and chemotherapy. Patients received 1 x 10e7 cells/ml of Vigil or placebo intradermally once a month for up to 12 doses or disease progression. RFS was the primary endpoint assessed by blinded independent central review. HRD status was determined according to the Myriad Genetics myChoice CDx assay (HRD score < 42 for proficient). Using tumor annotated DNA polymorphism data, a protein-protein interaction network was constructed using the STRING database. Properties of this network including topological distance and the identification of hub genes were used to predict a target molecular population sensitive to Vigil. Results: In the per-protocol population (PP, n=91), 62 BRCA-wt patients were tested for HRD status. Forty-five patients were HR proficient (HRP) and 17 patients were HR deficient (HRD). No HRP patients in the Vigil group reported treatment related Grade 3 or higher adverse events. From the time of study randomization median RFS was improved with Vigil (n=25) in HRP patients compared to placebo (n=20) (Table 1). Similarly, overall survival (OS) benefit was observed in the Vigil group compared to placebo (Table 1). Improved RFS was demonstrated for a subset of patients with STRING predicted molecular profile. Conclusions: Vigil immunotherapy as frontline maintenance in Stage III/IV ovarian cancer is well tolerated and showed clinical benefit in both BRCA-wt and HRP molecular profile patients. Results suggest a unique molecular network that enhances sensitivity to Vigil therapy. Clinical trial information: NCT02346747. [Table: see text]
The correlation between BRCA status and surgical cytoreduction in high-grade serous ovarian carcinoma.
Authors: Kim Rachel Soyoun , Malcolmson Janet , Li Xuan , Bernardini Marcus , Hogen Liat Frida , May Taymaa
Published: June 2021

5543

Background: High grade serous ovarian cancers (HGSC) with BRCA mutation are biologically unique, with distinct molecular and clinical behaviour from sporadic cases. It is unclear if these biological differences translate to favorable outcomes at the time of primary cytoreductive surgery (PCS). The aim of this study is to compare the amount of residual disease following PCS in BRCA-mutated (BRCAm) and wildtype (BRCAwt) HGSC, and to assess whether BRCA status is an independent predictor of residual disease. Methods: We conducted a retrospective analysis of patients with HGSC with known germline and somatic BRCA mutation status, treated with PCS from 2000 to 2017. We compared the cytoreduction outcomes between the BRCAm and the BRCAwt cohorts and built a predictive model to assess whether BRCA status was associated with amount of residual disease at the time of PCS. Results: Of 355 women, 144 harbored germline or somatic BRCA mutations (41%) and 211 were BRCAwt (59%). BRCAm women tended to be younger (54 vs. 59; p < 0.001), but there were no differences between the two groups in stage, disease burden at presentation, surgical complexity score, length of surgery, or perioperative complications. The BRCAm group had a higher rate of complete cytoreduction to no residual disease (0mm) [75% vs. 54%], and a lower rate of optimal cytoreduction (1-9mm) [16% vs. 34%] or suboptimal cytoreduction (≥10mm) [9% vs. 12%] (p < 0.001). In our predictive model, after accounting for length of surgery, CA-125 level, stage, disease scores and surgical complexity scores, BRCAm status was predictive of complete cytoreduction to 0mm residual disease (OR 4.78; 95% CI 2.32-9.85; p < 0.001). Conclusions: BRCA status is predictive of complete cytoreduction at time of PCS in HGSC. Timely availability of BRCA testing is paramount as it may aid in the therapeutic decision making between PCS or neoadjuvant chemotherapy in women with newly diagnosed HGSC.
Feasibility of an adapted schedule of carboplatin plus paclitaxel in elderly women with advanced ovarian cancer: A retrospective cohort.
Authors: Nicaise Benjamin , Mebarki Soraya , Gisselbrecht Mathilde , Ashton Elisabeth , Azais Henri , Koual Meriem , Bats Anne-Sophie , Fournier Laure , Le Frère - Belda Marie-Aude , Medioni Jacques , Paillaud Elena , Oudard Stephane , Delanoy Nicolas
Published: June 2021

