Imaging approaches to assess the therapeutic response of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): current perspectives and future trends of an exciting field in development

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a family of neoplasms with a complex spectrum of clinical behavior. Although generally more indolent than carcinomas, once they progress beyond surgical resectability, they are essentially incurable. Systemic treatment options have substantially expanded in recent years for the management of advanced disease. Imaging plays a major role in new drug development, as it is the main tool used to objectively evaluate response to novel agents. However, current standard response criteria have proven suboptimal for the assessment of the antiproliferative effect of many targeted agents, particularly in the context of slow-growing tumors such as well-differentiated NETs. The aims of this article are to discuss the advantages and limitations of conventional radiological techniques and standard response assessment criteria and to review novel imaging modalities in development as well as alternative cancer- and therapy-specific criteria to assess drug efficacy in the field of GEP-NETs

Cabozantinib plus Atezolizumab in Advanced, Progressive Endocrine Malignancies: A Multicohort, Basket, Phase II Trial (CABATEN/GETNE-T1914)

Cabozantinib; Atezolizumab; Advanced progressive endocrine malignanciesCabozantinib; Atezolizumab; Neoplasias endocrinas avanzadas y progresivasCabozantinib; Atezolizumab; Neoplàsies endocrines avançades i progressivesPurpose: Multikinase inhibitors have shown efficacy in endocrine neoplasms, and synergism with immune checkpoint inhibitors has been noted in other tumors. Patients and Methods: This is a prospective, multicenter, open-label, Simon two-stage optimal design, phase II study including patients with advanced and refractory endocrine and neuroendocrine neoplasms in six cohorts: lung well-differentiated neuroendocrine tumors, anaplastic thyroid cancer (ATC), adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PPGL), well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NET), and grade 3 extrapulmonary neuroendocrine neoplasms. Patients received atezolizumab 1,200 mg intravenously every 3 weeks plus cabozantinib 40 mg/day orally until disease progression or unacceptable toxicity. The primary objective was the overall response rate (ORR) by RECIST 1.1. Results: From October 2020 to December 2022, 93 patients were included. The ORR was 14.3% [95% confidence interval (CI), 1.8–42.8] in ATC (N = 14); 8.3% (95% CI, 1.0–27.0) in ACC (N = 24); 15.4% (95% CI, 1.9–45.5) in PPGL (N = 13), and 16.7% (95% CI, 4.7–37.4) in GEP-NET (N = 24). Lung well-differentiated neuroendocrine tumors and grade 3 extrapulmonary neuroendocrine neoplasms had no responses. The duration of response was 20.4 months in ATC, 13.1 months in ACC, 12.2 months in PPGL, and 15.8 months in GEP-NET. Survival rates at 12 months in ATC and ACC were 47.6% and 47.6%, respectively. No unexpected toxicity was observed. Conclusions: Cabozantinib and atezolizumab were safely administered and showed promising ORR, and preliminary long-term survival rates were observed in aggressive and pretreated ACC and ATC, which warrants further investigation.This work was supported by the Grupo Español de Tumores Neuroendocrinos y Endocrinos. Roche provided atezolizumab, whereas Ipsen supplied cabozantinib and awarded a grant to Grupo Español de Tumores Neuroendocrinos y Endocrinos to cover the costs of the study. The funders have no role in the design, conduct, or analysis of the study. The authors thank all patients and families, investigators, and study staff involved in the CABATEN trial; special thanks to the MFAR Clinical Research team for their support in regulatory, monitoring, and quality assurance activities; Pau Doñate, Ph.D., and Fanny Rubio, Ph.D., for their assistance with manuscript and language editing; and Oriol Prat M.S. for his statistical support

Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin

Cancer immunotherapy; Neuroendocrine cancer; Tumour immunologyImmunoteràpia del càncer; Càncer neuroendocrí; Immunologia tumoralInmunoterapia del cáncer; Cáncer neuroendocrino; Inmunología tumoralSingle immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS.This work was supported by the Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE). AstraZeneca provided durvalumab and tremelimumab and awarded a grant to GETNE to pay the costs of the study. The funder did not have a role in designing or conducting the study. The authors thank all patients and families, investigators and study staff involved in the DUNE trial; the MFAR Clinical Research team for regulatory, monitoring, and quality assurance activities; Pau Doñate PhD for manuscript and language editing; and Jordi Curto M.Sc. and Arturo Alvarez PhD for statistical support

