bluuebunny/crossref_metadata_2025 huggingface dataset:
Defective mismatch repair associated mutational signatures, a prognostic and predictive biomarker in endometrial cancer.
Authors: Chang Yifan Emily , Adjei Naomi N , Khadraoui Wafa , Altwerger Gary
Published: June 2021

5528

Background: Mismatch repair (MMR) deficiency is the distinguishing molecular feature of a significant portion of endometrial cancers (UCEC), and tumors with MMR deficiency have been identified as candidates for immune checkpoint blockade therapy. We studied MMR deficiency in UCEC using defective mismatch repair associated mutational signatures (MMRd-ams). Methods: WES-derived somatic mutation data of 531 UCEC samples from TCGA Pan-Cancer Atlas were analyzed. COSMIC mutational signatures for each sample were calculated using the R package deconstructSigs. MMRd-ams were correlated with clinical and molecular features for 507 TCGA samples (cBioPortal). Samples were divided into High MMRd-ams ( n = 192) and Low MMRd-ams ( n = 315) groups by the average of the representative MMRd-ams (0.2396). Fractions of tumor immune infiltrates were derived from CIBERSORT. Results: A significantly higher percentage of patients (47/192, 24.5%) in the High MMRd group had somatic putative driver mutations in at least 1 of the MMR genes ( MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2 and EPCAM), compared with patients in the Low MMRd group (37/315, 11.8%, p = 0.0003). 15% (54/359) of tumors in the non-MSI subtypes expressed significant MMRd-ams and were categorized in the High MMRd-ams group. Patients in the High MMRd-ams group had longer progression-free survival (PFS) ( p = 0.0457, log-rank). Analysis of the inferred composition of tumor immune infiltrates revealed that the High MMRd-ams group had significantly higher fraction of CD8+ T cells ( p < 0.0001), higher fraction of T follicular helper cells ( p < 0.0001) and lower fraction of M2 macrophages ( p < 0.001). Tumors in the High MMRd-ams group also displayed higher mRNA expression levels of immune checkpoint genes: PDCD1 ( p = 0.0013), and CTLA4 ( p = 0.0016). Conclusions: MMRd-ams may be a prognostic and predictive biomarker with significant clinical impact. High MMRd-ams patients prognostically demonstrated longer PFS. Predictively, high MMRd-ams was associated with increased tumor immune infiltrates and elevated expression levels of CTLA4 and PDCD1 , known immune checkpoint genes exploitable by immune checkpoint therapies. MMRd-ams importantly characterized a subset of patients that were non-MSI but fit the MMR deficient phenotype by mutational signature. Together these findings open an avenue for recognizing and treating a previously unidentifiable group of patients.
A phase I study of mirvetuximab soravtansine (MIRV) and gemcitabine (G) in patients (Pts) with selected frα-positive solid tumors: Results in the ovarian cancer (EC) cohort.
Authors: Cristea Mihaela C. , Ruel Nora H. , Frankel Paul Henry , Synold Timothy W. , Stewart Daphne B. , Wang Edward Wenge , Jung Alex , Wilczynski Sharon , Tran Michael , Konecny Gottfried E. , Eng Melissa , Kilpatrick Lindsay , Chen Yi-Jen , Glaser Scott , Dellinger Thanh Hue , Hakim Amy , Lee Stephen , Morgan Robert , Han Ernest Soyoung
Published: June 2021

5542

Background: Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. MIRV has promising single agent activity in FRα-positive medium/high expression epithelial ovarian cancer (EOC), at 6 mg/kg, based on adjusted ideal body weight (AIBW) IV every (q) 21 days. This study evaluated MIRV and G in recurrent EOC, endometrial and triple negative breast cancer. The recommended phase 2 dose (RP2D) was established at MIRV 6 mg/kg AIBW IV, day 1 and G 800 mg/m2 IV, d1, 8 q21 days (J Clin Oncol 37, 2019, Abs. #3009). Here we report the results from the EOC cohort. Methods: Patients (pts) with FRα-positive platinum resistant EOC with ≤4 prior chemotherapy (CT) regimens, were eligible. FRα positivity was initially defined as ≥ 25% of cells with PS2+ staining intensity (low to high FRα expression) and was subsequently revised to require medium/high FRα expression (≥50%/ ≥75% of cells with PS2+ staining intensity). Results: From 10/2017 to 12/2020, 113 EOC pts underwent FRα screening, with 74 FRα-positive results. Thirty total EOC pts (with median 3 prior lines of therapy) were treated; 8 pts during dose escalation and 22 EOC pts at the RP2D (all evaluable for response). Fifteen (50%) pts had high FRα, 10 pts (33%) medium FRα, and 5 pts (17%) low FRα expression. Eleven (36%) of the 30 EOC pts achieved a partial response (PR), 15 pts (50%) had SD and 4 pts (13%) progressed. Among the 11 responders, 5 pts had high FRα, 4 pts medium FRα and 2 pts low FRα expression. Non-heme clinically significant adverse events (AEs) included: G2 sensory neuropathy (4 pts) G3 diarrhea (3 pts), G3 fatigue (2 pts), G3 pneumonitis (2 pts), and 1 pt with G5 respiratory failure (secondary to pneumonia but drug-induced pneumonitis could not be ruled out). Conclusions: MIRV in combination with G has promising clinical activity in late line platinum resistant FRα-positive EOC, with best responses observed in high FRα expression. The regimen is well tolerated with expected AEs based on the known toxicities of each agent. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by ImmunoGen Corp and Cancer Center Support Grant P30CA033572. Clinical trial information: NCT02996825.
Role of CD10 expression in endometriosis-associated mesenchymal stem cells on the progression of endometriosis-associated carcinoma.
Authors: Atiya Huda , Orellana Taylor , Coffman Lan Gardner
Published: June 2021

