bluuebunny/crossref_metadata_2025 huggingface dataset:
Blinded-assessment of a solution to evaluate olaparib maintenance treatment efficacy in patients with ovarian cancer from the GINECO/ENGOT PAOLA-1 trial.
Authors: Buisson Adrien , Saintigny Pierre , Constantoulakis Pantelis , Oikonomaki Katerina , Samara Stavroula , Harter Philipp , Pignata Sandro , Gonzalez Martin Antonio , Schauer Christian , Fujiwara Keiichi , Vergote Ignace , Colombo Nicoletta , Pujade-Lauraine Eric , Treilleux Isabelle , Ray-Coquard Isabelle Laure
Published: June 2023

5588

Background: SOPHiA DDM Dx HRD Solution (SOPHiA GENETICS, SA) combines analysis of genomic instability with mutational status of HRR genes, including BRCA1/2, generated through a single genomic workflow in order to to predict Homologous Recombination Deficiency (HRD) status in ovarian cancer (OvCa) samples. Previous evaluation of SOPHiA DDM Dx HRD Solution demonstrated its results to be highly concordant with a reference HRD method. As part of the ENGOT HRD initiative, we present updated clinical relevance results of SOPHiA DDM Dx HRD Solution. Methods: GINECO/ENGOT-Ov25 PAOLA-1 trial randomized (2:1) 804 patients (pts) to receive after the end of first-line platinum-based chemotherapy either maintenance olaparib+bevacizumab or placebo+bevacizumab for up to 2 years. DNA from a sub-cohort of 384 formalin-fixed paraffin-embedded (FFPE) OvCa pts samples included in the PAOLA-1 clinical trial were analyzed using SOPHiA DDM Dx HRD Solution(*). We combined SOPHiA DDM Dx HRD Solution genomic instability score, with BRCA mutational status obtained from a Clinical Decision Support module, and clinical interpretation of Variants of Unknown Significance to establish the pts HRD status and investigated differences in progression-free survival (PFS) in the olaparib+bevacizumab and placebo+bevacizumab arms between pts with HRD positive or HRD negative test. Results: We determined the HRD status of 98.4% of pts using SOPHiA DDM Dx HRD Solution. The median PFS time for pts with HRD positive tumors was 35.7 months longer in the olaparib+bevacizumab arm than in the placebo+bevacizumab arm (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.25-0.51, p< 0.001), confirming the findings of our previous interim analysis. No significant difference in PFS was observed between treatment arms in pts with HRD negative test (HR, 1.02; 95% CI, 0.71-1.48; p= 0.90). Conclusions: These clinical relevance results from the SOPHiA DDM Dx HRD Solution evaluation on the PAOLA-1 samples further support the value of combining low-pass whole genome and targeted sequencing in a unique workflow for reliable and cost-effective HRD testing and future patient stratification. (*) Comparison data generated using the CE-IVD pipeline with Clinical Decision Support module for BRCA status only available in EU, Switzerland, UK.
The role of Chemotherapy Response Score (CRS) in the decision making process for patients with advanced high grade serous ovarian cancer undergoing neoadjuvant chemotherapy.
Authors: Marchetti Claudia , Ergasti Raffaella , Capomacchia Filippo Maria , Giannarelli Diana , Sassu Carolina Maria , Zannoni Gian Franco , Scambia Giovanni , Fagotti Anna
Published: June 2023

5591

Background: The role of chemotherapy response score (CRS) in predicting PARP inhibitors (PARPi) response for high grade serous Advanced Ovarian Cancer (AOC) patients undergoing Neoadjuvant Chemotherapy (NACT) has never been investigated. Also, the correlation between CRS and Homologous Recombination status (HRs) is unclear. Methods: In this observational retrospective study, we collected data from patients with high grade serous AOC, FIGO stage III-IV, undergoing NACT and subsequent Interval Debulking Surgery (IDS) from 2017 to 2021. KELIM score, CRS and BRCA status were considered; additionally, HRs (Foundation test) was reported when available. Primary endpoint was Progression Free Survival (PFS) according to CRS (CRS 1/2 vs 3) in patients receiving PARPi. Results: We enrolled 309 patients; 102 had CRS3 and 193 had CRS1/2 (14 were undetermined). Patients with CRS3 and PARPi maintenance showed the best prognosis, compared to all other subgroups (median PFS Not Reached, p=0.014); additionally, in the BRCA wild type population, CRS3 was predictive of longer survival (median PFS for the CRS3+PARPi BRCAwt population 24 months compared with 15 months for the CRS1/2+PARPi BRCAwt patients, p=0.041). Furthermore, among the 44 patients with known HRs, 59.1% of HR Deficiency (HRD) positive patients had CRS3, conversely 22.7% of HRD negative ones had a CRS3 ( p=0.048) Finally, we found out that a favorable KELIM was significantly associated with CRS3 in the all-comers patients ( p=0.007) and in the BRCAwt ( p=0.04), but it was not predictive of PARPi response. Conclusions: Our findings suggested that the higher the CRS at the interval cytoreduction, the better the subsequent PARPi response. CRS correlates with PARPi response, as the HRD test does in other clinical trials and it may be considered as a surrogate of HRD status. We have planned to retrospectively perform HR test on a total sample size of 77 patients who received PARPi to corroborate this hypothesis. [Table: see text]
Real-world overall survival in second-line maintenance niraparib monotherapy vs active surveillance in BRCA wild-type patients with recurrent ovarian cancer.
Authors: Coleman Robert L. , Perhanidis Jessica , Kalilani Linda , Zimmerman Nicole M. , Golembesky Amanda , Moore Kathleen N.
Published: June 2023