5546

Background: The EWOC-1 trial compared Carboplatin monotherapy (C mono) to two different Carboplatin + Paclitaxel (CP) regimens (weekly or 3-weekly) in vulnerable elderly patients treated for advanced ovarian cancers (OC). This study was closed prematurely because of a worse outcome in the C mono group. Both CP regimens were equivalent in terms of feasibility and efficacy with different toxicity profiles. Optimal CP regimen in elderly patient is still unknown. Here we propose a study of another adapted regimen of CP (aCP) performed in elderly patients in our institution. Methods: We retrospectively analyzed OC patients ≥ 70 years who received a Carboplatin AUC 4-5 d1q3week + Paclitaxel 80 mg/m² d1-d8 q3week regimen between 2015 and 2019. Primary endpoint was treatment feasibility according to the EWOC-1 standard: completion of 6 courses of chemotherapy without early stopping for disease progression, death or unacceptable toxicity (adverse event (AE) related to chemotherapy or treatment procedure leading either to early treatment stopping, to an unplanned hospital admission or to death or to a dose delay lasting more than 14 days or more than 2 dose reductions). Results: We identified 36 pts with a median age of 79 years (table). All patient but one had an ONCODAGE-G8 score ≤ 14, 30.6% of patients had a comorbidity Charlson’s index > 4 and 52.5% had an albumin rate < 35 g/L. The feasibility endpoint was met in 58.3% of patients (IC95% = [25.6; 57.8]). Main causes of treatment failure (TF) were early discontinuation because of toxicity in 6 patients (16.7%) and progressive disease in 3 patients (8.33%). Median PFS was 35.3 months (IC95% = [22.7; NR]) and median OS was 62.1 months (IC95% = [31.4.0; NR]). The most frequent AE were asthenia (all grades = 94.4%, grade 3-4 = 13.9%), anemia (all grades = 94.4%, grade 3-4 = 27.8%), neutropenia (all grades = 66.7%, grade 3-4 = 38.9%) and neuropathy sensory (all grades = 61.1%, no grade 3-4). Non high-grade-serous histological type and a poor Charlson’s score were associated with a higher rate of TF (100% and 63.6%, respectively). Conclusions: These results are consistent with the findings of the EWOC-1 trial in both CP regimens and suggest that aCP could be non-inferior with an acceptable toxicity profile. Further prospective and comparative studies are mandatory to confirm this trend and to better identify predictive factors of TF in OC elderly patients.[Table: see text]
Dysregulation of soluble immune checkpoint proteins in newly-diagnosed early breast cancer patients.
Authors: Rapoport Bernardo Leon , Steel Helen C , Smit Teresa , Heyman Liezl , Theron Annette J , Hlatswayo T Nomsa , Kwofie Luyanda LI , Benn Carol , Anderson Ronald
Published: June 2021

556

Background: Checkpoint proteins regulate the immune system. Breast cancer (BC) cells exploit the up-regulation or down-regulation of these proteins to evade anti-tumor immune responses. Soluble forms of immune checkpoint molecules (ICM) can be measured in human plasma, however their biological and clinical significance remains essentially unknown. The aim of the present analysis was to measure the pre-treatment ICM in newly- diagnosed BC patients (pts) and compare them to healthy controls. Methods: Soluble forms of ICM, as well as cytokines and chemokines, were measured using Multiplex bead array and ELISA technologies. Plasma samples from 98 BC pts and 45 healthy controls were analyzed for each protein. Data was prospectively obtained. Measured levels were compared between BC pts and healthy controls using a non-parametric test (Mann-Whitney). P-values below 0.05 were considered statistically significant. Results: Soluble stimulatory molecules GITR (p < 0,000002), GITRL (p < 0,007), CD27 (p < 0,002), CD28 (p < 0,003), CD40 (p < 0,003), CD80 (p < 0,009), ICOS (p < 0,0006), as well as inhibitory molecules PD-L1 (p < 0.0000001), CTLA-4 (p < 0,005), TIM-3 (p < 0,00006), HVEM (p < 0,00002) TLR-2 (p < 0,05), levels were significantly lower in early BC pts compared to healthy controls. When analyzed according to BC characteristics (TNBC vs. non-TNBC, tumor size, stage, nodal status and age) no significant difference was detected between the soluble levels of these ICM between the different subsets. Additionally, serum CXCL5 (p < 0,000001), CCL23 (p < 0,04), IL-16 (p < 0,00005), interferon-α (p < 0,03) and IL1-RA (p < 0,03) were significantly lower compared to healthy controls. Serum CX3CL1 or fractalkine (p < 0,024465) was significantly higher compared with healthy controls. Serum interferon-γ (p < 0,2), IL-6 (p < 0.6) and IL-2 (p < 0.6) levels were not significantly different between the BC pts and the healthy controls. Conclusions: We identified low levels of both the stimulatory and inhibitory immune checkpoint molecules, in newly-diagnosed, non-metastatic BC pts compared to healthy controls. These results indicate that early BC is associated with a down-regulation of both soluble stimulatory and inhibitory immune-checkpoint pathways. Newly-diagnosed early BC pts have a generalized immune-suppression independent of subtype (TNBC vs non-TNBC) and stage, which, to our knowledge, is the first study to describe soluble immune checkpoints in early BC pts.
Outcomes of ovarian cancer patients treated with platinum or non-platinum based chemotherapy after PARP inhibitor maintenance.
Authors: Brann Ralynn , Kremer Kevin Michael , Carlson Matthew , LoCoco Salvatore , Lea Jayanthi Sivasothy , Miller David Scott , Lee Jessica
Published: June 2021

