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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

Background Cancers of the Vater ampulla (ampullary cancers, ACs) account for less than 1% of all gastrointestinal tumors. ACs are usually diagnosed at advanced stage, with poor prognosis and limited therapeutic options. BRCA2 mutations are identified in up to 14% of ACs and, differently from other tumor types, therapeutic implications remain to be defined. Here, we report a clinical case of a metastatic AC patient in which the identification of a BRCA2 germline mutation drove a personalized multimodal approach with curative-intent. Case presentation A 42-year-old woman diagnosed with stage IV BRCA2 germline mutant AC underwent platinum-based first line treatment achieving major tumor response but also life-threatening toxicity. Based on this, as well as on molecular findings and expected low impact of available systemic treatment options, the patient underwent radical complete surgical resection of both primary tumor and metastatic lesions. Following an isolated retroperitoneal nodal recurrence, given the expected enhanced sensitivity to radiotherapy in BRCA2 mutant cancers, the patient underwent imaging-guided radiotherapy leading to long-lasting complete tumor remission. After more than 2 years, the disease remains radiologically and biochemically undetectable. The patient accessed a dedicated screening program for BRCA2 germline mutation carriers and underwent prophylactic bilateral oophorectomy. Conclusions Even considering the intrinsic limitations of a single clinical report, we suggest that the finding of BRCA germline mutations in ACs should be taken into consideration, together with other clinical variables, given their potential association with remarkable response to cytotoxic chemotherapy that might be burdened with enhanced toxicity. Accordingly, BRCA1/2 mutations might offer the opportunity of personalizing treatment beyond PARP inhibitors up to the choice of a multimodal approach with curative-intent.

Liquid biopsy recently gained widespread attention as a noninvasive alternative/complementary technique to tissue biopsy in patients with cancer. As technological advances have improved both feasibility and turnaround time, liquid biopsy has expanded tumor molecular analysis with acknowledgement of both spatial and temporal heterogeneity, overcoming many limitations of traditional tissue biopsy. Because of its diagnostic, prognostic, and predictive value, liquid biopsy has been extensively studied also in metastatic colorectal cancer. Indeed, as personalized medicine establishes its role in cancer treatment, genetic biomarkers unveiling the emergence of early resistance are needed. Among the wide variety of tumor analytes amenable to collection, circulating DNA and circulating tumor cells are the most adopted approaches, and both carry clinical relevance in colorectal cancer. However, few studies focused on comparing feasibility between these two approaches. In this review, we discuss the potential implications of liquid biopsy in metastatic colorectal cancer, assessing the advantages and drawbacks of circulating DNA and circulating tumor cells, and highlighting the most relevant trials for clinical practice.

Background Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure. Case presentation We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15–20. Conclusions This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.

BackgroundWe aim to identify the prevalence and the role of the MAP2K1 K57N mutation in predicting resistance to anti-EGFR agents in metastatic colorectal cancer (mCRC) patients.MethodsWe retrospectively reviewed tumor-based next generation sequencing (NGS) results from mCRC patients screened for enrollment in the GO40872/STARTRK-2 clinical trial between July 2019 and March 2021. Then, in patients harboring microsatellite stable (MSS) RAS and BRAF wild-type MAP2K1 mutant mCRC, we reviewed outcome to treatment with anti-EGFR monoclonal antibodies.ResultsA total of 246 mCRC patients were screened. Most of them, 215/220 (97.7%), were diagnosed with MSS mCRC and 112/215 (52.1%) with MSS, RAS and BRAF wild-type mCRC. Among the latter, 2/112 (1.8%) had MAP2K1 K57N mutant mCRC and both received anti-EGFR monotherapy as third line treatment. In both patients, MAP2K1 K57N mutant tumors proved primary resistant to anti-EGFR agent panitumumab monotherapy. Of interest, one of these patients was treated with anti-EGFR agents three times throughout his course of treatment, achieving some clinical benefit only when associated with other cytotoxic agents (FOLFOX or irinotecan).ConclusionWe verified in a clinical real-world setting that MAP2K1 K57N mutation is a resistance mechanism to anti-EGFR agents in mCRC. Thus, we suggest avoiding the administration of these drugs to MSS RAS and BRAF wild-type MAP2K1 N57K mutant mCRC.

HER2 alterations are potential candidates for targeted treatments in metastatic urothelial/bladder cancer (mUC). ERBB2 gene amplification and mutations are found in around 6% and 4% of mUC, respectively.This is a systematic review of clinical trials evaluating HER2-targeting (amplification and mutations) in mUC. We assigned each study to one of the following strategies: HER2-targeting with single agents, anti-HER2 agents in combination with cytotoxic chemotherapy, dual HER2 blockade, HER2-targeted antibody-drug conjugates (ADCs), and other novel therapeutic approaches.36 clinical trials (17 with results and 19 ongoing) were included. As for ERBB2 amplification, anti-HER2 single agents (5 studies) and combinations with chemotherapy (4 studies) failed to provide any benefit, whereas dual HER2 blockade through monoclonal antibodies proved active in one trial in pretreated patients. Two studies assessed single-agent targeting for ERBB2 mutations with negative results. Most promising data come from 2 studies with ADCs in ERBB2 amplified tumors (disitamab-vedotin and trastuzumab-duocarmazine), while 2 other studies with TDM-1 and ADCT-502 was discontinued due to toxicity. In this category, trastuzumab-deruxtecan and other ADCs are still under investigation for either ERBB2-amplified or mutated mUC. Novel approaches include ADCs with immunotherapy (1 study with results), CAR-T cells, and HER2-sensitising vaccines.ERBB2 amplification could become a novel target in mUC, although the magnitude of clinical benefit remains to be clarified. To this regard, novel ADCs are the most promising strategy. ERBB2 mutations are still at very early stage of clinical study.

