bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetic and pharmacodynamic analysis of adavosertib in advanced ovarian cancer.
Authors: Oza Amit M. , Lheureux Stephanie , Madariaga Ainhoa , Cristea Mihaela C. , Mantia-Smaldone Gina , Olawaiye Alexander , Ellard Susan , Weberpals Johanne I , Wahner Hendrickson Andrea Elisabeth , Fleming Gini F. , Welch Stephen , Dhani Neesha C. , Speers Vanessa , Bowering Valerie , Wang Lisa , Zhang Wenjiang , Chen Eric Xueyu
Published: June 2022

5579

Background: Adavosertib (AZD-1775) is a potent small molecule inhibitor of Wee-1, currently in clinical development. In a double-blind, placebo-controlled, phase 2 trial (NCT02151292), adavosertib and gemcitabine significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with recurrent platinum-resistant or platinum-refractory high grade serous ovarian cancer (HGSOV) compared to gemcitabine alone. We investigated whether plasma and intra-tumoral adavosertib concentrations correlated with survival in these patients. Methods: Adavosertib was administered orally on Days 1, 2, 8, 9, 15 and 16 at 175 mg per day, and gemcitabine was administered on Days 1, 8 and 15 at 1000 mg/m2 every 28 days. Serial blood samples were collected on Day 1 of cycle 1 after adavosertib administration. Tumor biopsies were taken 1-2 weeks after initiation of study treatments. Plasma and tumor adavosertib concentrations were determined using validated HPLC-MS/MS. Patients were divided into groups with plasma or tumor adavosertib concentrations above or below the biologically active concentration (BAC) of 125 ng/ml (Leijen et al, J Clin Onco 2016). Survival was described using the Kaplan-Meier method. Results: Among 61 HGSOV patients who received adavosertib, plasma samples were available in 47, and tumor samples were available in 31 patients. Among 25 non-HGSOV patients (exploratory cohort), plasma and tumor samples were available in 21 and 17 patients respectively. The mean maximum adavosertib concentration (Cmax) was 355.3 ± 120.9 ng/ml and 358.6 ± 117.9 ng/ml respectively. Cmax was above BAC in all patients. The mean tumor adavosertib concentration was 609.2 ± 1129.2 ng/ml (range: 0.47 – 5501 ng/ml) for HGSOV patients, and 964.2 ± 1611.2 ng/ml (range: 0.22 – 6116 ng/ml) for non-HGSOV patients. There was no correlation between Cmax and tumor adavosertib concentrations. In HGSOV, the median PFS was 5.8 months for patients with tumor concentrations above BAC, and 3.5 months for those with tumor concentrations below BAC (Hazard ratio (HR): 0.46, 95% confidence interval: 0.19 – 1.14, p = 0.06). No difference in PFS was seen in non-HGSOV patients according to tumor adavosertib concentration. Tumor adavosertib concentration did not correlate with OS. Conclusions: Although Cmax was above BAC in all patients, there was a high variability in tumor adavosertib concentrations. In HGSOV, higher tumor adavosertib concentration was associated with a trend towards improved PFS, but not OS. Our results indicate that the current adavosertib dosing regimen may not produce the desired concentrations in tumors for some patients, and further optimization may be needed.
Real-world clinical outcomes in patients with local/regional HER2-low breast cancer: An NCDB analysis.
Authors: Jiang Changchuan , Perimbeti Stuthi , Deng Lei , Wang Qian , Gandhi Shipra , Shapiro Charles L.
Published: June 2022

558

Background: The development of novel anti-HER2 drugs opens new treatment options, including women with lower expression of HER2. This study aimed to compare local/regional HER2-low and HER2-0 breast cancer outcomes in the real world. Methods: Women diagnosed between 2010 and 2017 with clinical stage I-III breast cancers with low HER2 expression or HER2-zero (0) expression were identified in the National Cancer Database (NCDB), a nationwide oncology outcomes database in the United States. HER2-Low was defined as IHC1+ or 2+/ISH negative, whereas HER2-zero was IHC-0. The primary outcome was overall survival (OS). We performed a multivariable Cox regression model to estimate hazard ratios and adjusted for the following factors: age, race/ethnicity, education, insurance, comorbidities, grade, stage, lymph nodes, type of surgery, the type of cancer center, and if any chemotherapy, any hormonal therapy, and any adjuvant radiation in the first treatment course. Stratification factors were hormone receptor status. Subgroup analyses for those who received neoadjuvant (NAC), adjuvant (AC), and no chemotherapy were performed, and the pathologic complete response (pCR) rates in NAC groups were estimated. Results: 376,199 (68%) women with HER2-low tumors and 177,298 (32%) with HER2-0 tumors were analyzed. 336,147 (89%) of the HER2-low tumors and 141,528 (79%) of the HER2-0 tumors were HR-positive. Low HER2 expression was associated with longer OS in both HR-positive (adjusted Hazard Ratio (aHR): 0.94, 95%CI 0.93-0.96, p<0.001) and HR-negative diseases (aHR: 0.88, 95%CI 0.85-0.91, p<0.001). HR-positive, HER2-low tumors had statistically significantly better survival than HR-positive, HER2-0 tumors in NAC (aHR 0.84, 95%CI 0.79-0.90, p<0.001) and AC (aHR 0.90, 95%CI 0.85-0.94, p<0.001) groups, but not in the no-chemo group (aHR 1.02, 95%CI 1.00-1.05, p=0.09, p interaction<0.001). In contrast, HR negative, HER2-low tumors had better OS than HR negative, HER2-0 tumors in all subgroups, regardless of receipt or timing of chemotherapy (NAC aHR 0.88, 95%CI 0.83-0.94, p<0.001, AC aHR 0.86, 95%CI 0.81-0.92, p<0.001, No chemo aHR 0.93, 95%CI 0.87-0.99, p=0.03, p interaction=0.06). In NAC groups, HER2-low expression was linked to lower pCR rates in both HR-positive (8.9% vs. 11.2%, p<0.001) and HR-negative (31.2% vs. 34.1%, p<0.001). Conclusions: Local/regional HER2-low breast cancer has better survival than HER2-0 breast cancer, irrespective of its hormone receptor status. The survival advantage was observed in HR-negative disease and only with receipt of chemotherapy in HR-positive breast cancer. Specific therapies, such as trastuzumab deruxtecan, have activity in HER2-low breast cancers, and other therapeutics for HER-2 low diseases should be sought.
Stage 1 results of BrUOG 354: A randomized phase II trial of nivolumab alone or in combination with ipilimumab for people with ovarian and other extra-renal clear cell carcinomas (NCT03355976).
Authors: Dizon Don S. , Robison Katina , MacLaughlan David Shannon Diane , Machan Jason T , Hadfield Matthew James , Marks Eric I , Chudasama Rani , Evans Tarra , Lopresti Mary Lorraine , Safran Emma , Kastura Michaela , Hassinger Faith , Sturtevant Ashlee , Wood Roxanne , Wright Alexi A. , Strenger Rochelle , Matulonis Ursula A. , Bandera Christina , Campos Susana M. , Birrer Michael J.
Published: June 2022