5592

Background: The Phase 3NOVA trial assessed niraparib versus placebo as a maintenance treatment (tx) for patients (pts) with recurrent ovarian cancer (OC) who were platinum-sensitive after ≥2 regimens; progression-free survival was the primary endpoint and overall survival (OS) was a secondary endpoint (NCT01847274). The aim of this real-world study was to compare OS in a breast cancer gene wild-type ( BRCAwt) population of pts with recurrent OC and who received second-line maintenance (2Lm) niraparib monotherapy or were under active surveillance (AS). Methods: This study used the US nationwide Flatiron Health de-identified electronic health record (EHR)-derived database. Pts diagnosed with epithelial OC between 1Jan2011–31May2021 who completed 2L therapy between 1Jan2017–2Mar2022 were eligible for inclusion. Pts were BRCAwt, had an ECOG PS score 0–1, epithelial histology, and platinum-sensitive disease with ≥6 months between end of first-line tx and start of 2L tx. Pts were assigned to 2Lm niraparib or AS cohorts based on their management following 2L non-maintenance therapy (≤120 days). Follow-up was measured from the index date (end of 2L non-maintenance therapy) until end of study (31May2022), last activity, or death, whichever came first. A target trial emulation cloned inverse probability of censoring weighting (IPCW) methodology was selected a priori to minimize bias. IPCW median OS and hazard ratios (HR) for 2Lm versus AS were estimated with Kaplan-Meier curves and Cox regression models. Results: Overall, 266 BRCAwt pts were included and received niraparib 2Lm (N=123) or were under AS (N=143). Across 2Lm and AS cohorts, prior to cloning and IPCW, 23.6% and 34.3% of pts were aged ≥75 years, and 26.0% and 16.8% had an EHR value for race as other than White, respectively. The majority of pts were from community practice (80.5% and 90.2%, respectively), had serous OC (79.7% and 81.1%) and had Stage III disease (53.7% and 60.8%). Homologous recombination deficiency status was unknown for 92.7% and 86.0% of pts in 2Lm and AS cohorts, respectively. Median follow-up for 2Lm and AS cohorts was 16.8 (Quartile [Q] 1, Q3: 10.4, 28.7) and 10.2 (Q1, Q3: 4.1, 23.7) months, respectively. IPCW median OS was 28.1 (95% confidence interval [CI]: 22.5, 43.2) and 21.5 (95% CI: 14.7, 27.0) months (HR: 0.63 [95% CI: 0.45, 0.88]) for niraparib 2Lm and AS cohorts, respectively and survival rates at 24 months were 58.2% (95% CI: 47.5, 67.6) and 46.1% (95% CI: 33.6, 57.7). Conclusions: This analysis provides real-world data on OS among pts with OC receiving niraparib 2Lm or under AS in the 2L setting following chemotherapy. Funding: GSK study (219306). Editorial support was provided by Fishawack Health, funded by GSK.
OATH trial: A phase II clinical trial evaluating the combination of onapristone with anastrozole for women with hormone receptor positive endometrial cancer—Preliminary results.
Authors: Schilder Russell J. , Shahin Mark S. , Edelson Mitchell , Rosenblum Norman G. , Douglas Ashley , Bhattacharya Saveri , Sahmoud Tarek , Burton Elizabeth , Bhatia Avnish K
Published: June 2023

5601

Background: Endometrial cancer is the most common gynecologic cancer and is primarily treated with chemotherapy. Many endometrial cancers though express hormone receptors and may respond to hormonal therapy, a potentially attractive non-chemotherapy alternative in such a population of women. The aim of OATH is to investigate the potential of dual hormonal blockade through the combination of antiprogesterone and anti-estrogen therapy via the administration of onapristone extended release (ONA) plus anastrozole (ANA), respectively. OATH is an open-label, multicenter, investigator-initiated, non-randomized, phase 2 study to evaluate the safety and efficacy of ONA + ANA in patients (pts) with endometrial cancer (EC). ClinicalTrials.gov Identifier: NCT04719273. Methods: Pts received ONA 50 mg twice daily plus ANA 1 mg once daily and were treated until progressive disease (PD) or unacceptable toxicity. Co-primary endpoints were 4-month progression-free survival (PFS) rate and overall response rate (ORR). A sample size of 25 pts will achieve 80% power to detect an improvement in 4-month PFS estimates from 25% (historical) to 52% and an improvement in response rate from 15% (historical) to 37%, using two-sided exact test at 5% significance level. Secondary endpoints include PFS, disease control rate (DCR), and safety. Results: As of January 20, 2023, 14 pts were enrolled. Median age was 67 years (44-80). ECOG performance status was 0 (36%), and 1 (64%). Number of prior chemotherapy regimens was 0 (1 pt,7%), 1 (9 pts, 64%) and 2 (4 pts, 29%). Seven (50%) pts received radiotherapy and 3 (21%) pts received prior checkpoint inhibitor therapy. Median treatment duration was 4.2 (1.0-19.9) months, and 8 pts remain on treatment. Adverse events were mainly grade 1 and 2. The most common treatment-related adverse events (AEs) and abnormal laboratory values were hot flashes (36%), alanine transferase (ALT) increased (29%), aspartate aminotransferase (AST) increased (29%), nausea (29%), and diarrhea (21%). No treatment-related serious AE, deaths on treatment, or treatment-related drug discontinuations were reported. The 4-month PFS Kaplan-Meier rate was 63.5%. Among 13 pts who had at least one tumor assessment after baseline, the best overall response was: 1 complete response, 1 partial response (response rate: 15.4%), 9 (69%) stable disease, and 2 (15.4%) progressions. Updated results will be presented. Conclusions: Preliminary results of dual hormonal blockade using ONA and ANA in heavily pretreated pts with EC suggest that this combination ONA + ANA has promising activity and is well tolerated. Clinical trial information: NCT04719273 .
Association of the Duffy-null allele and endometrial cancer characteristics: An effort to explore racial disparity in Black women with endometrial cancer.
Authors: Webster Emily M. , Martini Rachel , Kulkarni Amita , Narayan Priyanka , Chao Max , Cantillo Evelyn , Frey Melissa Kristen , Holcomb Kevin , Elemento Olivier , Davis Melissa , Chapman-Davis Eloise
Published: June 2023