5563

Background: PARP inhibitors (PARPi) are approved for maintenance treatment of platinum sensitive ovarian cancers either after front-line therapy or after treatment for recurrence. Current recommendations include retreatment with platinum-based chemotherapy (PC) after progression on maintenance PARPi. There exists a theoretical concern that progression of disease (POD) on PARPi is indicative of the development of platinum resistance due to similar DNA targets of platinum chemotherapy and PARPi. Our objective was to evaluate the response to subsequent chemotherapy in patients who progressed on PARPi maintenance. Methods: All patients with ovarian, fallopian tube, or primary peritoneal cancer treated with PARPi treatment from 2017 to 2021 at two academic tertiary care centers were retrospectively identified. Patients were assessed for treatment time on PARPi, time to POD on PARPi (PFS), type of chemotherapy regimen following PARPi maintenance, and time to disease progression on subsequent therapy following PARPi (PFS2). Comparative statistical analyses were performed with appropriate two-sided statistical tests. Time to progression on chemotherapy after PARPi was calculated using the Kaplan-Meier method. Results: A total of 83 ovarian cancer patients treated with PARPi were identified, and of these, 61 (73.5%) were treated with PARPi in the maintenance setting. Among the patients treated with PARPi maintenance, 22 (36.1%) remain on treatment. 19 (31.1%) patients were started on PARPi maintenance after front-line chemotherapy. While on PARPi maintenance, 63.9% discontinued PARPi, the majority due to POD, and 26.2% due to patient intolerance of side effects. Following POD, 21/29 (72.4%) received subsequent PC and 8/29 (27.6%) received non-platinum based chemotherapy (NPC). Treatment time, PFS, and PFS2 are listed in Table. Of the patients who received PC, 14/21 (66.7%) had a PFS2 of over six months and 5/21 (23.8%) had a PFS2 of over 12 months. Of the patients who received NPC, 7/8 (87.5%) had a PFS2 of over six months and 2/8 (25.0%) had a PFS2 of over 12 months. Conclusions: Following POD on PARPi, patients responded to both PC and NPC. Time to progression on subsequent chemotherapy after treatment with PARPi does not differ significantly between PC and NPC regimens. Many patients continue to see benefit from PC after PARPi maintenance. Retreatment with PC following POD on PARPi maintenance should still be considered.[Table: see text]
Assessment of predictive biomarker prevalence in molecularly defined adult-type ovarian granulosa cell tumors.
Authors: Hillman Robert Tyler , Lin Douglas I. , Gershenson David Marc
Published: June 2021

5567

Background: The FDA has separately approved pembrolizumab for all advanced solid tumors with either microsatellite instability or high tumor mutational burden (≥10 mutations per megabase), and homologous recombination deficiency is an established biomarker for response to poly ADP ribose polymerase inhibitors in epithelial ovarian cancer. The detection of these predictive biomarkers in adult-type ovarian granulosa cell tumors could identify novel treatment strategies in this rare disease. The primary objective of this study was to determine the prevalence of established predictive biomarkers among molecularly defined adult-type ovarian granulosa cell tumors. Methods: With institutional review board approval, we performed a cross-sectional study examining de-identified FoundationOne companion diagnostic molecular profiles for 423 women with molecularly defined (FOXL2 c.C402G positive) adult type ovarian granulosa cell tumors. The dataset was comprised of coding variants for up to 406 genes as well as genomic signatures including microsatellite instability, tumor mutational burden, and genome wide loss of heterozygosity. PD-L1 expression by immunohistochemistry was also available for a subset of tumors. Descriptive statistics were used for comparison between groups and all statistical tests were two-sided. Results: Women in this cohort had a mean age of 57 years (range 24-87) at the time of sample submission for molecular profiling. The median tumor mutational burden was 1.3 mutations per megabase [mut/Mb] (range 0-8.8 mut/Mb). TP53-mutated aGCT had a higher tumor mutation burden than TP53 non-mutated tumors (median 2.4 mut/Mb, 95% CI 1.7-3.0 mut/Mb vs median 1.3 mut/Mb, 95% CI 1.5-1.9 mut/Mb; P=.02). All 384 tumors with available microsatellite instability testing were microsatellite stable. Sixty-seven tumors had PD-L1 expression measured and of these 94% (63/67) were negative with the remainder “low positive.” No tumors were positive for genome wide loss of heterozygosity. Apart from FOXL2 c.C402G, the most frequent short variants were TERT promoter mutations (-124C>T: 190/423, 45.0%; -146C>T: 39/423, 9.2%). Other frequently observed variants included truncating mutations in KMT2D/MLL2 (71/423, 16.8%), pathogenic TP53 mutations (35/423, 8.3%), CDKN2A/B deletions (43/423, 10.2%), and activating PIK3CA mutations (23/423, 5.4%). Conclusions: No women with molecularly defined adult-type ovarian granulosa cell tumors in this large cross-sectional study would be eligible for FDA-approved pembrolizumab based on either microsatellite instability or high tumor mutational burden. No tumors exhibited evidence of homologous recombination deficiency and molecularly targetable mutations were rare. The development of novel precision treatment options remains a critical unmet need for this rare disease.
Final results of phase 1 evaluation of the safety and clinical activity of sapanisertib in combination with serabelisib and paclitaxel in patients with advanced ovarian, endometrial, or breast cancer.
Authors: Starks David , Rojas-Espaillat Luis Alexander , Dey Nandini , De Pradip , Leyland-Jones Brian , Williams Casey B.
Published: June 2021

