bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of homologous recombination deficiency in ovarian cancer with neoantigen load and expression of immune checkpoints.
Authors: Fenerty Kathleen , Fares Charlene Marie , Konecny Gottfried E.
Published: June 2021

5536

Background: Immune checkpoint blockade (ICB) is being explored as a treatment option in ovarian cancer, but objective response rates for single agent ICB are modest at around 10-15%. Validated biomarkers are needed to predict which patients will respond to ICB. BRCA mutations and homologous recombination deficiency (HRD) status are the only validated integral biomarkers in ovarian cancer. HRD tumors exhibit defective DNA repair mechanisms that promote increased mutational burden, which we postulate may correlate with higher neoantigen load and increased expression of targetable immune checkpoints. Methods: The Cancer Genome Atlas (TCGA) ovarian cancer dataset was evaluated and previously published, well annotated samples were obtained for HRD status. HLA type was determined with OptiType. Nonsynonymous mutations were annotated with Ensembl VEP. pVAC-Seq using NetMHCpan algorithm predicted neoepitopes 9 amino acids in length for MHC class I, reporting only those with a predicted IC50 less than 500 nM. Immune checkpoint gene expression counts were normalized with TCGAbiolinks. Correlation between HRD status and neoantigen load was assessed by Wilcoxon test. After log2 transformation, Wilcoxon tests evaluated for association between HRD status and expression of immune checkpoints. The relationship between HRD status and PD-L1 protein abundance with reverse phase protein array was measured. Results: Data from 154 HRD positive and 198 HRD negative tumors were analyzed. HRD positive status correlated with higher neoantigen load (p = 0.038) and increased expression of the immune checkpoints CTLA4 (p = 0.024), TIGIT (p = 0.027), and PVR (p = 0.002), but not PD-L1 (p = 0.238), LAG3 (p = 0.583), HVEM (p = 0.805), GAL9 (p = 0.750), NECTIN2 (p = 0.874), VSIG3 (p = 0.438), PSGL1 (p = 0.205) or VISTA (p = 0.531). TIM3 (p = 0.064) and B7H3 (p = 0.052) both demonstrated a trend towards increased expression in HRD tumors. Interestingly, HRD status showed a negative association with PVRIG (p = 0.028). There was no association between PD-L1 protein abundance and HRD status. Conclusions: HRD positive ovarian tumors demonstrate higher neoantigen load than HRD negative tumors, as well as increased expression of certain immune checkpoints. This supports the hypothesis that increased neoantigen load leads to compensatory induction of immune checkpoints, and suggests that HRD status may predict response to ICB, particularly to drugs that target CTLA4, TIGIT, PVR, TIM3 and B7H4.
Circulating tumor DNA as a noninvasive marker of resectability in ovarian carcinomas.
Authors: Mari Roxane , Pomel Christophe , Colombo Pierre-Emmanuel , Narducci Fabrice , Garnier Séverine , Carbuccia Nadine , Guille Arnaud , Provansal Magali , Cappiello Maria-Antonietta , Rousseau Fréderique , Blache Guillaume , Lambaudie Eric , Birnbaum Daniel , Bertucci Francois , Sabatier Renaud
Published: June 2021

5548

Background: Ovarian cancer is the leading cause of death by gynecological cancer. Complete surgery remains one of the main prognostic factors. Laparoscopic exploration is mandatory to assess surgical resectability at diagnosis or after neoadjuvant chemotherapy. However, there is no clinical or biological marker that can correctly predict resectability and may be able to avoid a second laparoscopic exploration for initially unresectable diseases. Our aim was to assess circulating tumor DNA (ctDNA) value as a predictive non-invasive marker of evolution towards resectability for patients with epithelial ovarian cancer receiving first-line chemotherapy. Methods: We explored in this work one of the secondary objectives of the CIDOC study (NCT03302884). CIDOC is a multicenter prospective study aiming to explore ctDNA value as early marker of disease relapse after first-line treatment for epithelial ovarian cancer. Patients with mucinous histology or early stages not requiring chemotherapy are excluded. Plasma samples are collected at diagnosis, during neoadjuvant chemotherapy, and during follow-up. After DNA extraction, panel-based next generation sequencing is performed on both tumor samples and germline DNA, and somatic mutations of interest are selected for ctDNA monitoring. ctDNA analyses are conducted using droplet digital PCR (BioRad QX200) by measuring the variant allele fraction (VAF) of previously identified mutations. Results: This intermediary analysis has included 47 patients diagnosed between March 2017 and December 2019. Median age was 69 years old (48 – 84). Most of the patients had advanced disease (89.4% stage FIGO III or IV), serous histology (94.8%), and high grade tumor (92.3%). Most of the patients underwent complete interval cytoreductive surgery (76.3% vs 17.4% complete upfront surgery). Most of the tumors had TP53 mutations (85.1%), following by alterations involving DNA repair genes (38.3%). Median cell-free DNA concentration at baseline was 0.38 ng/µL (0 – 12.8). ctDNA was identified in 92.1% of patients at baseline with a median VAF of 1.84% (0 – 42.52%). ctDNA VAF was correlated to the peritoneal dissemination ( p= 0.039) assessed with the peritoneal cancer index. ctDNA clearance after preoperative chemotherapy tended to be correlated to achievement of complete interval surgery for patients receiving neoadjuvant chemotherapy ( p= 0.108). Conclusions: ctDNA may be a promising non-invasive marker to assess peritoneal cancer spreading and to predict surgical resectability after neoadjuvant chemotherapy. If confirmed in larger populations, this may enable to avoid additional surgical explorations for patients who remain ctDNA positive after chemotherapy. Clinical trial information: NCT03302884.
Association of the Khorana Score with development of venous thromboembolism in ovarian cancer.
Authors: Marcus Ellen , Kuo Dennis Yi-Shin , Nevadunsky Nicole Suzanne , Gressel Gregory M.
Published: June 2021