5561

Background: Endometriosis-associated carcinomas (EACs) such as ovarian clear cell cancer (OCCC) are rare, aggressive, chemo-resistant malignancies. While endometriosis is a known chronic inflammatory condition, the molecular mechanisms for the malignant transformation of endometriosis is unknown. Mesenchymal stem cells (MSC) are a critical component of the ovarian cancer microenvironment. Cancer cells reprogram MSCs to form carcinoma-associated MSCs (CAMSCs), which promote cancer growth, chemotherapy resistance, and metastases. MSCs are also found within the endometriotic microenvironment. CD10, a surface protein expressed by endometrial stromal cells, is also expressed on endometriosis-associated MSCs (enMSCs). Preliminary data demonstrate CD10 expression is lost in a subset of enMSCs and this loss is correlated with the acquisition of tumor-promoting properties. We hypothesized that the CD10 negative subset of enMSCs behave similarly to CAMSCs and support the growth of OCCC. Methods: EnMSCs were isolated from primary human benign endometriosis deposits involving the ovary or fallopian tubes. Flow cytometry was used to measure surface CD10 expression. We investigated the role of low CD10 enMSCs versus high CD10 enMSCs on OCCC tumor cell growth, chemotherapy resistance and stem-like cell properties in vitro and tumor cell engraftment, growth, and metastases in vivo. Luciferase-expressing OCCC cells were (1) used alone, (2) mixed with low CD10 enMSCs, or (3) mixed with high CD10 enMSCs and injected orthotopically into the ovarian bursa of NSG mice. In vivo imaging system was used to follow tumor progression and metastasis. Results: Our results demonstrated that enMSCs have variable CD10 expression. EnMSCs with low CD10 expression significantly enhanced OCCC proliferation, resistance to cisplatin, and sphere formation compared to OCCC alone. In contrast, high CD10 expressing enMSCs significantly reduce OCCC proliferation and sphere formation. Interestingly, low CD10 enMSCs selectively enhanced OCCC cell growth and had no effect on high grade serious ovarian cancer cell growth. Moreover, a reduction of CD10 expression was observed over time when high CD10 enMSCs were co-cultured with OCCC cells. Our results also showed enhanced tumor engraftment when OCCC cells were co-injected with low CD10 enMSCs to 100% one week post-injection, compared to 40% with OCCC and high CD10 enMSCs and 60% with OCCC alone. Further, mice co-injected with low CD10 enMSCs demonstrated increased metastasis and decreased survival compared to mice co-injected with high CD10 enMSCs. Conclusions: Our results indicate there is a sub population of enMSCs, marked by decreased CD10 expression, which selectively enhances OCCC growth. This highlights the existence of a tumor-promoting stromal cell within endometriosis which may be critical to the formation and propagation of EACs.
A phase 2 trial of talimogene laherparepvec (TVEC) in combination with neoadjuvant chemotherapy for the treatment of nonmetastatic triple-negative breast cancer.
Authors: Soliman Hatem Hussein , Han Hyo S. , Hogue Deanna , Mooney Blaise , Costa Ricardo L , Lee Marie Catherine , Niell Bethany , Williams Angela , Chau Alec , Falcon Shannon , Khakpour Nazanin , Soyano Aixa , Armaghani Avan J. , Weinfurtner Robert J , Hoover Susan , Kiluk John , Rosa Marilin , Fridley Brooke , Khong Hung T. , Czerniecki Brian J.
Published: June 2021

578

Background: TVEC is a modified oncolytic herpes simplex 1 (HSV1) virus currently FDA approved for the treatment of unresectable cutaneous and nodal melanoma. TVEC is designed to preferentially lyse tumor cells over normal tissue to release tumor associated antigens, produces GM-CSF to activate dendritic cells, and stimulates T cells to infiltrate the tumor (TILs). TILs in breast cancer are associated with better response to neoadjuvant chemotherapy (NAC), so we hypothesized that intratumoral TVEC may enhance response to NAC. We report results of a phase 2 trial combining NAC with TVEC in stage 2-3 TNBC. Methods: Stage II-III TNBC pts (N = 37) were to be enrolled into a single arm, optimal Simon 2 stage phase 2 trial with TVEC (10^6 PFU 1st dose then 10^8 PFU x 4 doses) weeks 1,4,6,8,10 + weekly paclitaxel (80mg/m2) IV x 12, followed by dose dense AC (doxorubicin/cyclophosphamide 60/600 mg/m2) IV q2weeks x 4 alone given preoperatively. Primary endpoint was residual cancer burden 0 rate (RCB0). Trial meets primary endpoint with ≥15 RCB0 responses out of 37 evaluable pts, assuming p1 = 45% vs. p0 = 30% with one sided type I error rate at 0.10 and power at 70%. Results: Forty pts were enrolled at Moffitt (5/2018 – 4/2020) and evaluable for safety with 3 pts non-evaluable for efficacy due to incomplete treatment. Study demographics: median age 49 (27-66), 67.5% White, 10% Black, 15% Hispanic, clinical stage II 83% and III 17%, node + 42%. The RCB0 rate = 16/37 (43%, 95% CI 27-61%) and additional 9 pts with RCB-1 (RCB0/1 rate 68%, 95% CI 50-82%). Toxicities did not differ significantly from expected NAC toxicities except for increased brief G1-2 fevers, chills, injection site pains. Four pts had G2-3 thromboembolic events (10%) slightly greater than expected 6% rate on NAC. Conclusions: Addition of TVEC to NAC increased RCB0 rates with manageable toxicities and warrants additional investigation in TNBC. Immune correlates and updated survival data will be presented at the meeting. Clinical trial information: NCT02779855.
Does timing of chemotherapy impact breast satisfaction after breast conservation therapy and mastectomy with immediate reconstruction?
Authors: Pawloski Kate R. , Moo Tracy-Ann , Sevilimedu Varadan , Nelson Jonas A. , Garcia Paula , Kirstein Laurie J. , Morrow Monica , Tadros Audree B.
Published: June 2021