5569

Background: Evidence suggests that activation of the PI3K/AKT/mTOR pathway by paclitaxel may play a role in the development of taxane resistance. Conversely, PI3K inhibitors have been shown to sensitize tumors to the effects of paclitaxel. Therefore, the link between taxane resistance and activation of the PI3K/AKT/mTOR signaling pathway suggests inhibition of this pathway in combination with antimitotic drugs like paclitaxel may improve treatment outcomes in many malignancies. To further investigate this hypothesis we combined the TORC 1/2 inhibitor sapanisertib (TAK-228), the PI3Kα isoform inhibitor serabelisib (TAK-117), and paclitaxel in a phase I trial of heavily pretreated patients to determine the safety, efficacy, and RP2D. Methods: This is an open label, cohort study of sapanisertib (TAK-228) and serabelisib (TAK-117) given on days 2-4, 9-11, 16-18, and 23-25 with paclitaxel on days 1, 8, and 15 of a 28-day cycle. A traditional 3+3 dose escalation design with a maximum of 5 dosing cohorts was used. All 5 cohorts plus an expansion cohort are presented. Results: Enrollment has been completed and the overall results are summarized. Nineteen patients were enrolled; the majority were heavily pretreated with the average number of prior regimens exceeding 4. Based upon ITT, the ORR is 37%. The ORR is 47% in patients that completed at least 3 cycles. The clinical benefit rate is 73% and the PFS currently stands at approximately 11 months. Two patients with endometrioid endometrial adenocarcinoma achieved a complete response. All patients received comprehensive genomic profiling and 7 patients received prior mTOR inhibitor. Overall, the combination was well tolerated, except by patients in cohort 5. One DLT occurred in the last patient enrolled. The most common non-laboratory AEs were nausea (6%), fatigue (5%), and mucositis (5%). There were 45 (9%) grade 3 or 4 events, and the most common were decreased WBC and non-febrile neutropenia. Hyperglycemia was common in patients with a history of diabetes mellitus. Conclusions: Overall, the combination of sapanisertib, serabelisib, and paclitaxel was safe and efficacious throughout the first 4 cohorts. There were few serious adverse events, and most side effects were managed with routine supportive care interventions. Preliminary clinical results appear very promising, especially for patients with PI3K/AKT/mTOR pathway mutations. The positive effects of the combination were routinely seen in the lowest dosing cohorts and clinical benefit was even seen in patients that had previously failed everolimus or temsirolimus. All patients were either resistant or refractory to paclitaxel at time of enrollment, so further exploration of this combination to elucidate the mechanism of benefit is warranted. Clinical trial information: NCT03154294.
Exploring molecular profiles and survival in hormone receptor-positive uterine serous carcinoma.
Authors: Craig Amaranta , Wilhite Annelise M. , Wu Sharon , Xiu Joanne , Mantia-Smaldone Gina , Hernandez Enrique , Brown Jubilee , Jones Nathaniel L.
Published: June 2021