5555

Background: The Khorana score is a previously validated method to identify patients at high risk of VTE during chemotherapy who would potentially benefit from thromboprophylaxis. The objectives of our study were to evaluate risk factors and timing associated with VTE in a large cohort of ovarian cancer patients and to assess the predictive ability of the Khorana score in this population. Methods: After IRB approval, a retrospective analysis was performed of all patients with ovarian cancer in the Albert Einstein Tumor Registry who received treatment between 2000 and 2020. Demographic, clinical, surgical and histologic data and information regarding timing of VTE were abstracted from the medical record. Khorana scores were retrospectively calculated for all patients who received chemotherapy based on their pre-chemotherapy laboratory indices. Bivariate analysis and multivariable logistic regression were used to examine the association between Khorana score and VTE. Results: A total of 472 patients were included over a median follow-up time of 33.7 (13.3, 61.1) months of whom 142 (31%) underwent diagnostic imaging to rule out VTE. A total of 62 patients (15%) were diagnosed with VTE with a median time from presentation to VTE of 8.7 (2.7, 30.3) months. Individual covariates which were significantly associated with VTE included stage III-IV disease, epithelial histology, open surgery, radical tumor debulking, and presence of residual disease after surgery. Of the 254 patients who received chemotherapy for their disease, 36 (14%) developed VTE within 3 weeks of receiving chemotherapy. Patients with Khorana scores of 2 (OR 1.73 95% CI 0.88-3.42) or 3 (OR 0.89 95% CI 0.33-2.44) were not significantly more likely to develop VTE during chemotherapy compared to patients with a score of 1. However, patients with a score of 4 were 6.74 times more likely to develop a VTE during chemotherapy (95% CI 1.39 - 32.73). Overall, a Khorana score of 2 or higher conferred no significant increased risk of developing VTE during chemotherapy than a score of 1 (OR 1.61 95% CI 0.85- 3.02). In a multivariable model, the Khorana score was not significantly associated with risk of VTE and a Khorana score of 2 or higher could explain only 0.86% of the variability in predicting VTE. The only variables significantly associated with VTE after adjustment were stage III-IV disease and hyperlipidemia. Conclusions: Patients with ovarian cancer are at high risk of developing VTE many months after diagnosis and initiation of chemotherapy. Current ASCO and SGO guidelines recommend thromboprophylaxis for those initiating chemotherapy with a Khorana score of 2 or higher, however our study found that these patients are not at increased risk compared to those with a score of 1. Future models should be developed and validated in large population-based cohorts to determine if there is a more accurate strategy to identify women with ovarian cancer who are at risk for VTE.
Improving the prediction of surgical outcome at secondary cytoreduction in patients with ovarian cancer: Results from retrospective part of HELP-ER study NOGGO TR2/ENGOT OV47-TR.
Authors: Braicu Ioana , Kassuhn Wanja Nikolai , Kulbe Hagen , Wimberger Pauline , Taskiran Cagatay , Pietzner Klaus , Mustea Alexander , Armbrust Robert , Grabowski J.P. P. , Schmidt Felix , Ayhan Ali , Beteta Carmen Rosa , Fotopoulou Christina , Sehouli Jalid
Published: June 2021

5558

Background: Complete resection at secondary cytoreductive surgery is associated with prolonged progression free and overall survival for patients with relapsed ovarian cancer. Secondary cytoreductive surgery has no impact on survival rates, if macroscopically tumor clearance cannot be achieved. Therefore, in order to avoid unnecessary perioperative morbidity and mortality, selection of patients who will undergo secondary tumor debulking is crucial. This study aims to improve upon the contemporary Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score by including additional clinical variables like circulating HE4 and CA125 levels to predict surgical outcome at secondary cytoreduction. Methods: A total of 90 patients underwent secondary cytoreductive surgery and were retrospectively assigned a positive AGO score. Of those patients, 62 (68.9%) achieved optimal surgical outcome at secondary debulking with 28 (31.1%) patients retaining residual tumor mass ( > 0mm). Utilizing clinical variables including circulating HE4 and CA125 levels, we implemented a machine learning workflow to predict suboptimal surgical outcome in patients despite a positive AGO score. Results: We elucidated significantly lower levels of circulating HE4 (p = 0.0038) in patients with optimal surgical outcome compared to patients that retain macroscopic residual tumor at secondary cytoreductive surgery. Moreover, machine learning algorithms trained on clinical variables (e.g. serum HE4 level, serum CA125 level, age, Risk of Ovarian Malignancy Algorithmus (ROMA) score and occurrence of peritoneal carcinomatosis) achieved a mean area under the curve (AUC) of 78.4% based on 100 consecutive executions with randomized training and test sets. Conclusions: The application of machine learning allows to further improve the prediction of patients with high likelihood of achieving optimal surgical outcome at secondary cytoreduction. In turn, it might identify patients that would benefit from amplified treatment efforts. However, machine learning relies on large amounts of data to account for biological and clinical variation and produce predictions of sufficient/adequate quality. Given this limitation, we would validate this data within the prospective multicentric cohort of patients collected within NOGGO/ENGOT HELP_ER Trial.
Photodynamic therapy for preinvasive vaginal cancer.
Authors: Ivanova Viktoria A. , Verenikina Ekaterina V. , Nikitina Vera P. , Zhenilo Oksana E. , Ardzha Anna Yu.
Published: June 2021