5603

Background: Efforts are needed to identify factors that account for the disparately high mortality in Black women with endometrial cancer. The Duffy antigen receptor for chemokines (DARC) is expressed on erythrocytes and endothelial cells and modulates levels of inflammatory chemokines in circulation and in tissues. The African ancestry-specific Duffy-null allele, in which erythrocyte expression and function of DARC is lost, is associated with worse breast cancer phenotypes and survival. Here, we characterize Duffy-null status and associated prognostic and clinical outcomes in patients with endometrial cancer. Methods: Patients with endometrial cancer were prospectively consented, and germline DNA was extracted from saliva or blood samples. Duffy-null genotype was determined using an allelic discrimination assay. Associations between Duffy-null genotype status and clinicopathologic characteristics were performed using Fisher’s Exact analysis. Results: 33 patients were enrolled (Table); 17 (51.5%) were Duffy-null, 5 (15.2%) were Duffy-null allele carriers, and 11 (33.3%) were non-carriers. Compared with non-carriers, Duffy-null patients were more likely to be Black (100% v 9.1%, p<0.0001) and have non-endometrioid histology (64.7% v 10%, p=0.0173). There was a trend towards higher rates of grade 3 histology (70.6% v 36.6%), intact tumor mismatch repair (MMR) (86.7% v 54.6%), estrogen receptor (ER) negative tumor status (25% v 10%), advanced stage (37.5% v 18.2%), and positive lymph nodes (25% v 0%) (Table). Over a minimum of 12 months of follow up, only Duffy-null individuals died from disease (4 v 0, p=0.0006). Conclusions: Duffy-null status was associated Black race, aggressive histologic subtypes, intact MMR mechanisms, and worse survival. Further investigation is needed to explore the underlying mechanism of the Duffy-null phenotype on endometrial cancer outcomes to better elucidate risk factors and underlying causes that may contribute to endometrial cancer disparities.[Table: see text]
Association of human epidermal growth factor receptor 2 expression with 21-gene recurrence score and survival among patients with estrogen receptor–positive breast cancer.
Authors: Ma Sung Jun , Gill Jasmin , Yendamuri Keerti , Yao Song , Oladeru Oluwadamilola Temilade , Singh Anurag K.
Published: June 2023

563

Background: Trastuzumab-deruxtecan was recently shown to improve survival for metastatic human epidermal growth factor receptor 2 (HER2)-low breast cancer. HER2-negative breast cancer has been redefined as a group of heterogeneous entities. However, HER2-low status is not considered as a prognostic factor among patients with nonmetastatic breast cancer, and the role of HER2 expression levels in the setting of 21-gene recurrence score (RS) remains unclear. We performed an observational cohort study using a national oncology database to evaluate the association of HER2 expression levels with RS and survival among patients with estrogen receptor (ER)-positive breast cancer. Methods: The National Cancer Database was queried for women diagnosed between 2006 and 2018 with ER-positive, pT1-3N0-1aM0 breast cancer who received surgery followed by adjuvant endocrine therapy with or without chemotherapy. HER2 expression levels were stratified by 3 groups: HER2-0 (immunohistochemistry [IHC] 0), HER2-1 (IHC +1), and HER2-2 (IHC +2 and in situ hybridization [ISH] negative). Logistic and Cox multivariable analysis (MVA) were used to identify factors associated with high RS (26 or higher) and overall survival (OS), respectively. Interaction term was analyzed to evaluate any heterogeneous associations in survival outcomes between HER2 levels and RS. Subgroup analysis was performed by repeating Cox MVA stratified by RS. Holm-Bonferroni correction was used to adjust for multiple comparisons, with p value less than 0.05 considered as statistically significant. Results: Among 108,973 women, 31,738 (29.1%), 52,839 (48.5%), and 24,396 (22.4%) patients had HER2-0, HER2-1, and HER2-2, respectively. Logistic MVA showed that, compared to HER2-0, HER2-2 was associated with higher RS (adjusted odds ratio [aOR] 1.09, 95% confidence interval 1.04-1.15, p < 0.001), but HER2-1 was not (aOR 0.96, 95% CI 0.91-1.00, p = 0.05). Cox MVA showed that both HER2-1 (adjusted hazards ratio [aHR] 1.03, 95% CI 0.97-1.10, p = 0.34) and HER2-2 (aHR 1.06, 95% CI 0.98-1.14, p = 0.14) were not associated with OS. There was an interaction between HER2 expression levels and RS (interaction p = 0.03). Among those with RS < 26, compared to HER2-0, HER2-2 was associated with worse OS (aHR 1.10, 95% CI 1.01-1.20, p = 0.02), but HER2-1 was not (aHR 1.04, 95% CI 0.97-1.12, p = 0.24). Among those with RS 26 or higher, both HER2-1 (aHR 1.00, 95% CI 0.88-1.13, p = 0.98) and HER2-2 (aHR 0.94, 95% CI 0.82-1.09, p = 0.41) were not associated with OS. Conclusions: To our knowledge, this is the largest study using nationwide oncology database to suggest that, when compared to HER2-0, HER2-2 was associated with higher RS and poor survival among patients with RS < 26. Further studies would be warranted to evaluate the role of HER2 expression levels for risk stratification to tailor interventions.
Correlation of gene signatures of Kaiso and LC3A/B protein expression with distinct tumor ecosystems and to predict response to breast cancer therapy.
Authors: Singhal Sandeep K. , Gardner Kevin
Published: June 2023

