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Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRASG12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRASG12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73–1.20; P = 0.85). In contrast, patients with KRASG13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15–0.55; P KRASG12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.

(1) Background: Precision oncology is opening new treatment opportunities for patients suffering from solid tumors. In the last two decades, the advent of CDK4/6 inhibitors, immunotherapy, and antibody–drug conjugates (ADC) improved survival outcomes for advanced or metastatic breast cancers (BC). Nevertheless, some patients progress to approved therapies and still maintain good clinical conditions. (2) Methods: With the aim to estimate the accrual rate to experimental precision oncology treatments, we collected molecular and clinical characteristics of BC patients evaluated at Phase 1 Unit of Fondazione Policlinico Gemelli. Clinical data were retrieved from hospital records. Molecular analysis was performed using Next-Generation Sequencing (NGS) FoundationOne CDx on tissue or blood. (3) Results: Among the 38 BC patients referred to our unit, 35 completed the genomic analysis. All patients were female with advanced (mean number of metastatic sites: 3, range 1–6) BC. Median age at our evaluation was 52 (IQR, 48–59). ECOG PS was good in 97% of the study population, although heavily pre-treated (median number of systemic treatments: 5, IQR 3–7). Half of referred patients were HR+/HER2− BC, with 39% triple negative breast cancer (TNBC). NGS testing was performed on relapsed disease among most (71%) participants, in particular lymph nodes and soft tissue. Liquid biopsy was requested in 23% of cases. The median time from sample collection to NGS testing was 1 month and from diagnosis 54 months. The median value of mutations, VUS, and TMB were 6, 11, and 5, respectively. TP53, PIK3CA, BRCA2, ESR1, and RAD21 were the genes with the highest number of molecular alterations. In 5 patients (14%), the molecular analysis was helpful to assign targeted therapy in the context of clinical trials with a median progression-free survival of 5 months. (4) Conclusions: HR+/HER2− and TNBC were the most frequent subtypes referred for NGS testing. Tissue biopsy of relapsed disease was feasible in 71% of cases. The molecular analysis offered a new treatment opportunity in 14% of patients. The real benefit of these treatments remains to be evaluated in larger cohorts.

Background Endometrial cancer risk stratification may help target interventions, screening, or prophylactic hysterectomy to mitigate the rising burden of this cancer. However, existing prediction models have been developed in select cohorts and have not considered genetic factors. Methods We developed endometrial cancer risk prediction models using data on postmenopausal White women aged 45-85 years from 19 case-control studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Relative risk estimates for predictors were combined with age-specific endometrial cancer incidence rates and estimates for the underlying risk factor distribution. We externally validated the models in 3 cohorts: Nurses’ Health Study (NHS), NHS II, and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Results Area under the receiver operating characteristic curves for the epidemiologic model ranged from 0.64 (95% confidence interval [CI] = 0.62 to 0.67) to 0.69 (95% CI = 0.66 to 0.72). Improvements in discrimination from the addition of genetic factors were modest (no change in area under the receiver operating characteristic curves in NHS; PLCO = 0.64 to 0.66). The epidemiologic model was well calibrated in NHS II (overall expected-to-observed ratio [E/O] = 1.09, 95% CI = 0.98 to 1.22) and PLCO (overall E/O = 1.04, 95% CI = 0.95 to 1.13) but poorly calibrated in NHS (overall E/O = 0.55, 95% CI = 0.51 to 0.59). Conclusions Using data from the largest, most heterogeneous study population to date (to our knowledge), prediction models based on epidemiologic factors alone successfully identified women at high risk of endometrial cancer. Genetic factors offered limited improvements in discrimination. Further work is needed to refine this tool for clinical or public health practice and expand these models to multiethnic populations.