5592

Background: Photodynamic therapy (PDT) is an effective method for the treatment of various cancers resulting in apoptosis, autophagy and ischemic necrosis of irradiated tissues. The purpose of the study was to analyze the efficacy of PDT for pre-invasive vaginal cancer treatment. Methods: PDT results were studied in 20 patients aged 32-65 years with verified pre-invasive vaginal cancer. All patients received PDT with the Latus diode laser and Photolon or Photolan photosensitizers. The effect was evaluated with extended colposcopy. The criteria for efficiency included normalization of the colposcopic picture and the absence of atypical cells. The sizes of the irradiation fields varied from 1.5 to 2 cm, the number of fields - from 1 to 4, the power density - from 0.1 to 0.17 W/cm2, the light dose - from 40 to 100 J/cm2. The duration of a PDT session varied from 10 to 30 min, depending on the number of irradiation fields. The irradiation field necessarily included an area of normal tissue 3-5 mm surrounding the lesion. 4 to 6 sessions were required to restore the normal layer of stratified squamous epithelium. The antitumor efficacy of PDT was evaluated based on the results of visual observation of changes in the area of the treated pathological foci and information on the presence or absence of clinical symptoms of the disease 1 and 3 months after the treatment (WHO criteria). Results: Complete regression was registered in 100% of patients after 3 months. Repeated courses of PDT were required in cases with a wide spread of pathological foci and the impossibility of their simultaneous irradiation. At follow-up after 1 month, 3 of 20 patients (15%) showed local foci of atypical changes in the epithelium managed with repeated PDT courses. In 6 months, stable remission of the disease clinical symptoms in the treated pathological foci was registered. The results of the cytological study performed 3 months after PDT were normal in 100% patients; no negative changes were registered 6 and 12 months after PDT. Conclusions: The results of PDT in the treatment of patients with pre-invasive vaginal cancer demonstrated its high therapeutic efficacy and a minimal number of adverse reactions, which allows recommending PDT in the treatment of pre-invasive vaginal cancer.
Race, subjective social status and metabolic syndrome in women with breast cancer.
Authors: Greco Giampaolo , Gallagher Emily J. , Leroith Derek , Lin Sylvia , Yagnik Radhi , Feldman Sheldon M. , Killelea Brigid K. , Friedman Neil B , Pilewskie Melissa Louise , Choi Lydia , Bickell Nina A.
Published: June 2021

560

Background: Metabolic syndrome (MS) is associated with worse breast cancer prognosis. Black women have higher rates of advanced breast cancer, as well as MS, diabetes and obesity. As socioeconomic status is associated with MS, we asked whether the subjective perception of social status (SSS), might influence this association in black and white women with a new breast cancer (BC) diagnosis. Methods: We surveyed, obtained serum and conducted anthropometric measures of 1206 women with a new BC diagnosis. Triglycerides, systolic blood pressure (SBP), waist circumference (cm), HDL and glucose were used to calculate a severity index of MS (MS-Zscore: mean=0; sd=1). Women reported their SSS on the 10 rung McArthur US social status ladder, their household income, education attained, diet quality (5 point scale), and exercise measured with metabolic equivalents (METS). Data were analyzed with multivariable generalized linear models. Missing data were imputed with multiple imputation. Results: Average age was 58 yrs of 295 black and 911 white women. BC stage > II was in 11.6% of black and 2.4% of white women. On average black women had higher BMI (31.5 vs 26.6; p<0.001), waist circumference (103 vs 93; p<0.001) glucose (96 vs 92; p<0.001) and SBP (132 vs 126; p<0.001); lower triglycerides (92 vs 104; p<0.001) and HDL (59 vs 68; p<0.001). Black women were more likely than white women to live in poverty (23.7% vs 4.6%; p<.001); report poor diet (32.4% vs 10.4%; p<.001) and less exercise (29.7% v 23.6% in the 25th %ile), and less likely to graduate college (30.3% vs 70.4%). MSZ-score was positively associated with age (.02 per year; p<.001) and black race (0.35; <.001) and negatively with better diet (-.20 per point in 4 point scale); p<.001), exercise (-.11 per quartile increase in METS; p<.001) and SSS (-.04 per ladder rung; p=.004). SSS was lower in black women within the same levels of income and education). Conclusions: Race, age, diet, exercise and subjective social status all impact metabolic syndrome, a risk factor for breast cancer. Of concern, among breast cancer patients, black women are more likely to rate their SSS below white women, within each education or income level. Subjective social status among women with a new breast cancer diagnosis is associated with MS and may be important to address as a risk factor among breast cancer patients.[Table: see text]
Updated report of a phase II randomized trial of transoral surgical resection followed by low-dose or standard postoperative therapy in resectable p16+ locally advanced oropharynx cancer: A trial of the ECOG-ACRIN cancer research group (E3311).
Authors: Ferris Robert L. , Flamand Yael , Weinstein Gregory S. , Li Shuli , Quon Harry , Mehra Ranee , Garcia Joaquin J. , Ringash Jolie , Lewin Jan S. , Duvvuri Umamaheswar , O'Malley Bert W. , Ozer Enver , Thomas Giovana R. , Koch Wayne , Kupferman Michael Elliot , Bell Richard Bryan , Saba Nabil F. , Lango Miriam , Wagner Lynne I. , Burtness Barbara
Published: June 2021