5598

Background: Clear Cell Carcinoma (CCC) outside the kidney is a rare tumor that can arise from multiple organs, including the ovary, endometrium and cervix. Extra-renal CCC is chemoresistant and has a poor prognosis. Data suggest that CCC of the gynecologic tract resembles the genomic profile of Renal Cell Carcinoma (RCC), which is responsive to immune checkpoint inhibition (ICI) therapy. We are conducting a two-stage phase 2 trial evaluating immunotherapy for extra-renal CCC. The primary objective is to assess overall rate of response (ORR); Progression-Free (PFS), Overall Survival (OS), and correlative biomarker studies are secondary. Here we present the results of Stage 1. Methods: This is a randomized two-stage non-comparative phase II study evaluating nivolumab (240mg IV every two weeks) alone (N) and in combination with ipilimumab (1mg/kg every six weeks, [N+I]) in patients with relapsed extra-renal CCC after at least one prior chemotherapy (no prior ICI), and measurable disease. Treatment was continued until disease progression or unacceptable toxicity. Stage 1 of this trial called for up to 30 volunteers (15 per arm) after which the study was closed. Consideration to reopen to stage 2 called for two or more responses in either arm. Here we present the completion of Stage 1; the release of results was approved by Brown University Oncology Group (BrUOG) Data Safety and Monitoring Committee. Results: Between July 2018 and October 2021, 30 patients were enrolled and 29 were treated (Table). The majority (83%) had CCC of the ovary (n=24). The ORR with N and N+I was 14.2 and 26.7%, respectively. The 6 month PFS rate was 19.1 and 43.8%; median PFS was 2.7 (95%CI 1.3-5.1) and 5.1 months (95%CI 0.9-NR), respectively. Grade ≥3 treatment-related toxicities occurred in 4 (28.6%) on N and 5 (33.3%) on N+I. There were no treatment-related deaths and no new safety signals. One volunteer enrolled on N+I stopped treatment after two years and remains in CR to date. Conclusions: Although sufficient activity was seen in CCC in both arms, the single-agent activity of N is similar to published reports in platinum-resistant epithelial ovarian cancer and decision made not to pursue it further. However, the combination of ipilimumab and nivolumab warrants additional investigation, and the second stage of this study will enroll 14 more patients to receive N+I. Clinical trial information: NCT03355976. [Table: see text]
Molecular characteristics and clinical outcomes of breast cancer with HRAS mutations.
Authors: Kareff Samuel , Rodriguez Estelamari , Dawar Richa , Trabolsi Asaad , Ocejo Gallegos Jesus Antonio , Yin Jun , Walker Phillip , Kang Irene , Bustos Matias A. , Neman Josh , Hoon Dave S. , Graff Stephanie L. , Spetzler David , Lopes Gilberto
Published: June 2022