5579

Background: Hormone receptor (HR) positivity has been reported as a good prognostic indicator in endometrial cancer. This study investigated estrogen receptor (ER) and progesterone receptor (PR) positivity as indicators of platinum response and improved survival in uterine serous carcinoma (USC), and determined differences in molecular profiles between these tumors and hormone receptor negative tumors. Methods: Tumor profiling was done with immunohistochemistry (IHC), next generation sequencing (NGS), and whole transcriptome sequencing (WTS). PD-L1 expression was determined by IHC using SP-142 (cut-off >1%). Microsatellite instability (MSI) status was evaluated with IHC and NGS, and tumor mutational burden (TMB) by totaling somatic mutations per tumor (high if > 10 mutations/ MB). Immune-cell fraction was determined with QuantiSeq. We used insurance claims data to calculate Kaplan-Meier estimates for overall survival (OS). Statistical significance was determined with chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons. Results: 2806 USC tumors were available for molecular profiling with 717 HR+/966 HR-, 1559 ER+/1059 ER- and 805 PR+/1809 PR-. Median OS for HR+ patients was longer than patients who were HR- regardless of treatment (1152 v 797 days; hazard ratio 0.68, 95% CI 0.58-0.80, p < 0.01). This OS benefit of HR positivity remained for patients receiving platinum therapy (1134 v 889 days; hazard ratio 0.75, 95% CI 0.58-0.98, p < 0.01). HR+ status trended towards improved OS in those treated with hormone therapy (407 vs 771 days, hazard ratio 0.78, 95% CI 0.59-1.02, p = 0.07). In addition to increased androgen receptor expression (54.2 vs 6.2%, p = < 0.001), PTEN mutations were more common in the HR+ group (10.3 vs 5.1%, p = 0.016). This resulted in in more frequent alterations of the PI3K pathway when compared to HR- tumors 64.5 vs 52.2%, p = < 0.001). PD-L1, TMB, and MSI status were similar between the two cohorts. Checkpoint inhibitor gene expression was notable for higher IDO expression in the HR+ group, but lower CD80, CD86, HAVCR2, IFNG, and PDC1 expression. The immune micro-environment was notable for less B-cells and M1 macrophages, but more M2 macrophages. Breaking the ER and PR positive cohort down to individual expression of each gene resulted in similar OS and molecular findings. Conclusions: HR positivity is associated with improved survival in allcomers with USC and those treated with platinum therapy, and there was a trend to improved OS with hormone therapy. More data is needed to determine if HR status is a prognostic marker for IO treatment response. This cohort had a distinct molecular profile compared to HR- tumors.
Molecular determinants of response to immune-oncology therapy in uterine carcinosarcoma.
Authors: Wilhite Annelise M. , Wu Sharon , Xiu Joanne , Erickson Britt Kristina , Rocconi Rodney Paul , Brown Jubilee , Herzog Thomas J. , Holloway Robert W. , Wallbillich John , Winer Ira Seth , Powell Matthew A. , Korn Wolfgang Michael , Jones Nathaniel L.
Published: June 2021

5582

Background: Uterine carcinosarcoma (UCS) is subtype of endometrial cancer (EC) with aggressive behavior and poor prognosis. UCS has not traditionally been included in EC clinical trials and treatment options are limited. Immune-oncology (IO) therapy has shown promise UCS, but it is unknown which patients benefit most. We sought to identify immunogenic markers in UCS and explore treatment response to IO therapy. Methods: Tumor samples were analyzed using Nex-Gen sequencing of the DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ).PD-L1 IHC used SP-142 (cut-off >1%). MSI was tested by FA, IHC and NGS. TMB was measured by totaling somatic mutations per tumor (high > 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. Overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank sum test and p values adjusted for multiple comparisons (q) to be <0.05. Results: A total of 1,144 UCS tumors underwent comprehensive tumor profiling. 68.4% of samples were obtained from primary tumors and 31.6% from metastatic sites. 21.6% of tumors expressed PD-L1, 8.5% were TMB-H and 6.8% were MSI-H/MMRd. UCS patients treated with IO had longer median overall survival than those not treated with IO (months: 31.2 vs 19.4; HR(95% CI): 0.39 (0.17-0.76) p=0.005). Median OS was also increased for dMMR/MSI-H (OS not yet reached vs 18.9 months); HR(95% CI): 0.56 (0.36-0.92) p=0.019) and TMB-H (OS not yet reached vs 18.9 months); HR(95% CI): 0.62 (0.38-0.99) p=0.047). More patients are needed to determine if these markers predict response to IO therapy. The most common mutations in UCS led to pathway dysregulation in the PI3K, RAS, chromatin remodeling, HR, and WNT pathways. dMMR/MSI-H tumors have distinct molecular profiles compared to MSS tumors (table). Additionally, dMMR/MSI-H tumors had higher TMB (96.9% vs 2.2%, q<0.01) and increased frequency of PDL-1 (23.6% vs 13.8%; q=0.04). Immune checkpoint genes were more often expressed in MSI-H tumors, though this was non-significant except for IFNG (4.66-fold increase; q=0.01). Conclusions: IO therapy is associated with improved survival in USC. MSI and TMB are markers of improved OS in patients with UCS. MSI tumors have a distinct molecular profile compared to MSS tumors, and they appear to be more immunogenic, which could contribute to the improved survival seen in patients who received IO therapy.[Table: see text]
Tumor-associated immune cells and progression-free survival in advanced endometrial cancer (EC), results from the PHAEDRA trial (ANZGOG 1601).
Authors: Smith Deborah , Robledo Kristy , Yip Sonia , Cummins Michelle , Kok Peey-Sei , Lee Yeh Chen , Friedlander Michael , Baron-Hay Sally E. , Shannon Catherine M. , Coward Jermaine , Beale Philip James , Goss Geraldine , Meniawy Tarek , Lombard Janine Margaret , Spurdle Amanda B. , Andrews John , Stockler Martin R. , Mileshkin Linda R. , Antill Yoland Catherine
Published: June 2021