6010

Background: Definitive or postoperative chemoradiation (CRT) is highly curative for human papillomavirus-associated (HPV+) oropharynx cancer (OPC) but induces significant toxicity. As a potential deintensification strategy, we studied primary transoral surgery (TOS) and, in intermediate pathologic risk patients, reduced dose postoperative RT (PORT). Methods: E3311 is a phase II trial with randomization to reduced- or standard-dose PORT for resected stage III-IVa (AJCC7) intermediate pathologic risk HPV+ OPC, stratified by smoking history. Primary endpoints have been reported; we now present updated 3-year PFS and patient-reported outcomes (PRO), including head and neck-cancer specific quality of life (FACT-H&N) and swallowing perception and performance (MDADI). Results: Of 519 enrolled patients, 495 underwent TOS. The primary oncologic endpoint was 2-year PFS for 50 Gy (Arm B) or 60Gy (Arm C). Among 360 eligible and treated patients (ETP), Arm A (observation, N = 38) enrolled 11%, Arms B (N = 100) or C (N = 109) randomized 58%, and Arm D (66Gy + weekly cisplatin, N = 113) enrolled 31%. With 35.1 months median follow-up, 3-year PFS Kaplan-Meier estimate is 96.9% (90% CI [91.9%, 100%]) for Arm A; 94.9% (90% CI [91.3%, 98.6%]) for Arm B; 93.5% (90% CI [89.4%, 97.9%]) for Arm C; and 90.7% (90% CI [86.2%, 95.4%]) for Arm D. Recurrences and death without recurrence were 4 and 1 in Arm B, and 5 and one in Arm C. Smokers ( > 10 pack-years) did not have worse 3-year PFS in Arms B or C. Treatment arm distribution and outcome for ineligible patients who started adjuvant therapy mirrored the 360 ETP. A comparison combining arms B/C versus arm D in the proportion of patients stable/improved in FACT-H&N total score, from baseline to 6 months post-treatment as a pre-specified endpoint, was 56% vs. 38% (p value = 0.011, one-sided Fisher’s exact test); however, underlying differences in treatment and risk may be confounding. An exploratory comparison between Arms B and C revealed improvement in FACT H&N (63% in Arm B vs. 49% in Arm C had a stable/improved score, p-value = 0.056). Conclusions: Primary TOS and reduced PORT retained outstanding oncologic outcome at 35 months follow up, with favorable QOL and functional outcomes, in intermediate risk HPV+ OPC. Clinical trial information: NCT 01898494.
Efficacy and toxicity of weekly paclitaxel, carboplatin, and cetuximab as induction chemotherapy or in cases of metastases or relapse for head and neck cancer in elderly or frail patients.
Authors: Forman Rebecca , Bhatia Aarti K. , Burtness Barbara
Published: June 2021

6042

Background: Standard of care treatments for locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC) are not well tolerated, particularly in elderly or frail patients. One combination that has been studied in recent years is paclitaxel, carboplatin and cetuximab (PCC). Studies have shown this regimen yields promising results when used as an induction chemotherapy for locally advanced disease. PCC has also been studied in patients with metastatic or recurrent incurable disease, and has shown good response with tolerable toxicity rates, but there is a relative dearth of evidence surrounding its use. Methods: This retrospective observational study utilized EMR data analysis software to generate the cohort of adult patients that received PCC for HNSCC in 2014-2019 as well as demographic data. Chart review was used to gather details about the patients’ tumors and clinical course. Modified RECIST response rates (MRRR), progression free survival (PFS) and overall survival (OS) were the primary end points calculated for the metastatic/recurrent group, and percentage of successful inductions (e.g., patients went on to definitive treatment, avoided surgery) and MRRR were used for the induction group. Results: There were 80 patients in the cohort. The average age was 65 (range 33-84) and the patients were 81% male. The most common tumor site was the tongue (25 patients), followed by tonsil (15), oropharynx (9), and larynx (7). 13 patients had p16 positive disease. Most patients had Stage IVA (36 patients), followed by IVB (20), and IVC (15); the remainder had stage III or below or unknown stage. The most common reasons patients did not receive cisplatin were performance status (13 patients), hearing loss (11), concern for nephrotoxicity (6) and age (5). 97.5% of patients experienced at least one adverse effect. The most common adverse effect was dermatologic (69%), followed by hematologic (51%), fatigue (41%) and gastrointestinal symptoms (41%). 53 patients (66%) experienced at least one dose interruption due to adverse effects. 11 patients (14%) stopped treatment due to toxicities. 58 patients received PCC for metastatic or recurrent disease. They had received a median of 1 line of systemic treatment prior; 72% had prior radiation, and 26% had prior salvage surgery. The MRRR was 22% (5 patients with complete response, 8 partial response, 15 stable, 27 progression). There was a 7.0 month mean PFS, and 17.3 month mean OS. Of the 22 patients who received PCC as induction, 86% (19) successfully reached their induction endpoint. The MRRR was 64% (8 patients with complete response, 6 partial response). Conclusions: PCC is a relatively well-tolerated combination with a very good induction success rate. More research is needed around alternate options for frail and elderly patients with HNSCC.
Inductive camrelizumab and apatinib for patients with locally advanced and resectable oral squamous cell carcinoma: A single-arm trial (Icemelting trial).
Authors: Zhong Lai-Ping , Ju Wu-tong , Xia Rong-hui , Zhu Qi , Zhu Guopei , Dou Shengjin , Li Jiang , Dong Min-jun
Published: June 2021