561

Background: The RAS pathway regulates tumorigenesis and cell proliferation. HRAS is a RAS family member that activates via farnesylation. Indirectly targeting mutant HRAS with tipifarnib, a farnesyltransferase inhibitor (FTI), recently demonstrated efficacy in head and neck tumors. We aimed to investigate the molecular characteristics and clinical outcomes of HRAS mutations (HRASmut) for any potential role as a prognostic and therapeutic biomarker in breast cancer (BC). Methods: A total of 14,013 BC tissue samples had molecular profiling, including next generation DNA (592 Gene Panel, NextSeq, or WES, NovaSeq) or RNA sequencing (NovaSeq, WTS), and immunohistochemistry analyses, at Caris Life Sciences. MAP kinase (MAPK) activation and likelihood of a tumor’s response to anti-PD1 therapy were evaluated via MAPK Pathway Activity Score (MAPS) and interferon (IFN) score, respectively. Wilcoxon, Fisher’s exact, or Dunnett’s tests were used to determine statistical significance. Overall survival (OS) was calculated from date of tissue collection to insurance claims last contact using the Kaplan-Meier method. HRAS mutations (HRASmut) were compared to the general BC cohort (GC). Results: HRASmut were significantly enriched in older patients (median 69 vs 60 yrs; q<.0001), and in primary compared to metastatic BC tumor samples (55.9% vs 41.9%, p<.05). There were 70 total HRASmut (0.5%): Q61 was the most frequent (41.4%), followed by G12 (28.6%) and G13 (24.3%). Patients with Q61 HRASmut had significantly worse OS compared to GC (HR 1.86, 95% CI [1.10-3.13]; p<0.05). HRASmut had significantly higher MPAS compared to GC (1.26, all; 1.31, Q61; 1.7, G12; -.39, GC, q<.01). HRASmut were found in HR+/HER2- (22.6%) and TNBC (77.4%) tumors, but no HR-/HER2+ BC. TNBC samples with HRASmut displayed more PIK3CA (62.5% VS. 18.9%, q<.05) but less TP53 mutations (50% vs 84.9%, q<.05), higher expression of PD-L1 (41.2% vs 10.8%, p<.05) and androgen receptor (AR, 45.8% vs 24.4%, p<.05), and more frequent ARv7 fusions (20.7% vs 4.3%, p<.05) compared to HR+/HER2- (Table 1). Q61 HRASmut had the highest MPAS (2.39 vs -0.28, p<.01) in TNBC, whereas G12 HRASmut displayed the highest MPAS (2.01 VS -0.47, p<.05) in HR+/HER2- BC. Conversely, Q61 had the lowest IFN score (-0.45 vs -0.3) in HR+/HER2- but the highest (-0.18 vs -0.3) in TNBC. Conclusions: HRASmut were mutually exclusive with HER2+ BC. The association of Q61 HRASmut with worse survival highlights the oncogenic role of these mutations and supports therapeutic investigation using FTI. PIK3CA was significantly co-mutated in HRASmut, highlighting a potential benefit of combining PIK3CA inhibitors with tipifarnib. Overall, HRASmut displayed a subtype-specific distinct genomic landscape and may represent a key therapeutic target in BC. [Table: see text]
Associations of a breast cancer polygenic risk score with tumor characteristics and survival.
Authors: Lopes Cardozo Josephine , Andrulis Irene L. , Peter Devilee , Dörk Thilo , Drukker Caroline , Fasching Peter A. , Hooning Maartje J. , Keeman Renske , Nevanlinna Heli , Rutgers Emiel J. , van 't Veer Laura , Hall Per , Bojesen Stig Egil , Douglas Easton , Eccles Diana , Pharoah Paul , Schmidt Marjanka
Published: June 2022

563

Background: A polygenic risk score (PRS) consisting of 313 single nucleotide polymorphisms (PRS313) is associated with risk of breast cancer and contralateral breast cancer. One of the most promising clinical applications for the use of PRS is to provide a personalized risk assessment to individualize breast cancer screening programs. This study aimed to evaluate the association of the PRS313 with clinical-pathological characteristics and survival of breast cancer. Methods: Women of European ancestry with invasive breast cancer were included, 98,397 women from the Breast Cancer Association Consortium (BCAC) and 683 women from the MINDACT trial. Associations between PRS313 (continuous, per SD) and clinical-pathological characteristics, including the 70-gene signature for patients included in MINDACT, were evaluated with logistic regression analyses. Associations of PRS313 with overall survival (OS), breast cancer-specific survival (BCSS) and distant metastasis-free interval (DMFI) were evaluated with Cox regression analyses, adjusted for clinical-pathological characteristics and treatment. Results: The PRS313 was associated with favorable tumor characteristics. In BCAC, increasing PRS313 was mostly associated with lower grade, hormone receptor-positive tumors, and with smaller tumor size. In MINDACT, PRS313 was associated with a low risk 70-gene signature, but the association was attenuated after adjustment for clinical-pathological characteristics. In BCAC, univariable analyses showed an association of PRS313 with better survival, hazard ratio (HR) per unit SD increase of PRS313 for OS: 0.96 (95% confidence interval (CI): 0.94-0.97), for BCSS HR: 0.96 (95% CI: 0.94-0.98) and for DMFI HR: 0.98 (95% CI: 0.96-1.00). The association in the unadjusted analysis was explained by differences in clinical-pathological characteristics (and treatment) and disappeared after adjustment: OS HR: 1.01 (95% CI: 0.98-1.05), BCSS HR: 1.02 (95% CI: 0.98-1.07) and DMFI HR: 1.03 (95% CI: 0.99-1.07). Conclusions: An increased PRS313 is associated with favorable tumor characteristics but was not independently associated with prognosis. This information is crucial input for modelling effective stratified screening programs, especially in the current era of optimized (systemic) treatments. Given the significant increase in breast cancer risk associated with increasing PRS313, absolute breast cancer mortality will still be higher for women with higher PRS313.
Low TMB as predictor for additional benefit from neoadjuvant immune checkpoint inhibition in triple-negative breast cancer.
Authors: Karn Thomas , Denkert Carsten , Rey Julia , Weber Karsten Ernst , Holtrich Uwe , Hanusch Claus , Sinn Bruno Valentin , Jank Paul , Huober Jens Bodo , Blohmer Jens U. , Schmitt Wolfgang D. , van Mackelenbergh Marion , Schem Christian , Stickeler Elmar , Jackisch Christian , Untch Michael , Schneeweiss Andreas , Loibl Sibylle
Published: June 2022