566

Background: The multifunctional transcriptional repressor, Kaiso, is a member of the BTB/POZ (Broad complex, Tramtrak, Bric `aBrac/Pox zinc finger) family of zinc finger proteins. Kaiso protein levels in both the nucleus and the cytoplasm have each been shown to be highly sensitive and independent predictors of overall breast cancer survival. Through the use of gene signatures and/or gene modules developed through the analysis of RNA-seq data from breast cancer patients following biomarker stratification by either nuclear Kaiso, cytoplasmic Kaiso, or the Kaiso’s functional downstream target LC3A/B, we demonstrate the utility of Kaiso and LC3A/B derived signatures as predictors of treatment outcome. Methods: We used a machine Learning approach to assess a cohort of racially diverse 555 BC patients who underwent surgery for their primary BC in Greenville, NC and develop proteomics-based genomics (PbG) signatures. The cross-validated logistic regression modeling using publicly available gene expression data compiled from neoadjuvant clinical trials (N=996, JCO:30(16):1996-2004). Results: Kaiso and LC3A/B derived gene modules show accuracy in predicting pathological complete response (pCR, AUC = 0.728, 95% CI: 0.689-0.764). Moreover, predictive estimates of distant metastasis-free survival utilizing Kaiso and LC3A/B derived gene modules are also significant (overall DMFS, AUC= 0.737, 95% CI: 0.665-0.819) and (DMFS of non-pCR patients AUC= 0.71, 95% CI: 0.633-0.773). We then validate these findings in an independent, racially diverse breast cancer cohort receiving neoadjuvant treatment (N=443). Gene modules based on Kaiso and LC3A/B were also highly predictive in this independent cohort (total cohort pCR, AUC= 0.775, 95% CI: 0.687-0.838; pCR NHW (N=257), AUC= 0.762, 95% CI: 0.659-0.855; pCR Hispanic (N=125), AUC= 0.725, 95% CI: 0.493-0.873; and pCR NHB (N=42), AUC= 0.681, 95% CI:0.405-0.904). Conclusions: Combined analysis by multiplex immunofluorescence and deconvolution of gene expression data show that the protein expression of Kaiso and LC3A/B in tumors are associated with distinct tumor ecosystems where high levels cytoplasmic Kaiso are linked to an immune-suppressed tumor microenvironment.
Phase II randomized window of opportunity trial evaluating cytotoxic and immunomodulatory effects of intratumoral INT230-6 in early stage breast cancer: The INVINCIBLE trial.
Authors: Spears Melanie , Hopkins Megan , Keyhanian Kianoosh , Robertson Susan , Liao Linda , Talebian Vida , Awan Arif Ali , Pond Gregory Russell , Bartlett John , Bender Lewis H. , Walters Ian B. , Lopez-Ozuna Vanessa , Arnaout Angel
Published: June 2023

573

Background: Most breast cancers are considered immunological cold and are therefore minimally responsive to immunotherapies. Local cytotoxic therapies can induce cell death, expose tumor antigens, provide adjuvants for anti-tumor immune priming, and potentially increase responsiveness to immunotherapies. We conducted a randomized, double blind, Phase 2 presurgical Window-Of-Opportunity trial for intratumoral (IT) INT230-6 (comprising VINblastine (VIN) Cisplatin (VIN)) evaluating clinical and BioLogical Effects in patients with early-stage operable Breast Cancer (the INVINCIBLE trialNCT04781725. The trial evaluated the immune response within the tumor and microenvironment in vivo after IT INT230-6 injections. Methods: Women with newly diagnosed and awaiting surgery for early-stage intermediate or high-grade ER+ T1-T2 invasive breast cancers were recruited to the trial. Participating patients were allocated (2:1) to IT injections of INT230-6 vs saline placebo, prior to resection. RNA profiling of the pre- (baseline biopsy) and post- treatment (surgical resection) tumours using the Ion AmpliSeq Transcriptome Human Gene Expression (Thermo Fisher Scientific) and DNA sequencing using a large (500 gene) comprehensive genomic profiling panel (OCAPlus,) was performed. Results: Significant tumor necrosis was observed in the majority of subjects injected with INT230-6. In the 60 pre-treatment biopsies profiled with OCAPlus, the genes most frequently mutated included PIK3CA (38%), TP53 (23%), CDH1 (22%) and TBX3 (17%). Frequent copy number changes were identified in CCND1 (23%), FGFR1 (18%), and CDH1 (17%). Gene expression analysis showed significant differential gene expression between the baseline biopsy and surgical specimens in patients treated with the drug. Pathway analysis identified genes associated with TCR signaling, macrophage markers, IL-18 signaling and B cell receptor signaling were significantly up-regulated in the post treatment samples. Conclusions: This is the first study evaluating the potential biologic effects of intratumoral cytotoxicity with INT230-6 and its role as a potential immune priming therapy in traditional immune quiescent ER+ breast cancers.
Treatment outcomes in patients with discordant recurrence score and RSClin risk predictions.
Authors: Vannier Augustin , Dhungana Asim , Zhao Fangyuan , Chen Nan , Shubeck Sarah , Hahn Olwen Mary , Nanda Rita , Jaskowiak Nora T. , Fleming Gini F. , Olopade Olufunmilayo I. , Pearson Alexander T. , Huo Dezheng , Howard Frederick Matthew
Published: June 2023

574

Background: 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 tool, which integrates the 21-gene recurrence score (RS) and clinicopathologic features, was developed to better estimate CT benefit. Here, we studied patients with RSClin/RS discordance to determine if patients (pts) should be treated according to RS or RSClin. Methods: This was a retrospective cohort study of pts from the National Cancer Database who were diagnosed with HR+/HER2- node negative EBC from 2010-2020 who underwent RS testing and received adjuvant endocrine therapy with or without CT. Pts were classified as low RS ( < 26) or high RS (≥ 26) and low ( < 3%) versus high (≥ 3%) predicted CT benefit per RSClin. The primary outcome was overall survival (OS) benefit associated with CT administration for pts with discordant RS/RSClin, measured as hazard ratio [HR] for receipt of CT. Hazard ratios were adjusted for age and comorbidity index, and inverse probability of treatment weighting was performed for age, comorbidity index, race, ethnicity, and insurance status. Results: 262,748 pts with EBC were included, with a median follow-up of 58 months. Median age was 60 years; 82% were White, 7% Black, 5% Hispanic, and 4% Asian/Pacific Islander. Median tumor size was 1.5 cm, and median RS was 15. The 31,955 cases with concordant high RS/RSClin had an OS benefit with CT (HR: 0.71, 95% CI: 0.67 - 0.75, p < 0.001), while the 206,631 cases with concordant low RS/RSClin did not have a survival benefit (HR: 1.00, 95% CI: 0.95 - 1.04, p = 0.85, Table). High RS with low RSClin was seen in 435 cases – all with grade 1 tumors, with RS no greater than 28, and tumor size under 1.3cm. No significant CT benefit was seen in this small subset of pts (HR 1.57, 95% CI 0.75 – 3.26, p = 0.23). In 23,727 pts with low RS but high RSClin, a CT benefit was seen (HR 0.73, 95% CI 0.67 – 0.78, p < 0.001). These pts had high-intermediate RS (median 23, interquartile range 20 – 24) with other higher risk features. Similar results were seen in older (age > 50) and younger (age ≤ 50) subgroups – although no pts ≤ 50 were in the low RS/high RSClin group. Conclusions: RSClin may identify a small number of grade 1 tumors with high RS for which CT is not needed, and may help guide appropriate use of CT for EBC in the sizeable group with intermediate RS. [Table: see text]
Assessment of the differential profile of breast intratumoral bacteria in treatment responders and nonresponders.
Authors: Basgaran Amedra , Lymberopoulos Eva , Paschke Sophie , Hobbs Michael , Alomari Muhannad , Sharma Nikhil
Published: June 2023