6052

Background: In patients with locally advanced oral squamous cell carcinoma (LAOSCC), major pathologic response (MPR) to induction therapy may translate into improved survival. The induction therapy using chemo-free drugs, such as the combination of anti-PD1 and anti-VEGFR drugs, has not been well issued in LAOSCC. Methods: A prospective single arm trial (NCT04393506) has been performed to evaluate the induction therapy of anti-PD1 and anti-VEGFR protocol in LAOSCC patients at clinical stage III and IVA. The patients received three cycles of intravenous Camrelizumab (PD-1 antibody, 200mg) on d1, d15, d29; and oral Apatinib (anti-VEGFR inhibitor, 250mg) daily, initiating on d1, ending on the 5th day before surgery. Radical surgery was planned on d42-d45. Post-operative radiotherapy was planned within 1.5 months after surgery, based on clinical and pathological stage. The primary endpoints were MPR and safety; primary tumors were assessed for the percentage of residual viable tumor that was identified on HE staining, and tumors with no more than 10% viable tumor cells were considered as MPR. This study has been approved by institutional ethics committee at Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine. Results: From April to December 2020, 21 patients were enrolled in this trial, and one patient withdraw from the trial at the beginning of treatment. The induction therapy was well-tolerated with no grade 3-4 toxicity or serve induction therapy-related AEs. One patient required surgery delay for 7 days due to unexplainable cTnI elevation. One patient put off Camrelizumab for 14 days due to grade 2 thrombocytopenia. One patient suspended Apatinib for 21 days due to grade 2 Hyperbilirubinemia. The induction therapy did not effect on the subsequent standard treatment. MPR rate was 40% (8/20), including 5% (1/20) pCR. Radiological evaluation of response to induction therapy showed 3 PR, 10 SD, 5 PD and 2 NA. Weak correlation was found between pathologic and radiological evaluation on induction therapy. Combined positive score (CPS) of PD-L1 expression in biopsy was evaluated in 19 patients; all 4 patients with CPS≥ 20 had MPR, 3 out of 11 patients with 1≤CPS < 20 had MPR, and 1 out of 4 patients with CPS < 1 had MPR. Conclusions: The chemo-free protocol of induction therapy using Camrelizumab and Apatinib is safe and well-tolerated for the patients with LAOSCC. The MPR rate is much higher using the anti-PD1 and anti-VEGFR protocol than the traditional induction chemotherapy protocol in LAOSCC. Clinical trial information: NCT04393506.
Quality of life analysis of HPV-positive oropharyngeal cancer patients in a randomized trial of reduced-dose (rdCRT) versus standard (sdCRT) chemoradiotherapy: Five-year follow-up.
Authors: Takahashi Mai , Hwang Michael , Misiukiewicz Krzysztof , Bakst Richard Lorne , Miles Brett A. , Gupta Vishal , Bonomi Marcelo Raul , Sharma Sonam , Botzler John , Genden Eric Michael , Moshier Erin , Selkridge Isaiah , Posner Marshall R.
Published: June 2021

6062

Background: Human papillomavirus-positive oropharyngeal cancer (HPV OPC) portends a more favorable prognosis compared to HPV-negative cases. To prevent overtreatment, long-term morbidity and deterioration in functionality and quality of life (QoL), multiple studies have focused on de-intensification techniques for HPV OPC treatment. To this end, we prospectively assessed differences in patient reported QoL in locally advanced HPV OPC patients receiving rdCRTversus sdCRT)in a randomized trial using a sequential therapy plan. Methods: Patients were enrolled between December 2012 and February 2016; received 3 cycles of induction docetaxel, cisplatin, and 5-FU; and were randomized to sdCRT (70 Gy) or rdCRT (56 Gy) with weekly carboplatin. Patients were followed for Progression Free Survival (PFS), Overall Survival (OS), and changes in QoL as assessed by the MD Anderson Dysphagia Inventory (MDADI), MD Anderson Symptom Inventory (MDASI Head and Neck), Xerostomia Questionnaire (XQ), and the European Organization for Research and Treatment of Cancer Questionnaire (EORTC QLQ-C30) with the head and neck module (EORTC HN). A mixed model ANOVA was used to estimate changes from baseline QoL to that at each follow-up timepoint and to compare the difference in QoL changes between the treatment arms. Results: We randomized 20 HPV+ locally advanced (LA) patients (median age: 56.5 yrs) to rdCRT (12 subjects) or sdCRT (8 subjects). 70% had high risk features. At a median follow-up of 81.5 mos, PFS and OS were 87.5% and 83.3% for sdCRT and rdCRT, respectively with a median OS of 76 mos in both arms. One patient in the sdCRT arm developed an HPV negative retromolar trigone squamous cell cancer in the radiation field 7 yrs after therapy. Baseline QoL was identical in the 15 patients who completed the QoL modules. Patients receiving rdCRT hadsignificantly lower declines in QoL scores at 3-6 month follow-up. At 5 yrs, differences in QoL changes all favored the rdCRT arm (Table) and two QoL scales reached statistical significance (P<0.05). Conclusions: In HPV OPC patients, rdCRT resulted in comparable long-term survival and greater improvement in specific domains of QoL when compared to sdCRT. Our results support the need for a larger, long-term Phase 3 study in LA HPVOPC to assess these two treatments with respect to survival, QoL, and safety. Clinical trial information: NCT02945631. [Table: see text]
Selpercatinib efficacy and safety in patients with RET-altered thyroid cancer: A clinical trial update.
Authors: Sherman Eric Jeffrey , Wirth Lori J. , Shah Manisha H. , Cabanillas Maria E. , Robinson Bruce , Laskin Janessa J. , Kroiss Matthias , Subbiah Vivek , Drilon Alexander E. , Wright Jennifer , Soldatenkova Victoria , French Pearl Plernjit , Italiano Antoine , Weiler Daniela
Published: June 2021