589

Background: Receipt of chemotherapy is associated with decreased postoperative breast satisfaction, but whether timing as neoadjuvant (NAC) versus adjuvant (AC) affects this outcome after breast conservation therapy (BCT) and mastectomy with immediate reconstruction (M-IR) is unclear. Methods: We retrospectively identified patients treated with chemotherapy and breast surgery (BCT and M-IR), from 1/2017-12/2019, who completed ≥ 1 BREAST-Q survey through 12/2020. Mean (standard deviation [SD]) Q-scores for satisfaction with breasts (SATBR) were compared between NAC versus AC groups in BCT and M-IR cohorts, respectively. Higher Q-scores on a 0-100 scale indicate superior satisfaction. A minimum 4-point difference was considered clinically important. Chemotherapy timing and significant covariates on univariate analyses were entered in multivariable linear regressions of 1- and 2-year SABTR. Results: 640 patients had BCT and 602 had M-IR; 210 (33%) BCT patients and 294 (49%) M-IR patients had NAC. Compared with M-IR, SATBR was higher after BCT in both NAC and AC groups, at all postoperative timepoints (Table). Following BCT, SABTR was highest in both NAC and AC groups at 6 months and returned to baseline in the NAC group by year 3. In the M-IR cohort, 331 (55%) patients had radiation and 120 (20%) had complications requiring re-operation or hospitalization. Compared with baseline, mean (SD) Q-scores were substantially lower at 6 months but improved to near baseline at 3 years in both NAC and AC groups. On multivariable analysis, radiation was associated with decreased SABTR at 1 year (Beta, -11; 95% CI, -17, -5.0; p<0.001) and 2 years (Beta, -12; 95% CI, -19, -5.5; p<0.001), as were complications at 1 year (Beta, -6.1; 95% CI, -12, -0.34; p=0.038) but not 2 years (Beta, -5.5; 95% CI, -12, 0.92; p=0.09). After multivariable adjustment, NAC was not significantly associated with 1- or 2-year SABTR after M-IR or BCT. Conclusions: SABTR was higher in BCT compared with M-IR cohorts, independent of chemotherapy timing. Following BCT, SABTR was lower in the NAC group at years 2-3 but remained at baseline or higher at all timepoints. In the M-IR cohort, both groups endorsed lower than baseline SABTR in years 0-2 but returned to near baseline at 3 years. Radiation and complications were independent predictors of decreased SABTR, but our findings suggest that patients who experience complications after M-IR can expect return to baseline breast satisfaction by 2 years.[Table: see text]
Investigating survivin as a novel target in black women with breast cancer.
Authors: Walens Andrea , Olsson Linnea T , Van Alsten Sarah , Carey Lisa A. , Troester Melissa A. , Abdou Yara
Published: June 2021

594

Background: Black women with breast cancer have higher mortality than White women. Differences in tumor biology contribute to racial disparities in breast cancer outcomes. BIRC5 gene encodes survivin, an inhibitor of apoptosis protein, and an independent marker of poor prognosis in breast cancer. Cancer patients have anti-survivin antibodies and circulating survivin-specific T cells, suggesting that survivin may be targetable. Several ongoing antibody-mediated, vaccine strategies that target survivin are being developed. Nevertheless, most survivin studies were conducted in cohorts of White women. To date, the prevalence and/or role of survivin expression in breast tumors from Black women has not been studied. Methods: Associations between BIRC5 expression, clinicopathological and molecular features were measured in the population-based Carolina Breast Cancer Study (CBCS) and The Cancer Genome Atlas (TCGA) breast cancer cohort. Gene expression was measured by Nanostring RNA counting and split into BIRC5 high (4th quartile) and low categories based on log2 gene expression values. Relative frequency differences (RFD) for the association between BIRC5 high and clinicopathologic features were estimated. RNA based p53 mutant status and homologous recombination deficiency (HRD) status were included in RFD analysis. Receiver operating characteristic (ROC) curves were used to illustrate the potential of BIRC5 expression to distinguish patients who achieved pathological complete response (pCR) after receiving neoadjuvant chemotherapy in CBCS (133 Black, 49 non-Black). Results: BIRC5 gene expression was significantly increased in tumors from 966 Black patients compared to 1,497 non-Black (p < 0.00001), adjusting for stage and subtype. BIRC5 high tumors were significantly more expressed in higher stage and basal-like breast cancer subtypes. BIRC5 high tumors were also significantly enriched for expression of genes involved in p53 loss and HRD. Furthermore, in an analysis of 182 CBCS patients, BIRC5 gene expression alone predicted pCR with similar overall AUC to ROR-PT multigene signatures (AUC 0.62 vs 0.64). Conclusions: Our study shows that survivin expression is particularly high in breast tumors from Black women. This was associated with more aggressive clinicopathological features in addition to p53 mutant and HRD status. Black women with breast cancer represent an area of unmet clinical need and could potentially benefit from anti-survivin targetable treatment strategies. Further studies are needed to help close this gap which constitutes the largest disparity among cancer-specific diseases.[Table: see text]
Efficacy of concurrent cetuximab (CTX) and nivolumab (NIVO) in previously untreated recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
Authors: Chung Christine H. , Saba Nabil F. , Steuer Conor Ernst , Li Jiannong , Bhateja Priyanka , Johnson Matthew , Masannat Jude , Poole Maria , Hoening Dirk , Song Feifei , Hernandez-Prera Juan C. , Molina Helen , Wenig Bruce , Farinhas Joaquim , Kish Julie Ann , Muzaffar Jameel , Kirtane Kedar , Rocco James William , Schell Michael J. , Bonomi Marcelo Raul
Published: June 2021