Cancer research is a crucial pillar for countries to deliver more affordable, higher quality, and more equitable cancer care. Patients treated in research-active hospitals have better outcomes than patients who are not treated in these settings. However, cancer in Europe is at a crossroads. Cancer was already a leading cause of premature death before the COVID-19 pandemic, and the disastrous effects of the pandemic on early diagnosis and treatment will probably set back cancer outcomes in Europe by almost a decade. Recognising the pivotal importance of research not just to mitigate the pandemic today, but to build better European cancer services and systems for patients tomorrow, the Lancet Oncology European Groundshot Commission on cancer research brings together a wide range of experts, together with detailed new data on cancer research activity across Europe during the past 12 years. We have deployed this knowledge to help inform Europe's Beating Cancer Plan and the EU Cancer Mission, and to set out an evidence-driven, patient-centred cancer research roadmap for Europe. The high-resolution cancer research data we have generated show current activities, captured through different metrics, including by region, disease burden, research domain, and effect on outcomes. We have also included granular data on research collaboration, gender of researchers, and research funding. The inclusion of granular data has facilitated the identification of areas that are perhaps overemphasised in current cancer research in Europe, while also highlighting domains that are underserved. Our detailed data emphasise the need for more information-driven and data-driven cancer research strategies and planning going forward. A particular focus must be on central and eastern Europe, because our findings emphasise the widening gap in cancer research activity, and capacity and outcomes, compared with the rest of Europe. Citizens and patients, no matter where they are, must benefit from advances in cancer research. This Commission also highlights that the narrow focus on discovery science and biopharmaceutical research in Europe needs to be widened to include such areas as prevention and early diagnosis; treatment modalities such as radiotherapy and surgery; and a larger concentration on developing a research and innovation strategy for the 20 million Europeans living beyond a cancer diagnosis. Our data highlight the important role of comprehensive cancer centres in driving the European cancer research agenda. Crucial to a functioning cancer research strategy and its translation into patient benefit is the need for a greater emphasis on health policy and systems research, including implementation science, so that the innovative technological outputs from cancer research have a clear pathway to delivery. This European cancer research Commission has identified 12 key recommendations within a call to action to reimagine cancer research and its implementation in Europe. We hope this call to action will help to achieve our ambitious 70:35 target: 70% average 10-year survival for all European cancer patients by 2035.

ObjectiveTo evaluate the role of different specific types of germline breast cancer susceptibilityBRCAmutations on the age of onset of high grade serous ovarian cancer.MethodsThis was a multicenter, international, retrospective cohort of 474 patients diagnosed with recurrent or newly diagnosed high grade serous ovarian cancer, with known germline mutations inBRCA1/2genes, treated between January 2011 and December 2020 in three academic centers in Europe. Patients were classified into four groups related to the type ofBRCA1/2genes mutation: frameshift, missense, nonsense, and splicing. Data from patients with splicing mutations were removed from the analysis because of the small numbers. The other three groups were compared.ResultsExcluding the 29 patients with a splicing mutation, 474 patients were enrolled: 309 (65.2%) with frameshift mutations, 102 (21.5%) with nonsense mutations, and 63 (13.3%) with missense mutations. TheBRCA1gene was affected in 324 (68.4%) cases, whileBRCA2was involved in 150 (31.6%) women (p=0.06). We found a difference of more than 5 years in the age of onset of high grade serous ovarian cancer betweenBRCA1andBRCA2patients (mean 53.3 years vs 58.4 years; p=0.001), with a mean age of 55.1 years. Patients with nonsense germline mutations had the youngest age of onset, while women with frameshift mutations had the oldest age of onset of high grade serous ovarian cancer (mean 52.2 years vs mean 55.9 years), both in theBRCA1andBRCA2subgroups. There was no statistically significant difference in age of onset between early and advanced groups (mean 55.8 years vs 55.0 years; p=0.55).ConclusionDifferent types of germlineBRCAmutations could determine different ages for onset of high grade serous ovarian cancer. If confirmed in larger series, this finding might have a clinical impact, potentially leading to a more tailored approach for risk reducing surgery for the prevention of high grade serous ovarian cancer.