6073

Background: Selpercatinib, is a first-in-class, highly selective, CNS active and potent RET inhibitor approved in multiple countries for treatment of RET-fusion positive lung or thyroid cancers. Reported is an update of efficacy and safety results in RET-altered thyroid cancer, with a longer follow up (30 Mar 2020 data cutoff vs 16 Dec 2019) and additional enrolment. Methods: Patients (pts) with RET-mutant medullary thyroid cancer (MTC) and RET-fusion positive thyroid cancer (TC) were enrolled in the global (16 countries, 89 sites) Phase 1/2 LIBRETTO-001 trial (NCT03157128). The primary endpoint was objective response rate (ORR) per RECIST 1.1 by independent review committee (IRC). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), clinical benefit rate (CBR; CR+PR+SD ≥16 weeks), and safety. The integrated analysis set (IAS, n = 143) includes efficacy evaluable MTC pts previously treated with cabozantinib and/or vandetanib (cabo/vande). The primary analysis set (PAS), a subset of IAS, is the first 55 enrolled pts. Cabo/vande naïve MTC pts (N = 112) and TC pts with prior systemic treatment (N = 22) were also analyzed. Safety population includes all pts who received ≥1 dose of selpercatinib (MTC N = 315; TC N = 42) by data cutoff. Results: For MTC patients, the ORR for IAS was 69.2%, in the PAS it was 69.1%, and 71.4% for cabo/vande naïve MTC pts. The ORR for TC pts (n = 22) was 77.3% (see table). Most treatment-emergent adverse events (TEAEs) were low grade; the most common (≥25% of MTC and/or TC pts treated with selpercatinib) were dry mouth, diarrhea, hypertension, fatigue and constipation for both MTC and TC pts, increased ALT/AST, peripheral edema and headache in MTC pts and nausea in TC pts. 4.8% of MTC and TC pts discontinued selpercatinib due to TEAEs but only 1.9% with MTC and none with TC discontinued due to treatment-related adverse events. Conclusions: In this updated analysis, selpercatinib continued to show marked and durable antitumor activity in pts with RET-altered thyroid cancers. Selpercatinib was well tolerated and no new safety concerns were identified. A global, randomized, phase 3 trial (LIBRETTO-531) evaluating selpercatinib compared to cabo/vande in kinase inhibitor naïve MTC pts is ongoing. Clinical trial information: NCT03157128. [Table: see text]
NTRK, RET, BRAF, and ALK fusions in thyroid fine-needle aspirates (FNAs).
Authors: Wirth Lori J. , Hu Mimi I-Nan , Waguespack Steven G. , Dosiou Chrysoula , Ladenson Paul , Livhits Masha J. , Sadow Peter M. , Krane Jeffrey , Stack Brendan C. , Zafereo Mark , Ali Syed Z. , Weitzman Steven P , Hao Yangyang , Babiarz Joshua , Kennedy Giulia , Kloos Richard
Published: June 2021

6083

Background: Receptor tyrosine kinase (RTK) fusions may be targeted by small molecule inhibitors to treat various advanced tumors, including thyroid cancer. Clinical trials have studied selective inhibitors of ALK, BRAF, NTRK and RET, leading to several FDA-approved therapies. The Afirma Genomic Sequencing Classifier (GSC) classifies cytologically indeterminate thyroid nodules as molecularly benign or suspicious. The Xpression Atlas reports 905 genomic variants and 235 fusion pairs on GSC Suspicious, Suspicious for Malignancy (SFM), and Malignant FNA samples at the time of diagnosis. Here we report the prevalence of these fusion genes in real-world clinical practice. Methods: We analyzed anonymized data from 50,644 consecutive Bethesda III-VI nodule FNA samples submitted to the Veracyte CLIA laboratory for molecular testing using whole transcriptome RNA sequencing (RNA-Seq). Gene pairs are listed alphabetically. Results: 32,080 Bethesda III/IV nodules were classified as GSC Benign and 278 were Parathyroid Classifier positive. No ALK, BRAF, NTRK1/3, or RET fusions were identified among these samples. Among 16,594 Bethesda III/IV GSC Suspicious FNAs, 3% (n = 529) were positive for ALK, BRAF, NTRK1/3 or RET fusions. Among the 1,692 Bethesda V/VI FNAs, the proportion of positive nodules was 8% (n = 135). Among these combined cohorts of Bethesda III/IV GSC Suspicious and Bethesda V/VI, the most common gene fusions observed for each of the 5 studied RTK genes was: ETV6/NTRK3 (n = 164, 72% of NTRK3 fusions), CCDC6/RET (n = 104, 55% of RET), BRAF/SND1 (n = 32, 20% of BRAF), ALK/STRN (n = 20, 37% of ALK), and NTRK1/TPM3 (n = 14, 50% of NTRK1). BRAF showed the highest diversity of fusions, with 80 gene partners. Different gene partners with RET, ALK, NTRK1, and NTRK3 numbered 25, 11, 9, and 5 , respectively . Conclusions: Whole-transcriptome RNA-seq on small sample thyroid FNA specimens can identify clinically relevant ALK, BRAF, NTRK, and RET fusions across Bethesda categories. The prevalence ranges from 3% in Bethesda III/IV Afirma GSC Suspicious specimens to 8% among Bethesda V/VI specimens. Future studies need to determine if detection of precision medicine candidates by pre-operative FNA can optimize initial treatment, predict response to treatment, and prioritize selective targeted therapy should systemic treatment be needed.[Table: see text]
Cancer diagnosis and adverse financial events: Evidence from credit reports.
Authors: Shankaran Veena , Li Li , Fedorenko Catherine R. , Sanchez Hayley , Du Yuxian , Khor Sara , Kreizenbeck Karma L. , Ramsey Scott David
Published: June 2021