6017

Background: Current standard of care for patients (pts) with previously untreated R/M HNSCC that are incurable is either pembrolizumab (pembro) with/without chemotherapy depending on the Programmed Death-Ligand 1 (PD-L1) combined positive score (CPS). We evaluated the combination of CTX and NIVO for its efficacy. Methods: Pts were treated with CTX 500 mg/m2 IV on Day (D) -14 as a lead-in followed by CTX 500 mg/m2 IV and NIVO 240 mg/m2 IV on D1 and D15 every 28-D cycle (C). Pts with CTX infusion reaction or who did not receive C1D1 for any reason were non-evaluable and replaced. NIVO dose reduction was not allowed. Results: Fifty-four evaluable pts were analyzed. Median age was 62 (42-85). ECOG performance status at baseline was 0 (20, 37%), 1 (30, 56%), and 2 (4, 7%). Primary sites were oral cavity 19 (35%), oropharynx 22 (41%), hypopharynx 3 (6%), larynx 9 (17%), and unknown primary 1 (2%). p16 status is positive 22 (41%), negative 29 (54%), and unknown 3 (6%). PD-L1 CPS is < 1 in 6 (11%), >1 in 26 (48%), and unknown 22 (41%). Median follow up time for overall survival (OS) was 12.2 months. The most common grade 3 treatment-related adverse events (TRAEs) occurring in ≥2 pts were hypomagnesemia 2 (4%), hypophosphatemia 2 (4%), fatigue 4 (7%), and rash-acneiform 4 (7%). The only grade 4 TRAEs were hypomagnesemia in 1 (2%) and CTX infusion reaction in 1 (2%). The most common grade 3 immune-related adverse event (IRAE) occurring in ≥2 was fatigue 2 (4%). No grade 4 IRAEs is observed. Median progression-free survival (PFS) and OS were 7.8 and 14.5 months, while 1-year PFS and 1-year OS were 39% and 61%, respectively. There were no statistically significant differences in either PFS and OS based on tumor p16 or PD-L1 status. Conclusions: The clinical trial met its primary endpoint of 1-year OS. Our data indicate the combination of CTX and NIVO is safe and effective in pts with previously untreated incurable R/M HNSCC. Clinical trial information: NCT03370276.
Anlotinib in radioiodine-refractory differentiated thyroid carcinoma: A subanalysis based on ALTER01032 study for patients with poor baseline characteristics.
Authors: Chi Yihebali , Gao Ming , Zhang Yuan , Shi Feng , Cheng Ying , Guo Zhuming , Ge Minghua , Qin Jianwu , Zhang Jiewu , Li Zhendong , Zhou Xiaohong , Huang Rui , Chen Xiaohong , Liu Hui , Cheng Ruochuan , Xu Zhengang , Zheng Xiangqian , Li Dapeng , Tang Pingzhang
Published: June 2021

6022

Background: Anlotinib (anlo), a multikinase inhibitor, has demonstrated a significant survival benefit in treating locally advanced or metastatic radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC) with a nearly 4 folds prolongation in median progression-free survival (mPFS) (HR = 0.21, p < 0.0001) compared with placebo in a randomized, placebo-controlled phase 2 study (ALTER01032, NCT02586337). Older age, bone metastasis, structural progression within a short time are generally indicated as negative prognostic factors for thyroid cancer. This subanalysis explored the outcomes of patients (pts) enrolled in ALTER01032 study with these poor baseline characteristics. Methods: 113 pts were enrolled, 76 in anlo arm and 37 in placbo arm. The primary endpoint is PFS. Pts with older age (≥ 55), bone metastasis or radiographic documented disease progression within 3 months (mo) before enrollment were selected. The PFS and overall survival (OS) for these pts were estimated and compared. Since 64.9% pts in placebo arm received crossover treatment with open label anlo after progression while only 3 pts in anlo arm received post-study treatment, the penitential bias for OS from imbalance of subsequent treatment was adjusted by a two-stage estimation method. Results: The results of subanalysis were summarized in the table below. Pts with poor baseline characteristics showed higher risk of progression and death. Significant PFS prolongation was shown across all subgroups in pts received anlo compared with their counterparts who received placebo ( P < 0.05). In pts with bone metastasis or structural progression within 3 mo, anlo treatment achieved significant OS benefit ( P < 0.05). Also, in older pts, a trend of OS improvement was observed (HR = 0.85 (95% CI 0.37, 1.97)). Most pts in placebo arm received crossover anlo. After adjustment, a near-significant decrease of death risk was observed in older pts received anlo compared with those received placebo (HR = 0.48 (95% CI 0.20, 1.13)). Conclusions: This subanalysis showed anlo effectively improved both PFS and OS of pts with RAIR-DTC who have poor baseline characteristics above. Interestingly, although most pts in placebo arm received crossover anlo, they still have higher risk of death, indicating the importance of earlier treatment for these pts. Clinical trial information: NCT02586337. [Table: see text]
Phase II trial of combined durvalumab plus tremelimumab with proton therapy to boost the abscopal effect for recurrent or metastatic head and neck squamous cell carcinoma.
Authors: Kim Hana , Ahn Myung-Ju , Oh Dongryul , Park Sehhoon , Jung Hyun Ae , Lee Se-Hoon , Park Keunchil , Ahn Yong Chan
Published: June 2021