Prevalence of Homologous Recombination Deficiency Among Patients With Germline RAD51C/D Breast or Ovarian Cancer

Prevalence; Homologous recombination deficiency; Breast cancerPrevalença; Deficiència de recombinació homòloga; Càncer de mamaPrevalencia; Deficiencia de recombinación homóloga; Cáncer de mamaImportance RAD51C and RAD51D are involved in DNA repair by homologous recombination. Germline pathogenic variants (PVs) in these genes are associated with an increased risk of ovarian and breast cancer. Understanding the homologous recombination deficiency (HRD) status of tumors from patients with germline PVs in RAD51C/D could guide therapeutic decision-making and improve survival. Objective To characterize the clinical and tumor characteristics of germline RAD51C/D PV carriers, including the evaluation of HRD status. Design, Setting, and Participants This retrospective cohort study included 91 index patients plus 90 relatives carrying germline RAD51C/D PV (n = 181) in Spanish hospitals from January 1, 2014, to December 31, 2021. Genomic and functional HRD biomarkers were assessed in untreated breast and ovarian tumor samples (n = 45) from June 2022 to February 2023. Main Outcomes and Measures Clinical and pathologic characteristics were assessed using descriptive statistics. Genomic HRD by genomic instability scores, functional HRD by RAD51, and gene-specific loss of heterozygosity were analyzed. Associations between HRD status and tumor subtype, age at diagnosis, and gene-specific loss of heterozygosity in RAD51C/D were investigated using logistic regression or the t test. Results A total of 9507 index patients were reviewed, and 91 patients (1.0%) were found to carry a PV in RAD51C/D; 90 family members with a germline PV in RAD51C/D were also included. A total of 157 of carriers (86.7%) were women and 181 (55.8%) had received a diagnosis of cancer, mainly breast cancer or ovarian cancer. The most prevalent PVs were c.1026+5_1026+7del (11 of 56 [19.6%]) and c.709C>T (9 of 56 [16.1%]) in RAD51C and c.694C>T (20 of 35 [57.1%]) in RAD51D. In untreated breast cancer and ovarian cancer, the prevalence of functional and genomic HRD was 55.2% (16 of 29) and 61.1% (11 of 18) for RAD51C, respectively, and 66.7% (6 of 9) and 90.0% (9 of 10) for RAD51D. The concordance between HRD biomarkers was 91%. Tumors with the same PV displayed contrasting HRD status, and age at diagnosis did not correlate with the occurrence of HRD. All breast cancers retaining the wild-type allele were estrogen receptor positive and lacked HRD. Conclusions and Relevance In this cohort study of germline RAD51C/D breast cancer and ovarian cancer, less than 70% of tumors displayed functional HRD, and half of those that did not display HRD were explained by retention of the wild-type allele, which was more frequent among estrogen receptor–positive breast cancers. Understanding which tumors are associated with RAD51C/D and HRD is key to identify patients who can benefit from targeted therapies, such as PARP (poly [adenosine diphosphate–ribose] polymerase) inhibitors.This work was funded by Fundación SEOM (Dr Balmaña), Asociación Española de Cáncer de Mama Metastásico (Premio M. Chiara Giorgetti to Dr Balmaña), ERA-Net (RAD51predict, ERAPERMED2019-215 to Dr Serra), Asociación Española Contra el Cáncer (LABAE16020PORTT to Dr Serra and INVES20095LLOP to Dr Llop-Guevara) and LaCaixa Foundation and European Institute of Innovation and Technology/Horizon 2020 (CaixaImpulse grant LCF/TR/CC19/52470003 to Dr Llop-Guevara). Dr Gutiérrez-Enríquez received funding from Spanish Instituto de Salud Carlos III with European Regional Development FEDER Funds (PI19/01303 and PI22/01200); and resources from the Government of Catalonia (2021SGR01112)