581

Background: It is commonly anticipated that a high tumor mutational burden (TMB) is a predictor of response to immune checkpoint blockade (ICB). We previously showed that triple-negative breast cancer (TNBC) from the GeparNuevo study with high TMB displayed increased response both to neoadjuvant chemo-ICB with durvalumab but also to chemotherapy alone, with no significant interaction with treatment arm (Karn et al. Ann Oncol 2020). In contrast, we also observed that cases with very low TMB more often displayed a pCR after treatment with chemo-ICB than with chemotherapy alone. This may in fact suggest a benefit of ICB to those TNBC with rather low TMB. Methods: We have analyzed the distant disease-free survival (DDFS) of GeparNuevo patients according to TMB and treatment arm (neoadjuvant chemotherapy plus durvalumab or chemotherapy plus placebo). For TMB (mut/Mb) we applied the identical cutoff of the upper tertile as in our previous analysis. Results: The median follow-up of the time-to-event data was 43.7 months. Data of TMB was available in 149 of 174 patients. We found that within the high-TMB tumors (durvalumab: n=27; placebo: n=23), DDFS was similar between both arms of the trial (durvalumab vs. placebo: HR (hazard ratio) 0.95 [95%CI 0.19-4.69], p=0.95). Strikingly however, within the low-TMB group (durvalumab: n=47; placebo: n=52) we observed a significantly better DDFS in the durvalumab-chemotherapy combination arm, in contrast to the arm treated only with chemotherapy (durvalumab vs. placebo: HR 0.23 [95%CI 0.06-0.79], p=0.02; interaction test for TMB and treatment arm p=0.17). The observation was also robust to alternative TMB cutoffs. Similar results were obtained for invasive disease-free survival. Conclusions: Our results show, in contrast to other published data, that patients with early TNBC and low TMB/neoantigen counts may benefit from short-term neoadjuvant durvalumab treatment, while for those with high TMB, durvalumab plus chemotherapy does not improve efficacy over chemotherapy alone.
Peripheral lipidomics analyses with ensemble machine learning predict response to neoadjuvant therapy in breast cancer.
Authors: Wang Jiani , Ma Fei , Sun Xiaoying , Wang Jinsong , Guo Fengzhu , Liu Binliang , Wang Wenna , Li Qing , Xu Binghe
Published: June 2022

582

Background: Neoadjuvant therapy (NAT) is critical in the therapeutic strategy for locally advanced breast cancer (BC) patients. Biomarkers to predict the pathologic complete response (pCR) and to screen beneficial responders need to be urgently explored. Lipidomics is a high-throughput analysis technique, which has potential applications for peripheral biomarkers’ detection to overcome the difficulty in serial pathological biopsies and tumor heterogeneity. Machine learning is a method for mining high-dimensional information with high group and low intermolecular correlation. Here we construct multidimensional models with machine learning approach combining clinical clinicopathological and lipidomics data to predict NAT response. Methods: Plasma samples were collected from 119 BC patients before after two cycles of NAT. Peripheral lipidomic profiles at multiple levels of lipid composition, concentration, chain length, and saturation were dynamically monitored by using absolute quantitative lipidomics. Responders (pCR) and non-responders (non-pCR) groups were randomly sampled in a 1:1.5 ratio for subsequent analysis. Screening of candidate lipidomic biomarkers were performed according to the criteria “VIP>1, FC>2 or FC<0.5 and p<0.05”. Above feature screening were validated by using ensemble machine learning algorithms (Logistic regression, Random forest and Support vector machine). Pearson correlation coefficients were calculated for the expressions of candidate biomarkers. Multidimensional prediction models with the logistic regression algorithm were constructed by correlating candidate lipidomics features with clinicopathologic phenotypes prospectively collected with baseline and dynamic changes. The performance of the models constructed above were assessed by ROC analysis. Results: A total of 8 major classes, 39 subclasses, and 2292 molecules of lipid metabolites were identified in the 235 plasma samples. Most of the candidate biomarkers had lower correlations, indicating lower overlapping and more optimal combination of panels. The prediction models constructed by baseline correlating candidate lipidomics features with ensemble machine learning achieved an Area under the Curve (AUC) of 0.84 for the training set and 0.72 for the validation set with the accuracy 0.84, the specificity 0.92, and the sensitivity 0.71 when the cutoff value is 0.57.The prediction models constructed with lipidomics dynamic changes also achieved good performance. Conclusions: The study suggested a possibility that peripheral lipidomics provided a potential tool to develop multidimensional models with ensemble machine learning for predicting response to NAT for BC patients with good discrimination power, which might guide individual optimal NAT strategies and avoid unnecessary treatment.
Real-world outcomes of patients with human epidermal growth factor 2 (HER2)–positive breast cancer receiving neoadjuvant therapy without adjuvant ado-trastuzumab emtansine (T-DM1).
Authors: Di Iorio Massimo , Elliott Mitchell J. , Scott Jordan L , Mittal Abhenil , Molto Consolacion , Tamimi Faris , Cescon David W. , Amir Eitan , Meti Nicholas
Published: June 2022

584

Background: HER2-positive early-stage breast cancer (EBC) treated with neoadjuvant chemotherapy and HER2-targeted therapy has favourable outcomes, especially for those attaining pathologic complete response (pCR). Among those with residual invasive disease (RD), outcomes are variable. Replacing adjuvant trastuzumab with ado-trastuzumab emtansine (T-DM1) reduces the risk of recurrence, but increases toxicity and cost. The magnitude of benefit of T-DM1 may be small among patients with RD and favourable prognostic features. Here we report on real-world outcomes of patients with HER2-positive EBC treated with neoadjuvant therapy without adjuvant T-DM1. Methods: We performed a single institution, retrospective review of HER2-positive EBC treated with neoadjuvant chemotherapy and trastuzumab between January 1st, 2012 and February 1, 2021. We excluded patients who received adjuvant T-DM1. We collected clinical and pathologic characteristics, treatment data, and outcomes events. We estimated 3-year disease-free survival (DFS), a validated endpoint in HER2-positive EBC, using Kaplan-Meier with recurrence and/or death as events. Outcomes were reported in subgroups based on known prognostic factors. The study was approved by the University Health Network Research Ethics Board. Results: The study comprised 193 patients with a median follow-up of 30 months. The majority (n=160, 83%) received neoadjuvant anthracycline and taxane-based chemotherapy; 42 (22%) received neoadjuvant pertuzumab. All received adjuvant trastuzumab. Median age was 53 years (range 25-87), 113 (59%) patients had estrogen receptor (ER) positive disease, and 82 (42%) had pCR. In total, 16 events were observed, of which 13 (81%) were distant recurrences (including 5 (31%) in the brain) and 3 (19%) were locoregional. Of these, 14 (88%) occurred in the first 3 years of follow-up. Estimated 3-year DFS was 98.6% in patients with pCR, and 85.4% in patients with RD. Patients with ER positive disease had excellent outcomes, regardless of pathologic nodal (ypN) status. The highest risk of recurrence was in ER negative and ypN positive disease (Table). Conclusions: Real-world outcomes of patients with HER2-positive EBC treated with neoadjuvant therapy without adjuvant T-DM1 are favorable, including those with RD if ER positive. The expected benefit of adjuvant T-DM1 in this group is therefore likely to be small. Patients with ER- disease had poorer outcomes irrespective of nodal status. Further research to identify patients with RD for whom the benefit of T-DM1 is unlikely to merit its added toxicity and cost is warranted. [Table: see text]
Association of facility volume with pathologic complete response and overall survival in patients with non-metastatic breast cancer.
Authors: Ma Sung Jun , Hashmi Mahnoor , Yu Brian , Yao Song , Oladeru Oluwadamilola Temilade , Singh Anurag K.
Published: June 2022