Background Few studies analyzed the prognostic role of systemic inflammatory markers in early-stage ovarian cancer. The primary endpoint of the present study was to assess the prognostic impact of baseline inflammatory markers in early-stage ovarian cancer. The secondary endpoints were to compare the disease-free survival (DFS) of inflammatory markers with standard risk factors and to correlate these with BRCA mutational status. Methods Retrospective, single-center, observational study. Patients with FIGO-stage I–II and IIIA1 epithelial ovarian cancer undergoing primary surgery between 10/2012 and 12/2019 were included. Inflammatory markers were evaluated on the results of the complete blood count and coagulation tests, performed before ovarian cancer surgery. The Receiver Operating Characteristic curve was used to determine the optimal cut-off value of different baseline inflammatory biomarkers for the DFS analysis. Results Three hundred fifty-nine patients were included in the study period. Baseline neutrophil–lymphocyte ratio (NLR) ≥ 3 and systemic immune inflammation index (SII, defined as platelet x neutrophil–lymphocyte ratio) ≥ 1000 were associated with worse 3 year DFS and baseline SII ≥ 1000 was associated with worse 3 year OS. BRCA-mutated patients with SII ≥ 1000 and with NLR ≥ 3 had significantly worse DFS compared to SII I was the only independent risk factor for higher risk of recurrence. Conclusion SII ≥ 1000 and NLR ≥ 3 were associated with worse 3 year DFS and SII ≥ 1000 was associated with worse 3 year OS. The subgroups of BRCA-mutated patients with higher inflammation markers (SII ≥ 1000 and NLR ≥ 3) were associated with worse DFS. These findings might be helpful to design personalized treatment and more intensive surveillance.

Lipid metabolism impacts immune cell differentiation, activation, and functions, modulating inflammatory mediators, energy homeostasis, and cell membrane composition. Despite preclinical evidence, data in humans lack concerning tumors and immunotherapy (IO). We aimed at investigating the correlations between circulating lipids and the outcome of non-small cell lung cancer (NSCLC) patients treated with IO.We identified all patients with advanced NSCLC treated with IO at our Institution with available baseline plasma samples. Fatty acids (FAs) were analyzed through gas chromatography. Survival curves were estimated by the Kaplan-Meier method. Cox multivariate models were constructed through a stepwise procedure, with entry and exit P value set at .2.We identified 112 patients, mostly with performance status 1 (65.2%) and PD-L1≥1% (75.3%). Median progression-free survival (PFS) and overall survival (OS) were 2.8 and 11.0 months, respectively. Multivariable model for survival identified a positive association of circulating free (FFA) C16:0 (P .005) and esterified (EFA) C16:1 (P .030) with PFS, and a positive association of EFA C16:1 (P .001) and EFA C18:0 (P .020) with OS. EFA C16:0 was negatively associated with PFS (P .008).FFA C16:0 and FAs derived from its unsaturation (EFA C16:1) and elongation (EFA C18:0) are associated with a better outcome in NSCLC patients treated with IO. It is conceivable that the ratio among those FAs may modify membrane fluidity and receptor activity, influencing IO efficacy. These data pave the way for the investigation of lipid-modulating strategies in association with IO in NSCLC.

Cancer treatment is increasingly focused on targeting molecular alterations identified across different tumor histologies. While some oncogenic drivers such as microsatellite instability (MSI) and NTRK fusions are actionable with the very same approach regardless of tumor type ("histology-agnostic"), others require histology-specific therapeutic adjustment ("histology-tuned") by means of adopting specific inhibitors and ad hoc combinations. Among histology-agnostic therapies, pembrolizumab or dostarlimab demonstrated comparable activity in MSI metastatic colorectal cancer (mCRC) as in other tumors with MSI status (ORR 38% vs 40% and 36% vs 39%, respectively), while entrectinib or larotrectinib proved effective in NTRK rearranged mCRC even though less dramatically than in the overall population (ORR 20% vs 57%, and 50% vs 78%, respectively). Histology-tuned approaches in mCRC are those targeting BRAF