6034

Background: This phase 2 study investigated whether durvalumab plus tremelimumab with proton therapy improves objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) in heavily treated recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) via boosting abscopal effect. Methods: Thirty-one patients who have previously received more than one chemotherapy regimen, including at least one platinum-based regimen and have at least two measurable lesions enrolled at Samsung medical center. Patients received durvalumab 1500mg intravenously (IV) in combined with tremelimumab 75 mg IV every four weeks for four cycles followed by durvalumab 1500mg every four weeks. After one cycle of durvalumab and tremelimumab combination, proton therapy was performed with a total dose of 25 Gy in 5-Gy daily fractions to one of the measurable lesions. We assessed the target lesion response outside the radiation field by RECIST criteria 1.1 to evaluate the abscopal effect. Results: Between March 2018 and July 2020, 31 patients were enrolled. The median age was 59 years, and median two prior chemotherapy regimens were administered. With 24.8 months of follow-up, the median number of cycles of immunotherapy was three. The ORR was 27.3%, including one complete response and five partial responses. Median OS was 6.4 months (95% CI, 1.0 to 11.8), and median PFS was 2.4 months (95% CI, 0.6 to 4.2). Median duration of response was 15.9 months (range 3.7 – 21.2). Grade 3 or higher adverse events were observed in 6 (27.3%) patients; anemia (n = 1), constipation (n = 1), electrolyte imbalance (n = 2), hyperglycemia (n = 1), pneumonia (n = 1). Conclusions: Combination of durvalumab/tremelimuab with proton therapy is well tolerable and shows encouraging anti-tumor efficacy in non-irradiated tumor lesions of heavily treated HNSCC patients. These results suggest that the combination of immunotherapy with proton therapy might enhance the abscopal effect. Clinical trial information: NCT03450967.
Racial and regional differences in incidence of oropharyngeal cancer in the United States during 2001 to 2017.
Authors: Guo Fangjian , Chang Mihyun , Berenson Abbey
Published: June 2021

6041

Background: The incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has been reported to be increasing among both middle-aged and elderly adults in the United States. This study was to assess racial and regional differences in the incidence of OPSCC among adults in the US. Methods: We included 271,037 adult patients ≥ 20 years old diagnosed with potentially HPV-related OPSCC from the US Cancer Statistics 2001–2017 database which essentially covered the entire US population. Incidence of OPSCC was age- adjusted to the US standard population. Annual percentage change (APC) in the incidence was assessed across races/ethnicities and regions of residence. Results: Among these adults with potentially HPV-related OPSCC from 2001-2017, 5.3% were Hispanics, 83.0% were non-Hispanic Whites, and 9.2% were non-Hispanic Blacks, and 79.1% were male. Incidence of OPSCC increased from 3.9 per 100,000 in 2001 to 4.0 per 100,000 in 2017 (APC 0.43, 95% confidence interval (CI) 0.01, 0.85) in Hispanics, increased from 5.3 per 100,000 in 2001 to 8.6 per 100,000 in 2017 (APC 2.97, 95% confidence interval (CI) 2.71, 3.24) in non-Hispanic Whites, and decreased from 6.3 per 100,000 in 2001 to 5.1 per 100,000 in 2017 (APC -1.27, 95% confidence interval (CI) -1.56, -0.99) in non-Hispanic Blacks. The incidence increased from 5.8 per 100,000 in 2001 to 7.8 per 100,000 in 2017 (APC 1.94, 95% confidence interval (CI) 1.67, 2.21) in the South, increased from 5.0 per 100,000 in 2001 to 7.1 per 100,000 in 2017 (APC 2.13, 95% confidence interval (CI) 1.92, 2.34) in the Northeast, increased from 4.9 per 100,000 in 2001 to 6.3 per 100,000 in 2017 (APC 1.85, 95% confidence interval (CI) 1.53, 2.17) in the West, and increased from 4.9 per 100,000 in 2001 to 7.7 per 100,000 in 2017 (APC 2.79, 95% confidence interval (CI) -2.52, 3.07) in the Midwest. The incidence decreased from 0.9 per 100,000 in 2001 to 0.8 per 100,000 in 2017 (APC -0.81, 95% confidence interval (CI) -1.41, -0.20) among adults 20-44 years old, increased from 9.0 per 100,000 in 2001 to 12.7 per 100,000 in 2017 (APC 2.01, 95% confidence interval (CI) 1.66, 2.36) among adults 45-64 years old, and increased from 10.9 per 100,000 in 2001 to 16.7 per 100,000 in 2017 (APC 2.96, 95% confidence interval (CI) 2.75, 3.16) among adults 65+ years old. Conclusions: OPSCC incidence increased across racial/ethnic groups, regions, and age groups from 2001 to 2017, except that the incidence decreased among non-Hispanic Blacks and young people. Underlying causes for the decreasing trend in the incidence of OPSCC among certain groups need further investigation.
Palbociclib (P) in patients (pts) with head and neck cancer (HNC) with CDKN2A loss or mutation: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Pisick Evan P. , Rothe Michael , Mangat Pam K. , Garrett-Mayer Liz , Worden Francis P. , Bauman Jessica R. , Fu Siqing , Leidner Rom S. , Balmanoukian Ani Sarkis , Calfa Carmen , Carrizosa Daniel R. , D'Andre Stacy D. , Nabell Lisle , Park Min S. , Powell Steven Francis , Thota Ramya , Schilsky Richard L.
Published: June 2021