580

Background: Despite improvements in breast cancer therapy, many patients do not respond to treatment: the response rate varies between 31 and 80% [Walks et al., 2019]. The tumor microenvironment contains a microbiome which is both cancer type-specific and different to surrounding normal tissue [Nejman et al., 2020]. It plays an important role in tumour microenvironment crosstalk with tumor cells and has been implicated in disease pathogenesis, being recognised in the latest hallmarks of cancer [Hanahan et Weinberg, 2011]. It has also successfully predicted treatment response [Chen et al., 2022; Hermida et al., 2022]. Here, we use conventional microbiome analysis alongside our proprietary mechanistically-powered technology platform to compare the intratumoral bacteria between responders and non-responders. We hypothesise that there are significant differences between those groups regarding composition and mechanistic function of the bacteria. Methods: The tumor microbiome can be deduced from existing sequencing data of tumor biopsy samples. Using 34 tumor DNA samples from 5 breast cancer studies, we compared the intratumoral bacterial profiles of responders to non-responders of various treatments. We performed microbiome analysis in R, including alpha diversity, compositional abundance profiles, and PERMANOVA (permutational analysis of variance). Additionally, BioCorteX CarbonMirror version dated 2023-02-14 was used to infer mechanistic links between bacterial species and the up- and downregulation of genes implicated in the hallmarks of cancer. Results: The results show significant differences in diversity and compositional profile between responders and non-responders: Non-responders have significantly higher alpha diversity ( p<0.05) and a higher proportion of Proteobacteria. PERMANOVA analysis revealed that while responders are more likely to have commensal bacteria, non-responder tumour microbiomes are more likely to harbor pathogenic species such as Mycoplasmopsis fermentans. Mechanistic analysis showed that for all responders the tumor microbiome is consistently promoting tumor suppressor genes and downregulating proto-oncogenes. In non-responders, however, the tumor microbiome is upregulating and downregulating both with unclear consistency. Conclusions: Our results show microbiome differences between responders and non-responders which were mechanistically implicated in tumor pathogenesis. Further analysis divided by the hallmarks of cancer is required to fully understand the non-responder microbiome links. The reported findings could make the tumor microbiome a useful biomarker aiding patient stratification for both prognosis and treatment choice. They also highlight a potentially meaningful mechanistic link between tumour microenvironment and treatment response that could be leveraged as a novel therapeutic avenue.
Effect of tumor microenvironment on chemotherapy response of patients with triple-negative breast cancer receiving neoadjuvant chemotherapy.
Authors: Kim Jae-Joon , Kim Dongjin , Yu Yeuni , Jung Ki Sun , Kim Yun Hak
Published: June 2023

590

Background: Triple-negative breast cancer (TNBC) is a breast cancer subtype that has poor prognosis and exhibits a unique tumor microenvironment, including the corresponding immunological environment. Analysis of the tumor microbiome has indicated a relationship between the tumor microenvironment and treatment response. Therefore, we attempted to reveal the role of the tumor microbiome in patients with TNBC that were receiving neoadjuvant chemotherapy. Methods: We collected TNBC patient RNA-seq samples from the Gene Expression Omnibus (GEO; n of pathological complete response [pCR] = 38, n of residual disease [RD] = 50) and extracted microbiome count data using Kraken2 and Bracken. Differential and relative abundance were estimated with linear discriminant analysis effect size (LEfSe). We calculated the immune cell fraction with CIBERSORTx and conducted survival analysis using the Cancer Genome Atlas patient data (n = 115). Correlations between the microbiome and immune cell compositions were analyzed and a prediction model was constructed to estimate drug response using random forest (RF) and support vector machine (SVM). Results: Among the drug response group, the beta diversity varied considerably; consequently, 20 genera and 24 species were observed to express a significant differential and relative abundance using LEfSe analysis. The drug response prediction model accuracy exhibited 76.47 and 88.24 percent in RF and SVM, respectively; specifically, Pandoraea pulmonicola and Brucella melitensis were found to be important features in determining drug response. In correlation analysis, Geosporobacter ferrireducens, Streptococcus sanguinis, and resting natural killer cells were the most correlated factors in the pCR group, whereas Nitrosospira briensis, Plantactinospora sp. BC1, and regulatory T cells (Tregs) were key features in the RD group. Further, M2 macrophages and Brucella showed significant differences in survival between the pCR and RD groups (p < 0.05). Conclusions: Our study demonstrated that the microbiome analysis of tumor tissue can predict chemotherapy response of patients with TNBC receiving neoadjuvant chemotherapy. Further, the immunological tumor microenvironment may be impacted by the tumor microbiome, thereby affecting the corresponding survival and treatment response.
Neoadjuvant giredestrant + palbociclib (P) vs. anastrozole (A) + P in postmenopausal women with estrogen receptor-positive, HER2-negative, untreated early breast cancer (ER+, HER2– eBC): Patient (pt)-reported outcomes (PROs) in the randomized, open-label, international phase II coopERA BC study.
Authors: Park Yeon Hee , Quiroga Vanesa , Fasching Peter A. , Bardia Aditya , López-Valverde Vanesa , Badovinac Crnjevic Tanja , Steinseifer Jutta , Devine Jacob , Hurvitz Sara A.
Published: June 2023