Purpose To evaluate the association between the intake of specific fibers with prebiotic activity, namely inulin-type fructans (ITFs), fructooligosaccharides (FOSs) and galactooligosaccharides (GOSs), and colorectal cancer risk. Methods Within the PrebiotiCa study, we used data from a multicentric case–control study conducted in Italy and including 1953 incident, histologically confirmed, colorectal cancer patients and 4154 hospital controls. The amount of six prebiotic molecules [ITFs, nystose (FOS), kestose (FOS), 1F-β-fructofuranosylnystose (FOS), raffinose (GOS) and stachyose (GOS)] in a variety of foods was quantified via laboratory analyses. Subjects’ prebiotic fiber intake was estimated by multiplying food frequency questionnaire intake by the prebiotic content of each food item. The odds ratios (OR) of colorectal cancer for quintiles of intakes were derived from logistic regression models including terms for major confounders and total energy intake. Results GOSs intake was inversely associated with colorectal cancer risk. The OR for the highest versus the lowest quintile of intake were 0.73 (95% confidence interval, CI 0.58–0.92) for raffinose and 0.64 (95% CI 0.53–0.77) for stachyose, with significant inverse trends across quintiles. No association was found with total ITFs and FOSs. The association with stachyose was stronger for colon (continuous OR = 0.74, 95% CI 0.66–0.83) than rectal cancer (OR = 0.89, 95% CI 0.79–1.02). Conclusion Colorectal cancer risk was inversely associated with the intake of dietary GOSs, but not ITFs and FOSs.

Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations restricts their efficacy. We previously showed that RAS, BRAF and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies. We report here the results of CHRONOS, an open-label, single-arm phase 2 clinical trial exploiting blood-based identification of RAS/BRAF/EGFR mutations levels to tailor a chemotherapy-free anti-EGFR rechallenge with panitumumab (ClinicalTrials.gov: NCT03227926; EudraCT 2016-002597-12). The primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival, safety and tolerability of this strategy. In CHRONOS, patients with tissue-RAS WT tumors after a previous treatment with anti-EGFR-based regimens underwent an interventional ctDNA-based screening. Of 52 patients, 16 (31%) carried at least one mutation conferring resistance to anti-EGFR therapy and were excluded. The primary endpoint of the trial was met; and, of 27 enrolled patients, eight (30%) achieved partial response and 17 (63%) disease control, including two unconfirmed responses. These clinical results favorably compare with standard third-line treatments and show that interventional liquid biopsies can be effectively and safely exploited in a timely manner to guide anti-EGFR rechallenge therapy with panitumumab in patients with mCRC. Further larger and randomized trials are warranted to formally compare panitumumab rechallenge with standard-of-care therapies in this patient setting.

Purpose: Mammographic breast density (BD) is strongly associated to breast cancer (BC) risk; however, its association with survival is unclear.Methods: Using data from the Piedmont Cancer Registry (Registro Tumori Piemonte), we identified 693 women diagnosed with primary invasive BC between 2009-2014. We applied the Kaplan-Meier method to estimate overall survival in strata of BD and the log-rank test to assess survival differences. We evaluated the hazard ratios (HRs) of death using Cox proportional hazards model and HRs of BC-related and other causes of death using the cause-specific hazards regression model. Models included terms for BD (assessed according to the Breast Imaging Reporting and Data System [BI-RADS] density classification) and were adjusted for selected patient and tumour characteristics.Results: There were102 deaths, of which 49 were from BC. After 5 years, the overall survival was 70% in women with BI-RADS 1, 85% in those with BI-RADS 2, about 95% in those with BI-RADS 3-4 (p Conclusion: In women with BC, low BD has a negative prognostic impact.

Biliary tract cancers (BTCs) have poor prognosis and limited therapeutic options. The impact of O

Women at high inherited risk of ovarian cancer are offered risk-reducing salpingo-oophorectomy (RRSO) from age 35 to 45 years. Although potentially life-saving, RRSO may induce symptoms that negatively affect quality of life and impair long-term health. Clinical care following RRSO is often suboptimal. This scoping review describes how RRSO affects short- and long-term health and provides evidence-based international consensus recommendations for care from preoperative counselling to long-term disease prevention. This includes the efficacy and safety of hormonal and non-hormonal treatments for vasomotor symptoms, sleep disturbance and sexual dysfunction and effective approaches to prevent bone and cardiovascular disease.