6043

Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of HNC pts with CDKN2A loss or mutation treated with P are reported. Methods: Eligible pts had advanced HNC, no standard treatment options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received P at 125 mg orally once daily for 21 days, followed by 7 days off until disease progression. Pts matched to P had CDKN2A loss or mutation and no RB mutations. Simon 2-stage design tested the null disease control (DC) - defined as partial (PR), complete response (CR) or stable disease at 16+ weeks (SD 16+) - rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: 28 pts (64% male) with HNC with CDKN2A loss (20 pts) or mutation (8 pts) were enrolled from June 2016 to Sept 2019. All were eligible for efficacy and toxicity. Demographics and outcomes are summarized in Table. No objective response (OR) and 10 pts with SD16+ (9 with CDKN2A loss, 1 with mutation) were observed for a DC rate of 37% (95% CI: 21%, 50%); the null DC rate of 15% was rejected (p=0.005). 14 pts had at least one grade 3-5 adverse or serious adverse event (AE/SAE) at least possibly related to P with the most common being low WBC/platelets. Other grade 3-4 AEs included anemia, fatigue, hypocalcemia, and syncope. There was one pt with grade 5 respiratory failure likely due to extensive lung metastases and aspiration but P-related pneumonitis could not be ruled out. Conclusions: Monotherapy P demonstrated modest anti-tumor activity and clinically significant AEs in heavily pre-treated pts with HNC with CDKN2A loss or mutation. Additional study is warranted to confirm the efficacy of P in pts with HNC with CDKN2A loss or mutation. Clinical trial information: NCT02693535. [Table: see text]
Capecitabine maintenance therapy after induction chemotherapy in newly diagnosed metastatic nasopharyngeal carcinoma: An open-label, randomized, controlled, phase trial.
Authors: Liu Guo-Ying , Li Wang-Zhong , Wang De-Shen , Liang Hu , Lv Xing , Ye Yan-Fang , Zhao Chong , Ke Liang-Ru , Qiang Mengyun , Cao Xun , Lv Shu-Hui , Lu Nian , Bei Wei-Xin , Cai Zhuocheng , Chen Xi , Xie Jun-Zhi , Liang Chixiong , Guo Xiang , Xia Weixiong , Yanqun Xiang
Published: June 2021

6044

Background: Capecitabine maintenance therapy improves outcomes in various tumor types, but minimal data are available on the effect of capecitabine maintenance therapy in metastatic nasopharyngeal carcinoma (NPC). We aimed to investigate whether capecitabine maintenance therapy would prolong the progression-free survival (PFS) of newly diagnosed metastatic NPC, in comparison to best supportive care (BSC). Methods: This was an open-label, randomized, controlled, phase trial. Eligible patients for maintenance randomisation were aged 18-65 years old with newly diagnosed metastatic NPC at the Sun Yat-Sun University Cancer Center (SYSUCC), had completed 4 to 6 cycles of induction chemotherapy as per protocol and had achieved disease control to protocol treatment, including capecitabine. Patients were randomly assigned 1:1 to capecitabine maintenance (oral 1,250 mg/m2/day on days 1-14 every 21 days) for up to 24 months with BSC or BSC alone. The primary endpoint was PFS. The secondary endpoints included overall survival, duration of response, objective response rate and adverse effects. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02460419 and is ongoing and no longer recruiting new patients. Results: Between May 16th, 2015, and January 9th, 2020, 140 metastatic NPC patients were screened, and 104 eligible patients were randomly assigned to capecitabine maintenance plus BSC (n = 52) or BSC alone (n = 52). After a median follow-up of 33.1 months (IQR, 21.5-50.7 months), median PFS was 35.2 months in the capecitabine maintenance group and 9.1 months in the BSC group (HR: 0.426; 95%CI: 0.248-0.731, P = 0.001). The most commongrade 3 or 4 adverse events during maintenance therapy were hand-foot syndrome (10.0%), nausea/vomiting (6.0%), fatigue (4.0%), and mucositis (4.0%). Totally 37 deaths occurred during follow-up, 14 (26.9%) in the capecitabine maintenance group and 23 (44.2%) in the BSC group. Overall survival data was immature. No deaths in the capecitabine maintenance group were deemed treatment related. Conclusions: Capecitabine maintenance significantly improved PFS in patients with newly diagnosed metastatic NPC who achieved disease control after induction chemotherapy compared to BSC and exhibited low grade and manageable toxicities. Clinical trial information: NCT02460419.
Refining TNM-8 M1 categories with anatomic subgroups for previously untreated de novo metastatic nasopharyngeal carcinoma.
Authors: Chan Sik-Kwan , Lin Cheng , Huang Shao Hui , Chau Tin Ching , Guo Qiaojuan , O'Sullivan Brian , Lam Ka-On , Chau Sze Chun , Chan Ann SY , Tong Chi-Chung , Vardhanabhuti Varut , Kwong Dora LW , So Tsz Him , Ng Sherry CY , Leung To Wai , Luk Mai-Yee , Lee Anne WM , Choi Cheuk-Wai , Pan Jianji , Lee Victor Ho-Fun
Published: June 2021