586

Background: High facility volume has been previously shown to be associated with a higher likelihood of pCR among patients with breast cancer following neoadjuvant chemotherapy. However, factors underlying the association of high facility volume with pCR and the impact of facility volume on survival remain unclear. We performed an observational cohort study to investigate the association of overall survival (OS) with facility volume and identify variables associated with high facility volume. Methods: The National Cancer Database (NCDB) was queried for women diagnosed between 2010 and 2017 with non-metastatic breast cancer treated with neoadjuvant chemotherapy followed by surgery. Facility volume was stratified by tertiles of low, intermediate, and high. Logistic and Cox multivariable analyses (MVA) were performed to evaluate factors associated with facility volume and OS, respectively. Propensity score matching was used to reduce selection bias. Results: A total of 105,804 women met our inclusion criteria (low facility volume: n=6,172; intermediate facility volume: n=20,199; high facility volume: n=79,433). The median follow up was 49.2 months (IQR 32.7-71.3). On logistic MVA, both intermediate (adjusted odds ratio [aOR] 1.24, 95% confidence interval [CI] 1.14-1.35, p<0.001) and high (aOR 1.53, 95% CI 1.42-1.65, p<0.001) facility volumes were associated with pCR. On Cox MVA, high (adjusted hazards ratio [aHR] 0.89, 95% CI 0.83-0.96, p=0.001), but not intermediate (aHR 0.97, 95% CI 0.90-1.04, p=0.40), facility volume was associated with improved OS. Similar findings were noted in 18,671 matched pairs between high versus low or intermediate facility volumes (HR 0.90, 95% CI 0.85-0.94, p<0.001). On logistic MVA, patients were more likely to receive treatments at high volume facilities if they were academic (adjusted odds ratio [aOR] 5.47, 95% CI 5.24-5.71, p<0.001), African American (aOR 1.25, 95% CI 1.20-1.30, p<0.001) with private insurance (aOR 1.13, 95% CI 1.04-1.22, p=0.005), and higher tumor grades (grade 2: aOR 1.10, 95% CI 1.03-1.18, p=0.008; grade 3: aOR 1.12, 95% CI 1.05-1.20, p=0.001). Patients were less likely to undergo treatments at high volume facilities if they reside in urban (aOR 0.63, 95% CI 0.60-0.66, p<0.001) or rural (aOR 0.75, 95% CI 0.67-0.85, p<0.001) areas with limited education (aOR 0.90, 95% CI 0.87-0.93, p<0.001), had government-led insurance (aOR 0.87, 95% CI 0.80-0.94, p=0.001), and had time interval of <180 or >240 days between diagnosis and surgery (aOR 0.92, 95% CI 0.90-0.95, p<0.001). Conclusions: To our knowledge, this is the largest study using a nationwide oncology database to report the association of high facility volume with pCR and improved OS, with various patient demographics associated with high facility volume. Our findings suggest an integral role of facility volume on pCR and survival for breast cancer.
Combined assessment of metabolic response and tumor infiltrating lymphocytes as a predictor of outcomes following neoadjuvant therapy for HER2-positive breast cancer: Results from the randomized PREDIX HER2 trial.
Authors: Matikas Alexios , Johansson Hemming , Grybäck Per , Bjöhle Judith , Lekberg Tobias , Fredholm Hanna , Acs Balazs , Elinder Ellinor , Isaksson-Friman Erika , Agartz Susanne , Hellstrom Mats , Zerdes Ioannis , Hartman Johan , Bergh Jonas C. S. , Hatschek Thomas , Foukakis Theodoros
Published: June 2022