Background: Exposure to occupational carcinogens is an important and avoidable cause of cancer. We aimed to provide an evidence-based estimate of the burden of occupation-related cancers in Italy. Methods: The attributable fraction (AF) was calculated based on the counterfactual scenario of no occupational exposure to carcinogens. We included exposures classified as IARC group 1 and with reliable evidence of exposure in Italy. Relative risk estimates for selected cancers and prevalences of exposure were derived from large-scale studies. Except for mesothelioma, a 15–20-year latency period between exposure and cancer was considered. The data on cancer incidence in 2020 and mortality in 2017 in Italy were obtained from the Italian Association of Cancer Registries. Results: The most prevalent exposures were UV radiation (5.8%), diesel exhaust (4.3%), wood dust (2.3%) and silica dust (2.1%). Mesothelioma had the largest AF to occupational carcinogens (86.6%), followed by sinonasal cancer (11.8%) and lung cancer (3.8%). We estimated that 0.9% of cancer cases (N~3500) and 1.6% of cancer deaths (N~2800) were attributable to occupational carcinogens in Italy. Of these, about 60% were attributable to asbestos, 17.5% to diesel exhaust, followed by chromium and silica dust (7% and 5%). Conclusions: Our estimates provide up-to-date quantification of the low, but persistent, burden of occupational cancers in Italy.

Background US-indeterminate adnexal lesions remain an important indication for gynecologic surgery. MRI can serve as a problem-solving tool through the use of the Ovarian-Adnexal Imaging Reporting and Data System (O-RADS) MRI lexicon, which is based on the ADNEX MR scoring system. Purpose To perform a systematic review and meta-analysis of the diagnostic performance of pelvic MRI interpreted using the ADNEX or O-RADS MRI stratification systems to characterize US-indeterminate adnexal lesions and of the category-wise malignancy rates. Materials and Methods A systematic literature search from May 2013 (publication of the ADNEX MR score) to September 2022 was performed. Studies reporting the use of pelvic MRI interpreted with the ADNEX or O-RADS MRI systems to characterize US-indeterminate adnexal lesions, with pathologic examination and/or follow-up as the reference standard, were included. Summary estimates of diagnostic performance were obtained with the bivariate random-effects model, while category-wise summary malignancy rates of O-RADS MRI 2, 3, 4, and 5 lesions were obtained with a random-effects model. Effects of covariates on heterogeneity and diagnostic performance were investigated through meta-regression. Results Thirteen study parts from 12 studies (3731 women, 4520 adnexal lesions) met the inclusion criteria. Diagnostic performance meta-analysis for 4012 lesions found a 92% summary sensitivity (95% CI: 88, 95) and a 91% summary specificity (95% CI: 89, 93). The meta-analysis of malignancy rates for 3641 lesions showed summary malignancy rates of 0.1% (95% CI: 0, 1) among O-RADS MRI 2 lesions, 6% (95% CI: 3, 9) among O-RADS MRI 3 lesions, 60% (95% CI: 52, 67) among O-RADS MRI 4 lesions, and 96% (95% CI: 92, 99) among O-RADS MRI 5 lesions. Conclusion Pelvic MRI interpreted with the Ovarian-Adnexal Reporting and Data System (O-RADS) MRI lexicon had high diagnostic performance for the characterization of US-indeterminate adnexal lesions. Summary estimates of malignancy rates in the O-RADS MRI 4 and O-RADS MRI 5 categories were higher than predicted ones. © RSNA, 2022

A votive offering or ex-voto includes a variety of usually non-professional artworks offered to divinities and placed in religious sites to fulfill a vow or in gratitude for recovery from an illness or injury. Unfortunately, the ancient period lacks a scientifically verifiable understanding of the true nature of cancer and its natural history and, consequently, a lack of effective treatment. This paper discusses two ex-votos potentially related to breast cancer distant more than 2000 years, one from the other. The ex-votos convey the complex relationship of humans with illness through an art expression stemming from the heart and minds of ordinary people.