5584

Background: Activity of durvalumab in patients with deficient mismatch repair (dMMR) advanced endometrial carcinoma (EC) was confirmed in the PHAEDRA trial (ANZGOG 1601). This study investigated the association between immune biomarkers and clinical outcomes in PHAEDRA. Methods: Formalin-fixed paraffin embedded sections immunohistochemically stained for PD-L1 using the Ventana platform, were with matched H&E slides scored independently by two pathologists according to the Ventana PD-L1 (SP263) algorithm for urothelial carcinoma (UC). Immune biomarkers assessed were PD-L1 staining of tumor cells (TCP) and immune cells (IC), and presence of tumor-associated immune cells (ICP). Results: Sixty-seven of the 71 patients had sufficient tumor for PD-L1 testing. AUC were 0.667, 0.726 and 0.644 for TCP, ICP and IC, respectively for predicting tumor response. Optimal cutpoints were TCP≥1%, ICP≥10% and IC≥35%. ICP≥10% achieved the highest sensitivity (53%) and specificity (82%) of the individual cutpoints. The optimal cutpoint algorithm was able to identify patients who would not respond, (sensitivity 88%, negative predictive value 92%), but had low specificity (48%) and positive predictive value (37%). Differences in PFS were found using ICP≥10% (logrank p = 0.01), compared to TCP (p = 0.25), IC (p = 0.48) and the UC algorithm (p = 0.08) (Figure 1). PFS was shorter in patients with pMMR than dMMR after adjusting for ICP (HR 2.99, 95%CI: 1.61-5.57, p < 0.001). Adjustment for MMR reduced the prognostic significance of ICP≥10% for PFS (HR 0.59, 95% CI: 0.28-1.23, p = 0.16). For OS, differences were seen for the UC algorithm (p = 0.02), but not ICP (p = 0.07), TCP (p = 0.18) or IC (p = 0.23). Similarly to PFS, adjustment for MMR reduced the prognostic significance of the UC algorithm for OS (HR: 0.53, 95% CI: 0.25-1.12, p = 0.10). Conclusions: In this exploratory analysis, ICP was more closely associated with tumor response and PFS than TCP or IC. ICP alone was better than the UC algorithm for predicting PFS. The optimum cutpoint algorithm was promising for identifying non-responders, but requires external validation. Clinical trial information: ACTRN12617000106336.
Exploring molecular profiles of uterine carcinosarcoma with alterations in the chromatin remodeling pathway.
Authors: Wilhite Annelise M. , Wu Sharon , Xiu Joanne , Rocconi Rodney Paul , Erickson Britt Kristina , Klc Tenley , Lesnock Jamie Lee , Brown Jubilee , Herzog Thomas J. , Holloway Robert W. , Korn Wolfgang Michael , Powell Matthew A. , Jones Nathaniel L.
Published: June 2021