593

Background: Abundance of tumor infiltrating lymphocytes (TIL) is prognostic in early HER2-positive breast cancer (BC). Response to neoadjuvant therapy (NAT) according to positron emission tomography combined with computed tomography (PET-CT) has been shown to predict pathologic complete response (pCR). There is paucity of data regarding long-term prognostication using PET-CT and the potential value of the combined assessment of both these biomarkers. Methods: PREDIX HER2 (NCT02568839) is a prospective randomized phase 2 trial that compared standard NAT (docetaxel, trastuzumab, pertuzumab) with trastuzumab emtansine, in patients with HER2-positive BC. Overall, 202 patients were included (197 evaluable) and the primary efficacy analysis showed no difference in pCR or event-free survival (EFS) between the two groups (Hatschek, JAMA Oncology 2021). Assessment with fluorine 18–labeled fluorodeoxyglucose PET-CT was performed at baseline and after 2 and 6 treatment cycles, and SUVmax was evaluated as a continuous variable. TILs were assessed at baseline biopsies according to guidelines from the International TIL Working Group (J.H.). The aim of this secondary analysis was to investigate the combined assessment of TIL and PET-CT as an early predictor of response to NAT. Results: Overall, 112 patients underwent baseline PET-CT and 109 after C2, whereas 173 had baseline TIL. In multivariable analysis, baseline SUVmax did not predict pCR (ORadj= 1.04, 95% CI 0.97-1.12, p = 0.259) or EFS (HRadj= 1.07, 95% CI 0.98-1.17, p = 0.117). In contrast, higher SUVmax at C2 predicted lower pCR (ORadj= 0.65, 95% CI 0.48-0.87, p = 0.005) and worse EFS (HRadj= 1.18, 95% CI 1.04-1.34, p = 0.01). Baseline TIL > 10% (median cut-off) provided additional prognostic information to clinical parameters (stage and hormone receptor expression) and C2 SUVmax (LR-Δχ2 = 7.19, p = 0.007; ORadj= 3.52, 95% CI 1.37 – 9.06, p = 0.009). 75% of patients with high TIL and C2 SUVmax < 2.49 achieved pCR, compared with 13.8% of those with low TIL and high C2 SUVmax and 39.1%-41.3% for the intermediate groups (p = 0.001). Conclusions: SUVmax after two cycles of NAT for HER2-positive BC is an independent predictor of both short- and long-term outcomes. A combined assessment with TIL may facilitate early selection of good responders for de-escalation and poor responders for alternative treatment strategies. Clinical trial information: NCT02568839.
Prediction of pathologic complete response to neoadjuvant chemotherapy in breast cancer (SWOG S0800) using image analysis-based tumor infiltrating lymphocyte measurements.
Authors: Blenman Kim , Fanucci Kristina , Bai Yalai , Pelekanou Vasiliki , Nahleh Zeina A. , Shafi Saba , Burela Sneha , Barlow William E. , Sharma Priyanka , Thompson Alastair Mark , Godwin Andrew K. , Rimm David L. , Hortobagyi Gabriel N. , Pusztai Lajos
Published: June 2022

594

Background: Image analysis-based tumor infiltrating lymphocyte (TIL) quantitation methods are being developed to eliminate reader-to-reader variation in TIL assessment that hinders its clinical adoption as prognostic and chemotherapy response predictive marker. We evaluated the ability of an image analysis-based TIL score to predict pathologic complete response (pCR) and event free survival (EFS) in breast cancer. Methods: 113 pretreatment samples were analyzed from the SWOG S0800 trial that randomized stage IIB-IIIC HER-2-negative breast cancers to neoadjuvant chemotherapy with or without bevacizumab. TIL quantitation was performed on H&E sections using QuPath open-source software and a convolutional neural network cell classifier (CNN11). The digital easTILs% score was calculated as [sum of TIL Area (mm2) / Stromal Area (mm2)] x 100. Pathologist-read stromal TIL score (sTILs%) was defined using international guidelines. A previously validated threshold of easTILs% > 19.9% defined high easTILs% status. Results: Pretreatment easTILs% was significantly higher in cases with pCR compared to residual disease (RD) (means, 31% vs. 17%, p < 0.001). easTILs% high and low cases had pCR rates of 41% and 21% (p = 0.019), respectively. In logistic regression adjusting for other factors, easTILs% was prognostic for pCR as continuous score (p < 0.001) and as high vs low categories (p = 0.035). There was strong positive correlation between easTILs% and sTILs% (r = 0.606, p < 0.0001), and sTILs% was also predictive of pCR. The areas under the prediction curve (AUC) were 0.709 and 0.627 for easTILs% and sTILs%, respectively. There was no statistically significant interaction between easTILs% and bevacizumab benefit (p = 0.26), and higher easTILs% or sTILs were not associated with better EFS. Conclusions: Image analysis-based TIL quantification is predictive of pCR in breast cancer and had better pCR outcome discrimination than pathologist-read sTIL count. [Table: see text]
Final result for SAFIA trial for neoadjuvant palbociclib in patients with operable luminal breast cancer responding to fulvestrant.
Authors: Al-Saleh Khalid A. , El Zawahry Heba Mohamed , Bounedjar Adda , Oukkal Mohammed , Saadeddin Ahmed , Mahfouf Hassen , Kamel Bouzid , Bensalem Assia , Abdel-Razeq Hikmat , Kandil Alaa , Abulkhair Omalkhair A. M. , Al-Foheidi Meteb Owaish , Ghosn Marwan , Boussen Hamouda , Haddaoui Abderrazak , Ayari Jihene Braham , Alghamdi Mohammed , Abdulaziz Nashwa A. , Kullab Sharif Ahmed , Nabholtz Jean-Marc A.
Published: June 2022