591

Background: Endocrine therapies (ETs) are the therapeutic mainstay for ER+ BC but persistent adverse events (AEs; eg joint pain, especially with aromatase inhibitors) negatively impact quality of life, and resistance impacts efficacy. Giredestrant, a highly potent, nonsteroidal, oral selective ER antagonist and degrader (PO SERD), may help address these issues. coopERA BC (NCT04436744) evaluated giredestrant in eBC and met its primary endpoint, demonstrating a greater reduction of Ki67 with giredestrant vs. A after 2 weeks. Giredestrant was well tolerated as a single agent and with P. We report exploratory PRO analyses. Methods: Pts with cT1c-cT4a-c (≥ 1.5 cm within cT1c) ER+, HER2– untreated eBC and baseline Ki67 score ≥ 5% were randomized 1:1 to 30 mg PO daily (QD) giredestrant or 1 mg PO QD A on days (D)1–14 of a window-of-opportunity phase. A 16-week neoadjuvant phase added 125 mg PO QD P on D1–21 of four 28-D cycles. Presence/frequency/severity/interference of relevant symptomatic AEs were assessed at Cycles 1–4 via NCI PRO-CTCAE library items; overall burden due to AEs, via FACT-G item GP5. Results: PRO completion rates were > 80% at all time points. PRO-CTCAE postbaseline frequency scores were comparable between arms and mostly 0/1 (never/rare; reported for: Diarrhea > 80% of pts; hot flash > 60%; joint pain > 65%; nausea > 90%; vomiting > 90%). No rash was reported by > 90% of pts; fatigue at 0/1 severity (none/mild) by > 75% and at 0/1 interference (none at all/a little bit) by 80%. Hot flash frequency scores of 2–4 (occasionally/frequently/almost constantly) were reported by 30% of pts in the giredestrant + P arm and 37% in the A + P arm; joint pain frequency scores of 2–4, by 25% and 35%. Worst postbaseline scores of 3–4 are shown in the table. FACT-G GP5 showed greater proportions of “improved/no change” responses in the giredestrant + P than the A + P arm at Cycles 2–4 (Cycle 2 75%; Cycle 3 71%; Cycle 4 68% vs. 62%; 66%; 53%), and smaller proportions of “worsened” responses (25%; 29%; 32% vs. 38%; 34%; 47%). Conclusions: This is the first analysis to our knowledge of PROs with a PO SERD in eBC; it showed that most pts reported minimal symptomatic AEs at frequency and severity levels that were generally numerically lower in the giredestrant + P than the A + P arm (particularly joint pain). Furthermore, there were numeric trends towards greater stability and improvement and less worsening of treatment burden in the giredestrant + P arm. Studies to further assess giredestrant’s clinical benefit are ongoing in the adjuvant setting. Clinical trial information: NCT04436744 . [Table: see text]
Taxane combined with lobaplatin or anthracycline for neoadjuvant treatment of triple-negative breast cancer: A single-center, randomized, controlled, phase-II clinical study.
Authors: Wang Cheng , Wang Rui , Zhang Guozhi , Wan Andi , Xiong Siyi , Yuan Long , Tian Hao , Ma Dandan , Jiang Jun , Zhang Yi , Qi Xiaowei
Published: June 2023

593

Background: Previously, we showed that addition of lobaplatin (L) to taxane combined with anthracycline could improve the pathologic complete response (pCR) rate and lengthen survival significantly if employed as neoadjuvant therapy in patients with triple-negative breast cancer (TNBC). We evaluated the efficacy and safety of neoadjuvant chemotherapy of taxane (T) combined with lobaplatin (L) or anthracycline (E) for patients with TNBC. Methods: Ninety-five patients with TNBC (stage I–III) who had not undergone any type of treatment were divided randomly into two groups: TL (docetaxel at 75 mg/m2 and lobaplatin at 30 mg/m2, D1, one cycle = 21 days, a total of six cycles) or TE (docetaxel at 75 mg/m2 and epirubicin at 80 mg/m2, D1, one cycle = 21 days, a total of 6 weeks or epirubicin at 80 mg/m2 and cyclophosphamide at 600 mg/m2, sequential docetaxel at 75 mg/m2, D1, one cycle = 21 days, a total of eight cycles). Efficacy was evaluated every two cycles. The final surgical procedure was completed after fulfillment of neoadjuvant chemotherapy. The primary endpoint was the total pathologic complete response (tpCR) rate. The secondary endpoints were the objective response rate (ORR), safety, event-free survival (EFS), and overall survival (OS). The exploratory endpoint was biomarker analysis. Results: From June 2019 to November 2022, 97 patients were screened. Finally, 95 patients were enrolled. The median age of the study cohort was 49 years. Nine patients (9.5%) had stage-I disease, 61 patients (64.2%) had stage II, and 25 patients (26.3%) had stage III. Sixty-five patients (68.4%) had Ki67 ≥40% and 30 patients (31.6%) had Ki67 < 40%. Seventy patients (73.7%) were cytokeratin (CK)5/6+ and 25 patients (26.3%) were CK5/6−. Of 95 patients, 47 were in the TL group and 48 in the TE group. The tpCR rate in the TL group was 46.8% (22/47), which was significantly higher than that in the TE group (22.9% (11/48); odds ratio (OR) = 2.960, 95% confidence interval (CI) = 1.223–7.164, P = 0.016). The ORR in the TL group was 95.7% (45/47), which was significantly higher than that in the TE group (75.0% (36/48); OR = 27.500, 95% CI = 1.576–35.683, P = 0.011). The prevalence of grade III/IV neutropenia in the TE group was 41.0% (9/22), which was significantly higher than that in the TL group (7.7% (2/26); OR = 8.308, 95% CI = 1.557–44.320, P = 0.013). There was no significant difference in the prevalence of other adverse reactions between the two groups. Conclusions: In the neoadjuvant treatment of TNBC, the TL regimen had a higher tpCR rate and ORR than those of the TE regimen, and was safer. Clinical trial information: ChiCTR1900023776 .
Longitudinal MRI-based fusion novel model to predict pathological complete response in breast cancer treated with neoadjuvant chemotherapy: A multicenter, retrospective study.
Authors: Wang Kun , Huang Yuhong
Published: June 2023