Traditionally, lymphovascular invasion (LVI) has represented one of the foremost pathological features of malignancy and has been associated with a worse prognosis in different cancers, including breast carcinoma. According to the most updated reporting protocols, the assessment of LVI is required in the pathology report of breast cancer surgical specimens. Importantly, strict histological criteria should be followed for LVI assessment, which nevertheless is encumbered by inconsistency in interpretation among pathologists, leading to significant interobserver variability and scarce reproducibility. Current guidelines for breast cancer indicate biological factors as the main determinants of oncological and radiation therapy, together with TNM staging and age. In clinical practice, the widespread use of genomic assays as a decision-making tool for hormone receptor-positive, HER2-negative breast cancer and the subsequent availability of a reliable prognostic predictor have likely scaled back interest in LVI’s predictive value. However, in selected cases, the presence of LVI impacts adjuvant therapy. This review summarizes current knowledge on LVI in breast cancer with regard to definition, histopathological assessment, its biological understanding, clinicopathological association, and therapeutic implications.

Introduction Care for head and neck cancers is complex in particular for the rare ones. Knowledge is limited and histological heterogeneity adds complexity to the rarity. There is a wide consensus that to support clinical research on rare cancer, clinical registries should be developed within networks specializing in rare cancers. In the EU, a unique opportunity is provided by the European Reference Networks (ERN). The ERN EURACAN is dedicated to rare adults solid cancers, here we present the protocol of the EURACAN registry on rare head and neck cancers (ClinicalTrials.gov Identifier: NCT05483374). Study design Registry-based cohort study including only people with rare head and neck cancers. Objectives to help describe the natural history of rare head and neck cancers; to evaluate factors that influence prognosis; to assess treatment effectiveness; to measure indicators of quality of care. Methods Settings and participants It is an hospital based registry established in hospitals with expertise in head and neck cancers. Only adult patients with epithelial tumours of nasopharynx; nasal cavity and paranasal sinuses; salivary gland cancer in large and small salivary glands; and middle ear will be included in the registry. This registry won’t select a sample of patients. Each patient in the facility who meets the above mentioned inclusion criteria will be followed prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for the patient follow-up. Variables Data will be collected on patient characteristics (eg. patient demographics, lifestyle, medical history, health status); exposure data (eg. disease, procedures, treatments of interest) and outcomes (e.g. survival, progression, progression-free survival, etc.). In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will be also collected. Statistical methods The data analyses will include descriptive statistics showing patterns of patients’ and cancers’ variables and indicators describing the quality of care. Multivariable Cox’s proportional hazards model and Hazard ratios (HR) for all-cause or cause specific mortality will be used to determine independent predictors of overall survival, recurrence etc. Variables to include in the multivariable regression model will be selected based on the results of univariable analysis. The role of confounding or effect modifiers will be evaluated using stratified analysis or sensitivity analysis. To assess treatment effectiveness, multivariable models with propensity score adjustment and progression-free survival will be performed. Adequate statistical (eg. marginal structural model) methods will be used if time-varying treatments/confounders and confounding by indication (selective prescribing) will be present. Results The registry initiated recruiting in May 2022. The estimated completion date is December 2030 upon agreement on the achievement of all the registry objectives. As of October 2022, the registry is recruiting. There will be a risk of limited representativeness due to the hospital-based nature of the registry and to the fact that hospital contributing to the registry are expert centres for these rare cancers. Clinical Follow-up could also be an issue but active search of the life status of the patients will be guaranteed.