6504

Background: Increasing evidence shows that cancer patients (pts) experience financial hardships after diagnosis. Few studies, however, have used objective financial data to estimate the relative risk of adverse financial events (AFEs) in cancer pts versus individuals without cancer. Using a retrospective case-control design, we investigated whether cancer pts are at increased risk of new AFEs, as measured by their credit reports. Methods: Western Washington Surveillance Epidemiology and End Results (SEER) cancer registry (cases) and voter registry (controls) records from 2013 to 2018 were linked to quarterly credit records from TransUnion (2012-2020), one of the 3 largest national credit agencies. Controls were age and sex matched to cases and assigned an index date corresponding to the diagnosis (dx) date of the matched case. Individuals with evidence of any AFE in the credit report closest to index/dx date or did not survive to 24 months were excluded. Cases and controls experiencing any of the following AFEs within 24 months were compared, using two-sample z tests: severe (3rd party collections, charge-offs), more severe (tax liens, delinquent mortgage payments), and most severe (foreclosures, repossessions). Multivariate logistic regression models were used to evaluate the association between cancer dx and AFE, adjusting for age, sex, dx year, and available credit 6 months before the index/dx date. Results: A total of 332,825 individuals (84,185 cases and 248,640 controls, mean age 66 (SD 13), 52.7% female) were included. The mean available line of credit in the year before index/dx date was $12,303. AFEs were more common in cases versus controls (Table). After adjusting for age, sex, available credit above or below $12,303, and dx year, cancer dx was significantly associated with any AFE (OR 1.77, 95% CI 1.7-1.85, p<0.0001), severe AFEs (OR 1.94, 95% CI 1.85-2.03, p<0.0001), more severe AFEs (OR 1.23, 95% CI 1.12-1.36, p<0.0001), and most severe AFEs (OR 1.46, 95% CI 1.16-1.86, p=0.0016). Age >65 and higher available baseline credit were associated with decreased risk of any and each category of AFE. Conclusions: Within 24 months from dx, significantly higher proportions of cancer pts experienced AFEs relative to controls. Such events on credit reports have serious and long-lasting consequences on financial status. Studies that link clinical and financial data to investigate the impacts of these events on treatment decisions, quality of life, and clinical outcomes are needed.[Table: see text]
Mobile low-dose computerized tomography (LDCT): Three-year follow up of solution for early diagnosis of lung cancer in under-served populations.
Authors: Raghavan Derek , Doege Darcy L. , Wheeler Mellisa S , Dungan Kia , Davis Lauren , Doty John , Hickman Glenn , Weatherford Brooke , White Stephanie , Mileham Kathryn Finch , Carrizosa Daniel R.
Published: June 2021

6507

Background: Randomized trials have proven that screening high-risk patients with LDCT of chest reduces lung cancer mortality compared to screening with chest x-ray. Under-served patients lack access to this test due to geographic and socio-economic factors. We hypothesized that a mobile screening unit would improve access and increase survival in this group, which is most at risk of lung cancer deaths. Methods: We installed a BodyTom portable 32 slice low-dose CT scanner (Samsung Inc) into a 35 foot coach (Frazier Inc), reinforced to avoid equipment damage during road travel. It includes waiting area, high speed wireless internet connection for rapid image transfer, and electronic tablets to deliver smoking cessation and health education programs and shared decision-making video aids. We used LUNG RADS approach to lesion classification, yielding high sensitivity and specificity in assessment. All films were reviewed by a central panel. This is certified as a lung cancer screening Center of Excellence by the Lung Cancer Alliance. Protocol was approved by Advarra IRB. Medicare pts excluded as insurance covered them for LDCT, although this reduced potential number of cases diagnosed as this is highest risk population. Results: We screened 1200 uninsured or under-insured subjects, mean age 61 years (range 55-64), with average pack year history of 47.8 (30-150); 61% male; 18% Black, 3% Hispanic/Latino; 78% rural. We found 97 pts with LUNG RADS 4 lesions, 30 lung cancers (2.5%), including 15 at stage I-II treated with curative intent; 5 incidental non-lung cancers (renal CA 2, head & neck CA 1, pancreas CA 2); more than 50% with cardiovascular disease or COPD seen on LDCT. Of eligible first-screen subjects (J. Clin. Oncol., 2019, 37, 383S), 440 attended Year 1 repeat LDCT and 161 attended Year 2 LDCT. Only one pt with surgically resected CA lung has relapsed to date. Conclusions: Mobile LDCT yields higher screening rate for under-served pts than prior international studies, with strong protocol adherence and paucity of early cancer deaths in high-risk population with traditionally poor compliance.
Measuring disparities in quality of oncology care across oncology practices.
Authors: Keating Nancy Lynn , Landrum Mary Beth , Zaslavsky Alan , Samuel Cleo A. , Sinaiko Anna , Brooks Gabriel A. , Wright Alexi A. , Bai Barbara
Published: June 2021

6533

Background: Equity is now recognized as an essential aspect of health care quality. Racial inequities in clinical performance diminish overall system performance. We assessed the feasibility and reliability of practice-level measures of racial disparities in chemotherapy-associated emergency department (ED) visits and hospitalizations. Methods: Using fee-for-service Medicare data, we identified 1,196,970 Black or White fee-for-service Medicare beneficiaries with cancer receiving chemotherapy in 2016-2019, who were attributed to 5511 oncology practices that treated at least 1 Black and 1 White beneficiary (96.4% of all beneficiaries). We studied two CMS quality measures: chemotherapy associated ED visits and chemotherapy associated hospitalizations. For each outcome, we estimated multi-level models with separate practice-level random intercepts for Black and White patients to quantify practice-level Black-White disparities in adjusted rates of these measures and assess the associations of these rates with the proportion of Black patients in the practice. Results: Overall, 108,177 Black and 966,381 White beneficiaries with cancer were treated at 1321 practices with reliable estimates (reliability ≥70%) of Black-White differences in rates of chemotherapy-associated ED visits; 101,411 Black and 915,895 White beneficiaries were treated at 1,012 practices with reliable estimates of chemotherapy-associated hospitalizations. These practices treated 80% or more of all Black and White beneficiaries; 10% of these practices treated 75% of Black beneficiaries. The median adjusted Black-White rate difference across practices was +8.9% [interquartile interval (IQI) +5.0%, +12.8%; 5th, 95th percentile -1.8 to +19.2%] for chemotherapy associated ED visits and +4.4% [IQI +1.3%, +7.7%; 5th, 95th percentile -3.5% to +13.5%] for chemotherapy associated hospitalizations. Chemotherapy-associated ED visit rates were 3.2 percentage points higher for Black vs White patients (P <.001) at the practice with the mean % of Black patients, but the difference was smaller in practices with more Black patients (0.4 percentage points less for each 10% increase in Black share, P <.001). Chemotherapy-associated hospitalization rates were 0.6 percentage points lower for Black vs White patients (P =.01) but did not vary by practice racial composition. Conclusions: Using data from more than 1000 practices over 4 years, we calculated reliable estimates of practice-level racial disparities in chemotherapy-associated ED visits and hospitalizations. Practice-level performance for these quality measures was generally lower for Black versus White beneficiaries. Measuring and providing feedback on practice-level Black-White disparities in oncology performance measures may be one effective tool for advancing racial equity in care quality for cancer patients receiving chemotherapy.
What accounts for the racial disparity in survival from estrogen receptor-positive, axillary node-negative breast cancer in the United States? An analysis of the SEER-Oncotype database.
Authors: Hoskins Kent , Calip Gregory Sampang , Danciu Oana Cristina , Rauscher Garth H
Published: June 2021