599

Background: Accurate identification of pCR to neoadjuvant chemotherapy (NAC) is important for determining appropriate surgery strategy and guiding the resection extent in breast cancer. However, a non-invasive tool to predict pCR accurately is lacking. Our study aims to develop ensemble learning models using longitudinal multiparametric MRI to predict pCR for each molecular subtype of breast cancer. Methods: In this study, all patients underwent pre-NAC and post-NAC MRI examinations, and we collected multiparametric MRI sequences. Post-operation pathologic results were used to determine the pathologic complete response (pCR). We extracted 14676 radiomics and 4096 deep learning features and calculated a set of additional delta-value features. Then in the primary cohort (n = 409), inter-class correlation coefficient test, U-test, Boruta and the least absolute shrinkage and selection operator (LASSO) regression were used to select the most optimal feature set for each subtype of breast cancer. Finally, 20, 15 and 13 features were selected to construct the models based on 5 specific algorithms with cross-validation method for predicting pCR in HR+/HER2-, HER2+ and TNBC subtypes. The ensemble learning strategy was used to integrate the single-modality models outputs and improve the prediction performance. The diagnostic performances of models were evaluated in the three external cohorts with lager sample size of patients (n = 343, 170 and 340, respectively). Results: A total of 1262 patients with breast cancer from four centers were enrolled in this study, and pCR rates were 10.6% (52/491), 54.3% (323/595) and 37.5% (66/176) in HR+/HER2-, HER2+ and TNBC subtype. After model development, the Multi-Layer Perception (MLP) neural network yields the best diagnostic performances in all subtypes and feature sets. In the three subtypes, the stacking model integrating pre-, post- and delta- models yielded the highest AUCs of 0.959, 0.974 and 0.958 in the primary cohort, and AUCs of 0.882-0.908, 0.896-0.929 and 0.837-0.901 in the three external validation cohorts, respectively. In all subtypes, the stacking model had accuracies of 85.0%-88.9%, sensitivities of 80.0%-86.3%, and specificities of 87.4%-91.5% in the external validation cohorts. Conclusions: Our study established a novel tool to predict the responses of breast cancer to NAC and achieve excellent performance. The models could help to determine post-NAC surgery strategy for patients with breast cancer.
Results of the multicenter phase II FRAIL-IMMUNE trial evaluating the efficacy and safety of durvalumab combined with weekly paclitaxel carboplatin in first-line in patients (pts) with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) not eligible for cisplatin-based therapies.
Authors: Fayette Jerome , Cropet Claire , Gautier Julien , Toullec Clemence , Burgy Mickael , Bruyas Amandine , Sire Christian , Lagrange Aurelie , Clatot Florian , Calderon Benoit , Vinches Marie , Iacob Mariana , Martin Laurent , Neidhardt Berard Eve Marie , Kaminsky Marie-Christine , Vansteene Damien , Salas Sébastien , Champagnac Anne , Pérol David , Bourhis Jean
Published: June 2023

6003

Background: For pts with R/M SCCHN, new standard of care (SoC) has been recently established with pembrolizumab either alone or combined with platin-5FU (KN 048 – median Overall Survival (OS): 13 months when combined). For pts who need chemotherapy, platinum-5FU-pembrolizumab as first-line treatment appears associated with substantial toxicity that precludes its use in fragile patients. In this context, we investigated the efficacy and tolerance of PDL-1 inhibition with durvalumab combined with weekly carboplatin-paclitaxel as first-line treatment in frail R/M SCCHN pts. Methods: This single-arm phase II study enrolled pts in first-line of their R/M SCCHN and not eligible to standard cisplatin-based CT with an ECOG PS of 0 or 1. Pts received 4 cycles of CT (carboplatin AUC2; paclitaxel 80mg/m² both at D1, D8, D15) and durvalumab (D) 1500mg repeated every 4 weeks for a maximum of 12 months. The primary endpoint was OS Rate at 12 months (m). The study used a Fleming A’Hern design (inefficacy boundary: 47% and target efficacy: 65%), requiring 38 successes among 64 pts. Secondary endpoints were Progression-Free Survival (PFS), Time to Treatment Failure (TTF), objective response rate (ORR) and tolerance. Results: 64 pts (median age 69.5y; 90.6% males, 62.5% PS1) were included, regardless of their PDL-L1 status. Primary tumors were mainly located in oropharynx (37.5%) and larynx (28.1%) with 37.3% PD-L1 CPS≥20. 54.9% were metastatic. The efficacy rule for OS was met with 40 pts (62.5%, unilateral 95%CI: [51.5% - ]) alive at 12m. With a median follow-up of 27.1 m, median OS was 18.0 m (95% CI [11.9-NR]) and the 24m-OS rate was 45% [32%-57%]. Median PFS was 7.0 m (95% CI [5.4-9.9]) and median TTF was 6.0 m (95% CI [4.7-9]). 44/62 pts (71%) achieved an OR (11.3% complete response and 59.7% partial response). Median duration of response was 5.9 m (95% CI [3.4-9.6]). 20.3% of pts experienced G≥3 adverse events related to D, Toxicity led to permanent discontinuation of D in 3.1% of pts. No D-related death was reported. Conclusions: This study performed in fragile patients not amenable to cisplatin-based CT met its primary endpoint on OS and showed a 18 months median OS rate. This combination of durvalumab with weekly carboplatin/paclitaxel was associated with a favorable toxicity profile. Clinical trial information: NCT0372967 .
NEOSPACE trial: Neoadjuvant pembrolizumab-gemcitabine-cisplatin followed by concurrent pembrolizumab-chemoradiation and maintenance pembrolizumab for stage IVA nasopharyngeal cancer (NPC).
Authors: Hui Edwin P , Ma Brigette , Lim Darren Wan-Teck , Lam WK Jacky , Soong Yoke Lim , Li Leung , Wong Kenneth C.W. , Lam Daisy , Mok Florence , Tong Macy , Poon Darren MC , Wong Chi Hang , Mo Frankie , King Ann Dorothy , Lo Kwok-Wai , Chan Jason Y.K. , Chan KC Allen , Chan Anthony T. C.
Published: June 2023