PURPOSE This is a multicenter, single-arm phase II trial evaluating the efficacy and safety of an immune-sensitizing strategy with temozolomide priming followed by a combination of low-dose ipilimumab and nivolumab in patients with microsatellite-stable (MSS) and O6-methylguanine–DNA methyltransferase (MGMT)–silenced metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Patients with pretreated mCRC were centrally prescreened for MSS status and MGMT silencing (ie, lack of MGMT expression by immunohistochemistry plus MGMT methylation by pyrosequencing). Eligible patients received two priming cycles of oral temozolomide 150 mg/sqm once daily, days 1-5, once every 4 weeks (first treatment part) followed, in absence of progression, by its combination with ipilimumab 1 mg/kg once every 8 weeks and nivolumab 480 mg once every 4 weeks (second treatment part). The primary end point was the 8-month progression-free survival (PFS) rate calculated from enrollment in patients who started the second treatment part, with ≥ 4 out of 27 subjects progression-free by the 8-month time point as decision rule. RESULTS Among 716 prescreened patients, 204 (29%) were molecularly eligible and 135 started the first treatment part. Among these, 102 (76%) were discontinued because of death or disease progression on temozolomide priming, whereas 33 patients (24%) who achieved disease control started the second treatment part and represented the final study population. After a median follow-up of 23.1 months (interquartile range, 14.9-24.6 months), 8-month PFS rate was 36%. Median PFS and overall survival were 7.0 and 18.4 months, respectively, and overall response rate was 45%. Grade 3-4 immune-related adverse events were skin rash (6%), colitis (3%), and hypophysitis (3%). No unexpected adverse events or treatment-related deaths were reported. CONCLUSION The MAYA study provided proof-of-concept that a sequence of temozolomide priming followed by a combination of low-dose ipilimumab and nivolumab may induce durable clinical benefit in MSS and MGMT-silenced mCRC.

ObjectiveCurrently, there is no clear guidance defining the ideal candidate for minimally invasive interval debulking surgery. This study aimed to identify predictive factors for a minimally invasive approach in patients with advanced ovarian cancer who are candidates for interval debulking surgery after neoadjuvant chemotherapy.MethodsThis was a single institution retrospective study conducted between January 2014 and June 2020 Perioperative variables were used to predict the likelihood of minimally invasive interval debulking surgery using multivariable models. A nomogram was developed, and internal validation was performed using the bootstrapping correction technique. This nomogram was built to visualize the effect of perioperative variables on the estimated probability of minimally invasive interval debulking surgery in patients with a clinical response after neoadjuvant chemotherapy. We used the four significant perioperative variables according to logistic regression.ResultsA total of 108 (28.4%) and 272 (71.6%) patients underwent interval debulking surgery by a minimally invasive or open approach, respectively. Absence of omental cake (odds ratio (OR) 9.15, 95% confidence interval (CI) 4.26 to 19.64, pConclusionsOur nomogram may serve as a useful tool to choose the surgical approach in patients with advanced ovarian cancer undergoing interval debulking surgery.

The importance of integrating biomarkers into the TNM staging has been emphasized in the 8th Edition of the American Joint Committee on Cancer (AJCC) Staging system. In a pooled analysis of 2148 TNBC-patients in the adjuvant setting, TILs are found to strongly up and downstage traditional pathological-staging in the Pathological and Clinical Prognostic Stage Groups from the AJJC 8th edition Cancer Staging System. This suggest that clinical and research studies on TNBC should take TILs into account in addition to stage, as for example patients with stage II TNBC and high TILs have a better outcome than patients with stage I and low TILs.

Background In patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC), growing evidence supports anti-epidermal growth factor receptor (EGFR) retreatment, whereas little is known on the outcomes of anti-EGFR-based reinduction therapy during the upfront strategy. Methods We included patients enrolled in the Valentino study who had disease progression and received at least one dose of post-progression therapy. The Kaplan–Meier method and Cox proportional hazards regression were used for the survival analysis. When comparing the outcomes of anti-EGFR-based reinduction versus any second line, a propensity score–based matching was used. Results Liver-limited/single site of disease (P < .001 and P = .002), left-sidedness (P = .029), surgery of metastases (P = .003), early tumor shrinkage, and deeper responses (P = .018 and P = .036) were associated with the use of anti-EGFR-based reinduction versus any other second line. All patients treated with reinduction had an anti-EGFR-free interval of at least 3 months. In the propensity score–matched population, progression-free survival (PFS) was similar in the 2 treatment groups, the overall survival (OS) was significantly longer for patients treated with reinduction (P = .029), and the response rate was higher in patients treated with reinduction (P = .033). An oxaliplatin-free interval ≥12 months, left-sidedness, and molecular hyperselection beyond RAS/BRAF were associated with significantly better outcomes after anti-EGFR-based reinduction. Conclusions Reinduction strategies with anti-EGFR-based regimens are commonly used in clinical practice. Our data highlight the importance of clinical–molecular selection for re-treatments and the need for prospective strategy trials in selected populations.