596

Background: Luminal, human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) encompasses the most common subtype of breast malignancies. Neoadjuvant strategies of operable BC are primarily based upon chemotherapy (CT), while neoadjuvant hormone therapy (NAHT) has not been well studied in the Middle East and North Africa (MENA) region. However, these tumors might respond poorly to neoadjuvant CT with significant side effects, emphasizing the need to identify patients who could be candidates for NAHT. Methods: The SAFIA trial is a prospective multicentre, international, double-blind, neoadjuvant phase-III trial using upfront 21-gene Oncotype DX Breast Recurrence Score assay (RS) <31) to select operable Luminal HER2-negative patients for induction hormonal therapy with Fulvestrant 500 mg +/– Goserelin (F/G) before randomizing responding patients to F/G + Palbociclib (Cyclin-Dependent Kinase 4/6 inhibitor / CDK 4/6) versus F/G + Placebo. The primary endpoint of this study was the complete pathologic response (pCR) rate. Results: A total of 354 patients were enrolled, leading to 277 patients treated with induction F/G. Of these, 253 responding patients were randomized to F/G fulvestrant with palbociclib or Placebo. Two hundred and thirty patients were evaluable for pathologic response. No statistically significant differences were identified in terms of pCR rates between F/G with palbociclib or placebo: 2% versus 7%, respectively. According to the radiologic responses post- induction F/G, the hormone sensitivity rate was 89.8%, while the clinical benefit of 8–9 months of neoadjuvant F/G was 96%. Safety in the MENA population was acceptable with a grade 3-4 neutropenia rate of 25% in the F/G plus palbociclib arm. The feasibility of performing the 21-gene breast recurrence score assay on core biopsy specimens was optimal in 96.4% of cases. Conclusions: The addition of palbociclib to neoadjuvant F/G did not show any additional benefit in terms of pathologic response, including pCR in neoadjuvant therapy of Luminal HER2-negative BC responding to induction F/G. The use of an upfront 21-gene assay appeared feasible on biopsy specimens, and the identification of tumors with RS<31 allowed to select endocrine sensitive patients, leading ultimately to a 96% clinical benefit with 8–9 months of F/G neoadjuvant therapy. Clinical trial information: NCT03447132. [Table: see text]
Changes in opioid prescription, potential misuse, and substance use disorder in pediatric cancer survivors following the 2016 CDC opioid prescribing guideline.
Authors: Ji Xu , Hu Xin , Brock Katharine Elizabeth , Effinger Karen Elizabeth , Zhang Bo , Lipscomb Joseph
Published: June 2022

6506

Background: The 2016 Centers for Disease Control and Prevention (CDC) guideline for prescribing opioids, despite not being intended for cancer-related pain, has been shown to be associated with declines in opioid prescriptions among adults with cancer. We examine the changes in opioid prescription, potential misuse, and substance use disorder (SUD) following the guideline release among pediatric cancer survivors, a population at high risk for chronic pain. Methods: Using nationwide private insurance claims data, we identified survivors (aged ≤21 years at cancer diagnosis) who completed treatment for leukemia, lymphoma, central nervous system, bone, or gonadal cancers in 2009-2018 (N=8,969). We also identified enrollees without cancer who were matched based on age, gender, and region as a control group (N=44,845). Outcomes included (1) any opioid prescription and (2) any indicator for potential misuse or SUD within 1-year post-therapy. We conducted interrupted time series analysis, where time period was assessed by quarters based on the quarter-year of patients’ therapy completion. Segmented linear regression was conducted to estimate the immediate change (“level” change) and the change in the time trend (“slope” change) in each outcome after the guideline release in March 2016, accounting for autocorrelation. Results: Before the guideline release, opioid prescription rate (21.1% vs. 7.2%) and rate of potential misuse or SUD (5.6% vs. 1.9%) were higher among survivors than controls ( p<0.05). Post guideline release, we found a declining trend in opioid prescription rate among survivors (slope change = -1.0 percentage point [ppt]; p<0.001). Survivors also experienced an immediate level decrease (-2.0 ppt; p=0.040) and a decreasing trend (slope change = -0.4 ppt; p=0.004) in the rate of potential misuse or SUD. Among controls, there were decreasing trends in opioid prescription rate (slope change = -0.3 ppt; p<0.001) and rate of potential misuse or SUD (slope change = -0.1 ppt; p=0.042). By three years post guideline release, relative reductions in opioid prescription rate and rate of potential misuse or SUD were 51.8% and 76.0%, respectively, among survivors ( p<0.05), with controls experiencing smaller relative reductions (29.4% and 36.5%; p<0.05). Conclusions: Following the release of the CDC opioid prescribing guideline in March 2016, there were reductions in opioid prescription rate and rate of potential opioid misuse or SUD among both pediatric cancer survivors and controls, with survivors experiencing greater reductions.
Representation of women in clinical trials supporting the FDA-approval of contemporary anticancer therapies.
Authors: Babcook Melissa A. , Nidhi Neha , Carter Rebecca R , Bonsu Janice , Yildiz Vedat , Wei Lai , Ruz Patrick , Paskett Electra D. , Addison Daniel
Published: June 2022

6521

Background: Contemporary anticancer drugs frequently have different efficacy and side effects in men and women. Yet, whether women are well-represented in pivotal trials supporting contemporary anticancer drugs is unknown. The objective of this study was to characterize the representation of women in trials supporting the use of contemporary anticancer drugs. Methods: We retrospectively evaluated all pivotal (phase II and III) trials supporting FDA-approval of anticancer drugs from 1998 to 2018, derived from Drugs@FDA, clinicaltrials.gov, MEDLINE, and publicly available FDA-drug reviews. Expected population rates were derived from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program, and US Census databases. The primary outcome was the report of any gender-specific analysis of efficacy and/or safety, irrespective of treatment-arm. The secondary outcome was the proportional representation of women across trials, evaluated by a participation-to-prevalence ratio (PPR) of 0.85, according to cancer-type. Female representation was also assessed as change across time. Differences in pooled binary endpoint hazard ratios, by the presence or absence of adequate female representation, were also assessed. Results: In total, there were 97,566 participants, enrolled in 189 clinical trials, evaluating 123 anticancer therapies. Gender was reported in 182 (96.3%) clinical trials, of which 43.4% (42,299) were women, compared to 55.6% (55,267) men ( P < 0.01). Overall, women were under-represented in clinical trials of anticancer therapies by a mean of 16.5% compared to the proportional incidence of all cancers in women. Women were the most under-represented in gastric (PPR = 0.821) and liver (PPR = 0.619) cancer trials. Sex-based drug efficacy analysis was only published in 36.8% of trials. Over time, the trend of percentage women recruited into clinical trials increased, but not at a rate comparable to prevalence (-5.0 to -5.5% of prevalence), and the gap in under-representation of women in anticancer therapy clinical trials is widening. Conclusions: Among pivotal clinical trials supporting contemporary FDA-approved cancer drugs, women were frequently under-represented. Additional studies are needed to understand the impact of under-representation on contemporary anticancer therapy outcomes.
Impact of equal access by race and ethnicity on patients in the Veterans Health Administration (VHA) treated for diffuse large B-cell lymphoma (DLBCL).
Authors: Ananth Snegha , Al-Abayechi Alaq , Blaize Jean-Pierre , Boyle Lauren , Djoufack Djoumessi Raissa Lakene , Espinoza Gutarra Manuel Ricardo , Franklin Kathleen , Lu Lindsey , Lucero Kana , Mader Michael , Nazarewicz Phillip , Nooruddin Zohra , Pandya Abhishek , Roman Souza Gabriel , Song Michael Meansup , Warnecke Brian , Whitehead Jennifer , Williams Madison H. , Williams Ryan A.
Published: June 2022