6046

Background: The eighth edition TNM (TNM-8) classified de novo metastatic (metastatic disease at presentation) nasopharyngeal carcinoma (NPC) as M1 without further subdivision. However, survival heterogeneity exists and long-term survival has been observed in a subset of this population. We hypothesize that certain metastatic characteristics could further segregate survival for de novo M1 NPC. Methods: Patients with previously untreated de novo M1 NPC prospectively treated in two academic institutions (The University of Hong Kong [n = 69] and Provincial Clinical College of Fujian Medical University [n = 114] between 2007 and 2016 were recruited and re-staged based on TNM-8 in this study. They were randomized in 2:1 ratio to generate a training cohort (n = 120) and validation cohort (n = 63) respectively. Univariable and multivariable analyses (MVA) were performed for the training cohort to identify the anatomic prognostic factors of overall survival (OS). We then performed recursive partitioning analysis (RPA) which incorporated the anatomic prognostic factors identified in multivariable analyses and derived a new set of RPA stage groups (Anatomic-RPA groups) which predicted OS in the training cohort. The significance of Anatomic-RPA groups in the training cohort was then validated in the validation cohort. UVA and MVA were performed again on the validation cohorts to identify significant OS prognosticators. Results: The training and the validation cohorts had a median follow-up of 27.2 months and 30.2 months, respectively, with the 3-year OS of 51.6% and 51.1%, respectively. Univariable analysis (UVA) and multivariable analysis (MVA) revealed that co-existing liver and bone metastases was the only factor prognostic of OS. Anatomic-RPA groups based on the anatomic prognostic factors identified in UVA and MVA yielded good segregation (M1a: no co-existing liver and bone metastases and M1b: co-existing both liver and bone metastases; median OS 39.5 and 23.7 months respectively; P =.004). RPA for the validation set also confirmed good segregation with co-existing liver and bone metastases (M1a: no co-existing liver and bone metastases and M1b: co-existing liver and bone metastases), with median OS 47.7 and 16.0 months, respectively; P =.008). It was also the only prognostic factor in UVA and MVA in the validation cohort. Conclusions: Our Anatomic-RPA M1 stage groups with anatomical factors provided better subgroup segregation for de novo M1 NPC. The study results provide a robust justification to refine M1 categories in future editions of TNM staging classification.
Planned drug holiday in a cohort study exploring the effect of lenvatinib on differentiated thyroid cancer.
Authors: Tahara Makoto , Takami Hiroshi , Ito Yasuhiro , Okamoto Takahiro , Sugitani Iwao , Sugino Kiminori , Takahashi Shunji , Takeyama Hiroshi , Tsutsui Hidemitsu , Hara Hisato , Mitsuma Ayako , Yamashita Hiroyuki , Ohashi Yasuo , Imai Tsuneo
Published: June 2021

6070

Background: Lenvatinib is now available for unresectable radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). However, toxicities are considerable and require frequent dose interruption and modification. Recently, planned drug holidays, which are dose interruptions in accordance with the timing of severe or intolerable adverse events, have been proposed to avoid severe adverse events due to lenvatinib (Tahara M.ESMO Open 2018). Our retrospective study demonstrated that progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who used planned drug holidays than those who did not (Matsuyama C et.al, 2020 Annual Meeting of the Japan Association of Endocrine Surgeons). Methods: In this prospective observational study, patients with curatively unresectable and progressive RAI-refractory DTC were treated with lenvatinib in a real-world clinical setting. Lenvatinib was administered orally at a dose of 24 mg daily. Dose modification for toxicities were permitted. Primary endpoint was OS, and secondary endpoints were time to treatment failure (TTF), time to failure of strategy (TFS), PFS with clinical progressive disease, response rate, quality of life, safety, and patient reports. This study was registered with UMIN Clinical Trials Registry (UMIN000022243). Results: 262 patients were accrued. Of 255 evaluable, 153 were female; median age was 70 (range 27.0-88.0); histology was papillary thyroid carcinoma/follicular thyroid carcinoma/poorly DTC in 204/45/4; previous therapy was surgery/RAI/molecular targeted drug in 246/164/14; reason for initiation of lenvatinib was disease progression/unsuitable for RAI in 241/4. 1-year OS was 85.6% (95%CI: 80.6-89.4%); 1-year TTF rate was 74.9% (95%CI: 69.1-79.8%); 1-year TFS rate was 80.8% (95%CI: 75.4-85.2%); and 1-year PFS rate was 84.4% (95%CI: 79.3-88.4%). Overall response by RECIST was 3 (1.2%) in CR and 151 (61.9%) in PR. Most common grade 3 or 4 toxicities were hypertension (61.4%), hand foot syndrome (10.2%), fatigue (9.1%), anorexia (8.3%) and diarrhea (4.7%). Grade 5 toxicities occurred in 4 patients (fistula, hypoxia, respiratory failure, trachea stenosis). Of 253 patients evaluable for efficacy, 73 used planned drug holidays. TTF, TFS and PFS were significantly longer in patients who used planned drug holiday than those who did not (Table). Conclusions: Planned drug holiday for lenvatinib demonstrated significantly better clinical outcomes, including TTF, TFS and PFS, than daily oral administration. These data further support use of a planned drug holiday in RAI-refractory DTC patients receiving lenvatinib. Clinical trial information: 000022243. [Table: see text]
Efficacy of selpercatinib after prior systemic therapy in patients with RET mutant medullary thyroid cancer.
Authors: Wirth Lori J. , Sherman Eric Jeffrey , Weiler Daniela , Cabanillas Maria E. , Robinson Bruce , Italiano Antoine , Laskin Janessa J. , Subbiah Vivek , Drilon Alexander E. , Soldatenkova Victoria , French Pearl Plernjit , Wright Jennifer , Kroiss Matthias , Shah Manisha H.
Published: June 2021