5587

Background: In a preliminary data analysis to identify prognostic molecular biomarkers in uterine carcinosarcoma (UCS), we found that alterations in KMT2C, a gene involved in the chromatin remodeling pathway, correlated with improved survival. We sought to explore relevant biomarkers of KMT2C-mutated (KMT2C-mut) tumors compared to wildtype (KMT2C-wt) tumors. Methods: Tumor samples were analyzed using next generation sequencing (NGS) of the DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ).PD-L1 IHC used SP-142 (cut-off >1%). Microsatelite instability (MSI) was tested by FA, IHC and NGS. TMB was measured by totaling somatic mutations per tumor (high > 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. Overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank sum test and p values adjusted for multiple comparisons (q) to be <0.05. Results: Molecular analysis was performed on 1,144 UCS tumors. 7.7% were found to be KMT2C-mut. Patients with pathogenic alterations in KMT2C had longer median OS than patients without (OS not yet reached vs 19.0 months HR(95% CI): 0.37(0.19-0.72) p< 0.01). The most common mutations in KMT2C-mut tumors are shown in Table and resulted in more frequent dysregulation in the following pathways compared to KMT2C-wt tumors: chromatin remodeling (100% vs 28%; q<0.01), WNT (39% vs 12%; q=0.01), base/nucleotide excision repair (29% vs 5%; q<0.01), homologous recombination (26% vs 6%; q=0.02), DNA damage sensors (23% vs 4%; q=0.02) and Fanconi anemia (13% vs 1%; q=0.04). KMT2C-mut tumors were more frequently MSI-H (32% vs 6%; q<0.01) and TMB-H (42% vs 5%; q<0.01). Among MSS tumors, KMT2C-mut tumors had increased mutations in JAK1 and POLE (q<0.01) and higher frequency of TMB-H (24% vs 1%; q<0.01) than KMT2C-wt tumors. Additionally, MSS patients with KMT2C-mut had longer OS than patients with KMT2C-wt tumors (OS not yet reached vs 18.9 months; HR(95% CI): 0.33(0.15-0.75) p< 0.01). Conclusions: Mutations in KMT2C correlate with improved OS in UCS. KMT2C-mut tumors have distinct molecular profiles from wild type tumors. They exhibit greater immunogenicity, including more frequent MSI-H and TMB-H. This suggests a potential role for Immune-oncology (IO) therapy. Further study of the impact of IO therapies in the cohort is warranted as this may contribute to the improved survival of these patients.[Table: see text]
Immune-response markers and actual response to immune-oncology therapy in uterine serous carcinoma.
Authors: Jones Nathaniel L. , Wu Sharon , Xiu Joanne , Craig Amaranta , Mantia-Smaldone Gina , Hernandez Enrique , Rocconi Rodney Paul , Brown Jubilee , Herzog Thomas J. , Holloway Robert W. , Korn Wolfgang Michael , Powell Matthew A. , Wilhite Annelise M.
Published: June 2021

5590

Background: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer with poor prognosis and limited treatment options. Immune-oncology (IO) agents have shown promise USC, however data is limited regarding which patients benefit most from IO therapy. In other malignancies, PD-L1, MSI-H status and high TMB have been predictive of IO response. We sought to characterize the immune profiles of USC and investigate treatment response to IO therapy. Methods: Tumor samples were analyzed using Nex-Gen sequencing of the DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ).PD-L1 IHC used SP-142 (cut-off >1%). MSI was tested by FA, IHC and NGS. TMB was measured by totaling somatic mutations per tumor (high > 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. Real-world overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank sum test and p values adjusted for multiple comparisons (q) to be < 0.05. Results: Molecular analysis was performed on 2,806 USC tumors. The median age was 67 years. 65.3% were from primary tumors, 34.7% from metastatic sites. In total, 92 patients were treated with IO therapy and had a significantly longer median survival than those not treated with IO (months: 59.6 vs 31.2; HR(95% CI): 0.38(0.24-0.61) p < 0.001), resulting in a survival advantage of 867 days. PD-L1 expression was present in 19.1% of cases, but only 2.3% of tumors were MSI-H and 4.2% were TMB-H. Patients with these markers trended toward a better median survival, but this was not significant; PD-L1 (months: 34.4 vs 31.2; HR(95% CI): 0.90 (0.74-1.1), MSI-H (OS not yet reached vs 31.6 months; HR(95% CI): 0.69(0.38-1.25) and TMB-H (months: 36.4 vs 31.6; HR(95% CI): 0.84(0.50-1.39). Regarding the immune microenvironment, the most common infiltrating immune cells were M2 Macrophages (5.35%), B cells (4.71%), myeloid dendritic cells (3.45%), NK cells (2.94%) and regulatory T cells (1.59%). There were few CD8 T cells and non-regulatory CD4 T cells. Conclusions: IO therapy was associated with a median survival benefit of more than 2 years in USC. We did not identify any prognostic markers of IO-therapy response. MSI-H and TMB-H are rare in USC, but PD-L1 is present in nearly 20% of cases. Notably these markers did predict a significant survival benefit, which has important clinical implications. Further study is warranted.
Association of allograft rejection response score with biological cancer aggressiveness and with better survival in triple-negative breast cancer (TNBC).
Authors: Oshi Masanori , Le Lan , Angarita Fernando A , Tokumaru Yoshihisa , Yan Li , Matsuyama Ryusei , Endo Itaru , Takabe Kazuaki
Published: June 2021