6010

Background: Stage IVA NPC had the worst prognosis despite the current standard of neoadjuvant chemotherapy and concurrent chemoradiation (CRT). There is no safety and efficacy data combining immune checkpoint inhibitor (ICI) and CRT in NPC. Methods: We conducted an open label, single arm, multi-site, phase 2 clinical trial in AJCC 8th Edition Stage IVA (T4 and/or N3, M0) WHO type 2/3 Epstein Barr virus (EBV) +ve NPC (Clinical trial register NCT03734809). The experimental treatment consisted of neoadjuvant pembrolizumab (200 mg D1), gemcitabine (1000 mg/m2 D1+8) and cisplatin (80 mg/m2 D1) q3w x2 followed by concurrent pembrolizumab (200 mg x3 week 1, 4 and 7) and cisplatin (40 mg/m2 weekly x7) during intensity-modulated radiation (IMRT), and maintenance pembrolizumab 200 mg q3w x12 from 4 weeks post-RT. By Fleming one-stage design (type I error 0.05, power 0.80, 10% drop out), planned sample size is 46. Primary endpoint is 2-year (yr) progression free survival (PFS). Secondary endpoints include safety and tolerability. Plasma EBV DNA (pEBV DNA) was monitored. Results: Accrual was completed with 46 subjects recruited at two study sites from May 2019 to June 2022 in Hong Kong (n=31) and Singapore (n=15). This protocol specified analysis included 37 subjects with >12 months post-treatment follow up (median 26.8 months, 95% CI 21.3-32.9). Patient demographics: mean age 52 (range 27 - 84); M:F 31:6; ECOG 0=23, 1=14; stages: T4N1-2 (16), T1-3N3 (18), T4N3 (3). Overall compliance rate: neoadjuvant cisplatin 98.6%, gemcitabine 97.7%, concurrent cisplatin 73.7%, pembrolizumab 100% (neoadjuvant), 77.5% (concurrent), 77% (maintenance), IMRT 99.7% (69.96 Gy). Treatment related adverse events (≥ grade 3, >10%): dysphagia (32.4%), mucositis (29.7%), neutropenia (29.7%), radiation dermatitis (24.3%), anemia (18.9%), hyponatremia (13.5%), thrombocytopenia (10.8%). No ≥ grade 4 mucositis/dermatitis. The 2-yr PFS was 69.6% (95% CI 53.8 - 88.5%). At the end of neoadjuvant, CRT and maintenance phases, molecular remission (pEBV DNA = 0) was achieved in 24.3%, 70.3% and 70.3% of patients respectively, which strongly correlated with PFS (p=0.0253, 0.0007 and <0.0001 respectively, Table). Conclusions: Pembrolizumab incorporated into neoadjuvant, CRT and maintenance protocol is safe with promising results. This strategy of combining ICI with neoadjuvant chemotherapy and CRT is being tested in several ongoing phase 3 trials in advanced NPC. Clinical trial information: NCT03734809 . [Table: see text]
Phase II trial of adjuvant de-escalated radiation + adjuvant nivolumab for intermediate-high risk P16+ oropharynx cancer.
Authors: Skinner Heath Devin , Zandberg Dan Paul , Raben Adam , Sridharan Shaum , Kubik Mark , Zevallos Jose , Kim Seungwon , Duvvuri Umamaheswar , Ohr James , Gooding William E. , Ferris Robert L.
Published: June 2023

6014

Background: Treatment de-intensification for resected, human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is an area of active investigation, with a goal of providing a less toxic adjuvant regimen compared to the current standard of care 66 Gy of radiation (RT) combined with concurrent cisplatin defined in recently reported as Arm D of the ECOG3311 trial. Here, the programmed death 1 (PD-1) antibody nivolumab was added to de-intensified RT in high risk, resected HPV+ OPC. Methods: Eligible patients included transorally resected pathologic stage III or IVA HPV+ OPSCC using p16 immunohistochemistry, featuring high-risk neck disease factors (gross extracapsular extension >1mm or ≥5 positive lymph nodes) to mirror ECOG3311 Arm D patients accrued. Positive margin status was excluded except by PI approval. Postoperative treatment consisted of accelerated fractionation RT (50 Gy over 4 weeks) concurrent with nivolumab at 240 mg every 2 weeks, followed by 6 months of adjuvant nivolumab biweekly or monthly. The primary endpoint was progression-free survival (PFS). Swallowing and quality of life patient reported outcome (PRO) measures were collected at baseline and defined intervals after treatment. Results: Forty-one patients (n=41) were accrued and were analyzed. Forty of 41 patients remain alive with a median follow-up of 30 months (range 1 – 49 months). The probability of 3-year overall survival is 97% (95% CI = 90% - 100%) and the probability of 3-year PFS is 86% (95% CI = 68% - 100%). Two patients developed recurrent disease, one of whom died. One patient developed isolated metastasis while a second developed local, regional, and distant metastasis. The most common adverse grade ≥3 adverse events were lymphocytopenia (n=24), dysphagia (n=2) and oral mucositis (n=2). One grade 4 sepsis/multi-organ failure was reported. Comparison of PRO results with those observed in ECOG3311 trial are underway and will be reported. Conclusions: De-intensification of adjuvant treatment adding nivolumab to RT is tolerable and demonstrates favorable clinical outcome for high-risk, resected, HPV+ HNSCC patients. Further targeted immunotherapy combinations are warranted. Clinical trial information: NCT03715946 .