6534

Background: In a previous analysis of the SEER-Oncotype database (Hoskins, et al. JAMA Oncol, 2021), we reported that among women with estrogen receptor (ER)-positive, axillary node-negative breast cancer (BC), Black women were more likely than non-Hispanic White (White) women to have a high risk Oncotype Recurrence Score (RS), and the adjusted hazard for BC-specific death was 1.5-2.5 times higher for Black than for White women within each RS risk category. In this study we examined the role of health insurance, census tract socioeconomic status and tumor biology in the racial disparity in ER-positive BC mortality among US women. Methods: We obtained BC-specific survival data from the SEER-Oncotype database for women diagnosed with first primary, stages I-II, ER-positive, node-negative BC between 1/1/2004 -12/31/2015 who had an Oncotype Recurrence Score (RS) through Genomic Health Laboratory. The racial (Black:White) BC mortality disparity was estimated as a disparity hazard ratio (HR) from a series of Cox proportional hazards models of time to BC death. The baseline model adjusted for SEER registry and age at diagnosis (included in all models). We estimated the disparity HR after controlling for variable domains one at a time, as well as cumulatively in this order: neighborhood SES index (a composite measure including census tract education, income and poverty) and insurance (none, public, private); tumor biology (RS, PR status, tumor grade); tumor size; and treatment (surgery type, initiation of radiation and chemotherapy). Results: The analysis included 57,428 White and 6,003 Black women with node-negative, ER-positive BC (median follow-up = 54 months). The total disparity HR for BC death was 1.67 (95% CI: 1.37, 2.02). Tract SES and insurance together accounted for 21% of the disparity HR (adjusted HR 1.52, 95% CI: 1.22, 1.88); most of this was due to differences in insurance status, with tract SES accounting for 7% of the disparity when considered in isolation. Tumor biology (RS, PR status and grade) accounted for 30% of the disparity (adjusted HR = 1.41, 95% CI:1.14, 1.75); together, the domains of social determinants and tumor biology accounted for 50% of the disparity HR (adjusted HR = 1.30, 95% CI: 1.04, 1.62). Tumor size and treatment initiation each explained roughly 10% of the disparity HR when considered in isolation but did not account for any of the disparity once other factors were accounted for. Results obtained from additional methods for mediation analyses, including a method of rescaled coefficients and structural equation modeling (SEM) applied to discrete-time survival analysis will also be presented. Conclusions: In this study of node-negative, ER-positive BC, much of the BC survival disparity among US women could be explained by racial differences in measured tumor biology and social determinants of health.
One size does not fit all: Evaluating disparities in lung cancer screening eligibility amongst Hispanic/LatinX and African Americans.
Authors: Olazagasti Coral , Ehrlich Matthew , Kohn Nina , Seetharamu Nagashree
Published: June 2021

6538

Background: Lung cancer (LC) is the leading cause of cancer death among Hispanic men. African Americans (AA) have the highest LC mortality rate in the United States (US). We sought to identify the tendencies for screening eligibility amongst Hispanic/LatinX (H/L) and AA prior to their LC diagnosis according to the National Comprehensive Cancer Network (NCCN) and The United States Preventive Service Task Force (USPSTF) guidelines. Methods: We conducted an observational study in patients diagnosed with LC from 2016 to 2019. Current and former smokers were included in the analysis. Charts were reviewed for demographics, smoking history, family history, personal history of other malignancy, and prior exposures to assess screening their eligibility prior to LC. The chi-square test was used to examine the association between race and ethnicity with each screening criteria. Results: A total of 530 subjects were reviewed, of which 428 were included in the analysis. One hundred and fifty three and 245 subjects were ineligible for NCCN and USPSTF screening criteria prior to their LC diagnosis. Twenty-eight of the subjects failing to meet NCCN criteria identified as AA and 12 as H/L. Forty and 20 of the USPSTF ineligible subjects identified as AA and H/L. There was a significant association between ethnicity and individual screening eligibility, where 52% of H/L met NCCN eligibility compared to 20% of H/L who met USPSTF eligibility (p = 0.0010). There was a significant association between ethnicity and USPSTF criteria (p = 0.0166), as 80% of H/L subjects were screening ineligible under USPSTF criteria compared to 56% of non-Hispanic or other [Table]. Conclusions: In our study, H/L had significant lower tendencies of meeting the USPSTF LC screening eligibility criteria than non-H/L or other. Notably, there was a profound association between ethnicity and eligibility of screening criteria, where a proportionally higher number of H/L who were ineligible under USPSTF criteria met NCCN criteria. These findings suggest that leniency in the screening criteria can possibly lead to earlier detection of lung cancer in high-risk individuals. Our study is in line with developing data that minority individuals at high-risk for lung cancer can be missed, mainly if current USPSTF criteria was to be applied. Recently, USPSTF has modify their criteria which may benefit more of these individuals. To improve rates of screening and overall mortality of minorities, organizations should continue to re-evaluate and liberalize their screening guidelines.[Table: see text]