Genetic and clinical characterization of a novel FH founder mutation in families with hereditary leiomyomatosis and renal cell cancer syndrome

Common ancestor; Hereditary leiomyomatosis; Renal cell cancerAvantpassat comú; Leiomiomatosi hereditària; Càncer de cèl·lules renalsAncestro común; Leiomiomatosis hereditaria; Cáncer de células renalesBackground Hereditary leiomyomatosis and renal cell cancer syndrome is a rare autosomal dominant hereditary syndrome. Previously, we published the largest cohort of FH mutation carriers in Spain and observed a highly recurrent missense heterozygous variant, FH(NM_000143.4):c.1118A > G p.(Asn373Ser), in 104 individuals from 31 apparently unrelated families. Here, we aimed to establish its founder effect and characterize the associated clinical phenotype. Results Haplotype analysis confirmed that families shared a common haplotype (32/38 markers) spanning 0.61–0.82 Mb, indicating this recurrent variant was inherited from a founder ancestor. Cutaneous and uterine leiomyomatosis were diagnosed in 64.6% (64/99) and 98% (50/51) of patients, respectively, and renal cell cancer was present in 10.4% (10/96). The pathogenic FH_c.1118A > G variant is a Spanish founder mutation that originated 12–26 generations ago. We estimate that the variant may have appeared between 1370 and 1720. Individuals carrying this founder mutation had similar frequency of renal cell cancer and a higher frequency of renal cysts and leiomyomas than those in other cohorts of this syndrome. Conclusions In the Spanish province of Alicante there is a high prevalence of HLRCC because of the founder mutation FH c.1118A > G; p.(Asn373Ser). The characterization of founder mutations provides accurate and specific information regarding their penetrance and expressivity. In individuals with suspected HLRCC from the province of Alicante, genetic testing by direct analysis of the founder FH c.1118A > G; p.(Asn373Ser) mutation may be a faster and more efficient diagnostic tool compared with complete gene sequencing.Project founded by Spanish Society of Medical Oncology Foundation (FSEOM). SEOM + 1 Grant (UGP-19-428)

Phase II study of preoperative bevacizumab, capecitabine and radiotherapy for resectable locally-advanced rectal cancer

BACKGROUND: To evaluate whether the addition of bevacizumab (BVZ) to capecitabine-based chemoradiotherapy in the preoperative treatment of locally advanced rectal cancer (LARC) improves efficacy measured by the pathological complete response (pCR) rate. METHODS: A phase II two-step design was performed. Patients received four cycles of therapy consisting of: BVZ 10 mg/kg in first infusion on day 1 and 5 mg/kg on days 15, 29, 43, capecitabine 1800 mg/m(2)/day 5 days per week during radiotherapy, which consisted of external-beam irradiation (45 Gy in 1.8 Gy dose per session over 5 sessions/week for 5 weeks). Six to eight weeks after completion of all therapies surgery was undergone. To profile the biological behaviour during BVZ treatment we measured molecular biomarkers before treatment, during BVZ monotherapy, and during and after combination therapy. Microvessel density (MVD) was measured after surgery. RESULTS: Forty-three patients were assessed and 41 were included in the study. Three patients achieved a pathological complete response (3/40: 7.5%) and 27 (67.5%) had a pathological partial response, (overall pathological response rate of 75%). A further 8 patients (20%) had stable disease, giving a disease control rate of 95%. Downstaging occurred in 31 (31/40: 77.5%) of the patients evaluated. This treatment resulted in an actuarial 4-year disease-free and overall survival of 85.4 and 92.7% respectively. BVZ with chemoradiotherapy showed acceptable toxicity. No correlations were observed between biomarker results and efficacy variables. CONCLUSION: BVZ with capecitabine and radiotherapy seem safe and active and produce promising survival results in LARC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00847119. Trial registration date: February 18, 2009

Sex differences on multikinase inhibitors toxicity in patients with advanced gastroenteropancreatic neuroendocrine tumours