561

Background: Although the importance of immunity in the progression of breast cancer was widely reported, the clinical relevance of enhanced immune response is still unclear. We hypothesized that the enhanced immune response is associated with better breast cancer patient survival. Methods: We used 6,245 breast cancer patient sample data from publicly available data sets (METABRIC, GSE96058, TCGA cohorts). To elucidate the function of immunity in breast cancer, we calculated the immune function score using hallmark allograft rejection gene sets by Gene Set Variation Analysis algorithm. Results: The immune response score correlated most with cytolytic activity among hallmark immune-related gene sets in both cohorts (Spearman’s rank correlation (r) = 0.892 and 0.860, respectively, both p < 0.01). The score reflected the amount of infiltrating immune cells, including several anti-cancer immune cells (CD8+ T cells, CD4+ memory T-cells, T helper Type 1 cells, M1 macrophages, plasmacytoid dendritic cells), T helper Type 2 cells, and B cells. The score also correlated with expression levels of immune checkpoint molecule genes (all r > 0.500). A high score was significantly associated with high intratumor heterogeneity, homologous recombination deficiency (HRD), and mutation rate in the TCGA cohort (all p < 0.001). A high score was significantly associated with advanced Nottingham histological grade, advanced stage, and lymph node metastasis. High score breast cancer enriched not only immune-related gene sets but also pro-cancer-related gene sets, such as epithelial-mesenchymal transition (EMT) and p53 pathway, in both ER-positive/HER2-negative breast cancer and TNBC. The score was highest in TNBC compared to other subtypes, and TNBC with high score was significantly associated with better survival. Conclusions: The counterbalance between malignant biology and the enhanced immune response is an important factor in clinical outcomes.
Survival in male breast cancer (MaBC) over the past three decades.
Authors: Leone Jose Pablo , Freedman Rachel A. , Leone Julieta , Hassett Michael J. , Tolaney Sara M. , Vallejo Carlos Teodoro , Leone Bernardo Amadeo , Winer Eric P. , Lin Nancy U.
Published: June 2021

569

Background: Breast cancer mortality in women has declined significantly over the past several years. In men, it is unclear whether survival has changed over time. The aim of this study was to evaluate changes in breast cancer-specific survival (BCSS) and overall survival (OS) in MaBC over the past three decades. Methods: We evaluated men diagnosed with breast cancer between 1988 and 2017, with known cause of death reported in the Surveillance, Epidemiology, and End Results registry. Patients were categorized into 3 groups by year of diagnosis: 1988-1997, 1998-2007 and 2008-2017. BCSS and OS were estimated by Kaplan-Meier and differences between groups were compared by log-rank test. Cox proportional hazards regression was used to evaluate the independent association of tumor and patient characteristics with BCSS and OS. Results: We included 8,412 men diagnosed between 1988-1997 (N = 1,033), 1998-2007 (N = 2,938) and 2008-2017 (N = 4,441). Median age for the overall population and within each decade of diagnosis was 68 years. Median follow-up was 23.6 years, 14.3 years and 4.5 years in periods 1988-1997, 1998-2007 and 2008-2017, respectively. Overall, BCSS at 5 years was 83.5%, 83.6% and 84.3% in periods 1988-1997, 1998-2007 and 2008-2017, respectively; p = 0.8. There was no significant difference in BCSS between the three periods of diagnosis within each stage of breast cancer (stage I, II, III and IV). Among all patients, OS at 5 years was 64.7%, 67.2% and 69.3% in periods 1988-1997, 1998-2007 and 2008-2017, respectively; p = 0.01. In multivariate Cox models, older age at diagnosis, black race, grade 3 disease, increasing stage, hormone receptor negative status and no surgery were all independently associated with worse BCSS and OS. In these adjusted Cox models, each additional year of diagnosis had no significant association with BCSS (hazard ratio, 1.0; 95% CI, 0.99 – 1.01; p = 0.78), and a significant improvement in OS (hazard ratio, 0.99; 95% CI, 0.98 – 0.99; p = 0.01). Conclusions: Over the past three decades, there has been no significant improvement in BCSS in MaBC. The changes in OS over time suggest increasing life expectancy. Efforts to improve BCSS in MaBC are warranted.