6074

Background: Selpercatinib is a first-in-class, CNS active, highly selective, and potent RET kinase inhibitor which has demonstrated durable antitumor activity in patients (pts) with RET altered thyroid cancer and is approved in multiple countries for the treatment of RET fusion+ lung or thyroid cancers. As response rates to cancer therapy usually decline on subsequent lines of therapy, the efficacy of selpercatinib was examined in the context of the last prior therapy received before trial enrollment. Methods: Pts with RET mutant medullary thyroid cancer (MTC) previously treated with multikinase inhibitors (cabozantinib and/or vandetanib) were enrolled in the global LIBRETTO-001 trial (NCT03157128). This post-hoc exploratory intrapatient analysis, based on March 30, 2020 data cutoff date, was performed to compare the retrospective physician-reported objective response rate (ORR) from the last systemic therapy prior to enrollment, as reported in pts case reports, to ORR by independent review committee per RECIST 1.1 with selpercatinib treatment, with each patient serving as his/her own control. Results: Efficacy-evaluable pts, 64% male, 90% white with a median age of 58 years, received prior therapy for MTC (n = 143). Pts had a median of 2 (range 1-8) prior systemic regimens. The ORR on selpercatinib (69%) was markedly higher than for the last prior therapy (10%) received before enrollment. ORR improvements with selpercatinib were observed regardless of prior therapy: cabozantinib (66% vs 14%) or vandetanib (71% vs 12%). Fewer pts had progressive disease as their best overall response with selpercatinib (2/143; 1.4%) compared to last prior therapy (33/143; 23.1%). Notably selpercatinib achieved 62% ORR in pts that did not respond to their previous line of therapy prior to enrolment. This shift from non-responder to responder on selpercatinib therapy was consistent regardless of prior cabozantinib or vandetanib treatment, where pts achieved 57% and 61% ORR respectively when subsequently treated with selpercatinib. In contrast, only 3% of patients did not respond to selpercatinib after a previous response to the immediate prior therapy. Similarly, 5% and 2% of patients were non-responders on selpercatinib after a prior response with cabozantinib and vandetanib therapy respectively. Conclusions: Prior to selpercatinib, response with previous multikinase therapy was rare. By contrast, selpercatinib demonstrated robust efficacy regardless of response to or specific prior therapy in pts with RET mutant MTC. Clinical trial information: NCT03157128.
The impact of the COVID-19 pandemic on stage at diagnosis of breast and colorectal cancers.
Authors: Zhou Jade , Kane Shelly , Ramsey Celia , Akhondzadeh Melody Ann , Banerjee Ananya , Shatsky Rebecca Arielle , Gold Kathryn A.
Published: June 2021

6501

Background: Effective cancer screening leads to a substantial increase in the detection of earlier stages of cancer, while decreasing the incidence of later stage cancer diagnoses. Timely screening programs are critical in reducing cancer-related mortality in both breast and colorectal cancer by detecting tumors at an early, curable stage. The COVID-19 pandemic resulted in the postponement or cancellation of many screening procedures, due to both patient fears of exposures within the healthcare system as well as the cancellation of some elective procedures. We sought to identify how the COVID-19 pandemic has impacted the incidence of early and late stage breast and colorectal cancer diagnoses at our institution. Methods: We examined staging for all patients presenting to UCSD at first presentation for a new diagnosis of malignancy or second opinion in 2019 and 2020. Treating clinicians determined the stage at presentation for all patients using an AJCC staging module (8th edition) in the electronic medical record (Epic). We compared stage distribution at presentation in 2019 vs 2020, both for cancers overall and for colorectal and breast cancer, because these cancers are frequently detected by screening. Results: Total numbers of new patient visits for malignancy were similar in 2019 and 2020 (1894 vs 1915 pts), and stage distribution for all cancer patients was similar (stage I 32% in 2019 vs 29% in 2020; stage IV 26% in both 2019 and 2020). For patients with breast cancer, we saw a lower number of patients presenting with stage I disease (64% in 2019 vs 51% in 2020) and a higher number presenting with stage IV (2% vs 6%). Similar findings were seen in colorectal cancer (stage I: 22% vs 16%; stage IV: 6% vs 18%). Conclusions: Since the COVID-19 pandemic, there has been an increase in incidence of late stage presentation of colorectal and breast cancer, corresponding with a decrease in early stage presentation of these cancers at our institution. Cancer screening is integral to cancer prevention and control, specifically in colorectal and breast cancers which are often detected by screening, and the disruption of screening services has had a significant impact on our patients. We plan to continue following these numbers closely, and will present data from the first half of 2021 as it becomes available.
A successful model of biosimilar adoption in a community oncology practice.
Authors: Wilfong Lalan S. , Dave Neal , Garey Jody S. , Toth Sara , Schwartz Jim R. , Ortega Lance , Sellers Chris , Brooks Barry Don
Published: June 2021

6514

Background: The emergence of biosimilars creates an opportunity for more cost-effective treatment. Utilization of biologics in cancer care has increased and accounts for 70% of oncologic drug spending growth from 2010 to 2015. Biosimilars can play a vital role in controlling this rapid rise in cost. Practices focused on Value Based Care arrangements, such as the Oncology Care Model, can reduce total cost of care by increasing utilization of biosimilars. The process of interchange is complicated by the designation of each biosimilar which prevents simple interchange. Communication with physicians and the healthcare team along with patient education and consent must be performed. We describe a successful model for therapeutic interchange of brand drugs to biosimilars. Methods: Texas Oncology elected to increase utilization of biosimilars in 2020. We collaborated with McKesson Specialty Health to create educational materials for patients and clinical staff. Communication was sent to all personnel about the therapeutic interchange process. A central pharmacy team reviewed all new orders and substituted a biosimilar for brand, unless a payer insisted on origin drug or a biosimilar not in the practice formulary. Additionally, a report was generated weekly of all existing patients who would benefit from switching. The pharmacists, upon consultation with the physician, then substituted a biosimilar for brand drug. Patients were then educated and re-consented. We started with rituximab in 07/2020 followed by bevacizumab in 09/2020 then trastuzumab in 10/2020. Results: The table below shows our conversion rate for all administrations. We were able to increase utilization of biosimilars from January of 2020 to December of 2020 from 5% to 80% for Rituximab, 9% to 88% for bevacizumab and 8% to 74% for trastuzumab. Based on average ASP for a 70 kg patient, the potential savings per administration is $550 for bevacizumab, $850 for trastuzumab, and $1400 for rituximab. In one month alone, this project dramatically reduced cost by $4 million or 21% by conversion to these three biosimilars. Additional savings can be realized with the use of biosimilar multi-dose vials vs single dose vials. Conclusions: Our comprehensive team approach successfully deploys therapeutic interchange of biosimilars for brand drugs in a community oncology practice which leads to substantial cost savings. This has real implications in controlling the total cost of care.[Table: see text]