Purpose: There is an increasing interest in the role of sex and gender in cancer pa-tients. The impact of sex differences in oncological systemic therapies is still unknown, and there is a lack of evidence specially in uncommon neoplasms like neuroendocrine tumours (NET). In the present study, we combine the differential toxicities by sex in five published clinical trials with multikinase inhibitors (MKI) in gastroenteropancreatic (GEP) NET.Methods: We performed a pooled univariate analysis of reported toxicity in patients treated in five phase 2 and phase 3 clinical trials with MKI in the GEP NET setting: sunitinib (SU11248, SUN1111), Pazopanib (PAZONET), sorafenib-bevacizumab (GETNE0801) and Lenvatinib (TALENT). Differential toxicities between male and female patients were evaluated considering relationship with study drug and different weights of each trial by random effect adjustment.Results: We found nine toxicities which were more frequent in female patients (leukopenia, alopecia, vomiting, headache, bleeding, nausea, dysgeusia, neutrophil count decreased and dry mouth) and two toxicities being more frequent in male patients (Anal Symptoms and Insomnia). Asthenia and diarrhoea were the only severe (Grade 3-4) toxicities more frequent in female pa-tients.Conclusions: Sex-related differences in toxicity with the MKI treatment require targeted in-formation and individualised management of patients with NET. Differential reporting of toxicity should be promoted when clinical trials are published.(c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY -NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Prevalence of Homologous Recombination Deficiency Among Patients With Germline RAD51C/D Breast or Ovarian Cancer

IMPORTANCE RAD51C and RAD51D are involved in DNA repair by homologous recombination. Germline pathogenic variants (PVs) in these genes are associated with an increased risk of ovarian and breast cancer. Understanding the homologous recombination deficiency (HRD) status of tumors from patients with germline PVs in RAD51C/D could guide therapeutic decision-making and improve survival. OBJECTIVE To characterize the clinical and tumor characteristics of germline RAD51C/D PV carriers, including the evaluation of HRD status. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study included 91 index patients plus 90 relatives carrying germline RAD51C/D PV (n = 181) in Spanish hospitals from January 1, 2014, to December 31, 2021. Genomic and functional HRD biomarkers were assessed in untreated breast and ovarian tumor samples (n = 45) from June 2022 to February 2023. MAIN OUTCOMES AND MEASURES Clinical and pathologic characteristics were assessed using descriptive statistics. Genomic HRD by genomic instability scores, functional HRD by RAD51, and gene-specific loss of heterozygosity were analyzed. Associations between HRD status and tumor subtype, age at diagnosis, and gene-specific loss of heterozygosity in RAD51C/D were investigated using logistic regression or the t test. RESULTS A total of 9507 index patients were reviewed, and 91 patients (1.0%) were found to carry a PV in RAD51C/D; 90 family members with a germline PV in RAD51C/D were also included. A total of 157 of carriers (86.7%) were women and 181 (55.8%) had received a diagnosis of cancer, mainly breast cancer or ovarian cancer. The most prevalent PVs were c.1026+5_1026+7del (11 of 56 [19.6%]) and c.709C>T (9 of 56 [16.1%]) in RAD51C and c.694C>T (20 of 35 [57.1%]) in RAD51D. In untreated breast cancer and ovarian cancer, the prevalence of functional and genomic HRD was 55.2% (16 of 29) and 61.1% (11 of 18) for RAD51C, respectively, and 66.7% (6 of 9) and 90.0% (9 of 10) for RAD51D. The concordance between HRD biomarkers was 91%. Tumors with the same PV displayed contrasting HRD status, and age at diagnosis did not correlate with the occurrence of HRD. All breast cancers retaining the wild-type allele were estrogen receptor positive and lacked HRD. CONCLUSIONS AND RELEVANCE In this cohort study of germline RAD51C/D breast cancer and ovarian cancer, less than 70% of tumors displayed functional HRD, and half of those that did not display HRD were explained by retention of the wild-type allele, which was more frequent among estrogen receptor-positive breast cancers. Understanding which tumors are associated with RAD51C/D and HRD is key to identify patients who can benefit from targeted therapies, such as PARP (poly [adenosine diphosphate-ribose] polymerase) inhibitors

Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. Methods: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.Peer reviewe