6526

Background: Racial and ethnic disparities in access to care and outcomes are well-established and are critical issues across several malignancies, including DLBCL. Previous studies from national registry datasets have shown racial disparities in DLBCL disease characteristics, treatment and outcomes. The VHA is an equal access system providing a unique environment to investigate cancer disparities across the disease continuum. Methods: This is a retrospective chart review of 4033 randomly selected patients with an ICD code for lymphoma treated within the VHA between 01/01/2011 and 12/31/2017. Data abstractors collected baseline patient and disease characteristics and treatment responses for those with an initial diagnosis of DLBCL in that time frame. Survival time was determined via electronic health record query on 11/30/2021. Chi-square tests were used to analyze relationship between race and variables of interest. Cox proportional hazards model was used to estimate hazard ratios (HR) for race and controlling factors. Results: 2141 DLBCL patients met our inclusion criteria. 97% were male. Majority were Non-Hispanic Whites (NHW 75%) followed by Non-Hispanic Blacks (NHB 12.5%), Hispanics (H 5.7%) and others (O 6.8%). NHB were diagnosed at younger median age (63 years) when compared to the NHW, H and O (68 years). There was no statistically significant difference in stage at diagnosis, IPI score, cell of origin (COO) and hit status amongst racial subgroups. Outcomes analysis (Table) revealed similar treatment and response rates, median OS, 1- and 2- year survival across all racial subgroups. However, after adjusting for age, IPI, COO, and exposure to agent orange, and including up to 10-years of survival data, H had 36% lower risk of death (HR=0.64, 95% CI 0.44-0.93) than NHW, while NHB and O had similar outcomes to NHW. Conclusions: This large retrospective study is a continuation of our group’s work (Williams et al, 2020) that doubles the cohort size and confirms that when standard of care therapy is given with equal access to care, short-term treatment and survival outcomes are same for all races. Further studies are needed to analyze risk factors associated with differences in long term outcomes.[Table: see text]
Concrete resource needs and frailty among older adults with cancer: The Cancer and Aging Resilience Evaluation (CARE) Registry.
Authors: Williams Grant Richard , Giri Smith , Dai Chen , Al-Obaidi Mustafa , Harmon Christian , Bona Kira , Landier Wendy , Bhatia Smita , Wolfson Julie Anna
Published: June 2022

6546

Background: Concrete resource needs (CRN: insecurity of food, utilities, and/or housing) are important and modifiable indicators of poverty. Prior work among adults with chronic cardiometabolic diseases demonstrates that CRN-targeted interventions improve health outcomes. Poverty is associated with inferior health outcomes among patients with cancer. Frailty is a recognized state of increased vulnerability and is associated with increased toxicities from cancer therapies and reduced survival. The prevalence of CRN among older adults with cancer and its role in modifying the risk of frailty remains unknown. We aimed to (1) describe the prevalence of CRN and (2) examine the association between CRN and frailty among older adults with cancer. Methods: The CARE registry prospectively enrolls older adults (≥60y) with cancer seen at UAB as new patients. Single-item screening measures captured food, housing and utility insecurity in addition to the baseline CARE geriatric assessment beginning 8/2020. The 44-item CARE Frailty Index (based on the principles of deficit accumulation) was used to define frailty. Multivariable analysis examined association of CRN with frailty, adjusting for age, race, sex, education, employment, marital status, and cancer type and stage. Results: The cohort included 485 participants with a mean age at enrollment of 69y; 63.7% were male; 20.4% were non-Hispanic Black. The most prevalent cancer types included colorectal (33.0%), pancreatic (16.3%) and hepatobiliary (12.2%) cancers. Median time from cancer diagnosis to study enrollment was 35 days. The overall prevalence of CRN was 6.6% (insecurity of housing [2.9%], food [4.3%], and utilities [4.1%]). Participants with CRN were less educated ( < HS: 21.9% vs. 9.9%, p= 0.01), more often widowed/divorced (53.1% vs. 35.1%, p= 0.003) and more likely to be disabled (43.8% vs. 12.4%, p< 0.001). Overall, 33.8% of patients were frail. In multivariable analysis, patients with CRN had a 6.24 higher odds of frailty (95% CI 1.72-22.7, p= 0.005) compared to those without CRN after adjustment for above-mentioned covariates. Conclusions: CRN represents a novel exposure that is independently associated with frailty. In order to inform a CRN-targeted intervention for the growing number of older adults with cancer, future work is warranted to examine the CRN construct in this population, including examination of more detailed screening measures and CRN-associated cancer outcomes.