ERBB2 amplification is a driver oncogenic alteration in many cancers and it has recently been incorporated among therapeutically actionable biomarkers also in metastatic colorectal cancer (mCRC). In contrast, the role of ERBB2 point mutations, which are detectable in up to 3% of CRC patients, remains to be assessed. In this systematic review, we collected preclinical and clinical data addressing the role of ERBB2 point mutations in mCRC patients as a predictive biomarker for anti-EGFR and anti-HER2 targeted agents, and as mechanism of acquired resistance to ERBB2 amplified mCRC treated with any anti-HER2 regimen. In both preclinical and clinical studies, most ERBB2 point mutations were associated with resistance to anti-EGFR agents, particularly L755S and R784G, which occur in the HER2 protein kinase domain. No ERBB2 mutation was associated with tumor response to HER2-targeted agents in mCRC patients, although signals of activity were observed in preclinical models. Eight ongoing clinical trials are underway to test different anti-HER2 treatments in ERBB2 mutant mCRC. Several reports documented the emergence of ERBB2 mutations in the circulating tumor DNA (ctDNA) of ERBB2 amplified mCRC progressing to anti-HER2 agents, thus hinting a role in acquired resistance.

Background Patients with solid tumours have high COVID-19 mortality. Limited and heterogeneous data are available regarding the immunogenicity of SARS-CoV-2 mRNA vaccines in this population. Methods and Findings This is a prospective, single-center, cohort study aiming at evaluating seroconversion in terms of anti-spike antibodies in a population of patients with solid tumours undergoing cancer therapy within 2 months before the second vaccine dose, as compared with a cohort of controls. Subjects who were not SARS-CoV-2 naïve were excluded. 171 patients were included in the final study population (150 vaccinated with BNT162b2, 87.7%; 21 with mRNA-1273, 12.3%) and compared with 2406 controls. Median follow-up time from the second dose of vaccination was 30 days (12-42; IQR: 26-34). Most patients had metastatic disease (138, 80.7%). Seroconversion rate was significantly lower in cancer patients than in controls (94.2% vs 99.8%, p70 years). A multivariate logistic model confirmed cancer as the only significant variable in impairing seroconversion (OR 0.03, p2, as the only one of impact (OR 0.07, p=0.012). Conclusions There is a fraction of 6% of patients with solid tumours undergoing cancer treatment, mainly with poorer performance status, who fail to obtain seroconversion after SARS-CoV-2 mRNA vaccines. These patients should be considered for enhanced vaccination strategies and carefully monitored for SARS-CoV-2 infection during cancer treatment.

Background Oxaliplatin represents a main component of cytotoxic treatment regimens in colorectal cancer (CRC). Given its efficacy, oxaliplatin is frequently re-administered in the context of the continuum of care in metastatic CRC (mCRC). However, efficacy and tolerability of this therapeutic strategy has not been comprehensively assessed. Methods We performed a systematic review of the literature on September 19th 2020, according to PRISMA criteria 2009. The research was performed on PubMed, ASCO Meeting Library, ESMO library and ClinicalTrials.gov for citations or ongoing trials. Results 64 records were retrieved and 13 included in the systematic review: 8 full-text articles, 4 abstracts and 1 ongoing clinical trial. According to readministration timing, studies were classified as rechallenge/reintroduction (n = 8) or stop & go/intermittent therapeutic strategies (n = 4). The studies presented wide heterogeneity in terms of efficacy (Response Rate 6–31%; Disease Control Rate 39–79%; median Progression-Free Survival 3.1–7 months). Those patients who received retreatment after prior adjuvant oxaliplatin or exploiting a stop-&-go strategy appeared to achieve better outcomes. However, no formal comparisons on treatment outcomes were feasible. The most frequent grade 3 or higher adverse events were hematologic toxicities (5–27%), peripheral neuropathy (5–14%) and hypersensitivity reactions (5–20%). Conclusions Retreatment with oxaliplatin for mCRC is practiced based on scarce and heterogeneous data indicating efficacy and manageable toxicity. The best strategy to exploit this approach remains to be defined, and the most promising research avenue to improve therapeutic index of oxaliplatin is represented by selection of responder patients whose tumors harbor molecular defects in the DNA damage repair pathway.

Background The management of locally advanced rectal cancer (RC) is an evolving clinical field where the multidisciplinary approach can reach its best, and liquid biopsy for obtaining tumor-derived component such as circulating tumor DNA (ctDNA) might provide complementary informations. Methods A systematic review of studies available in literature of liquid biopsy in non-metastatic RC has been performed according to PRISMA criteria to assess the role of ctDNA as a diagnostic, predictive and prognostic biomarker in this setting. Results Twenty-five publications have been retrieved, of which 8 full-text articles, 7 abstracts and 10 clinical trials. Results have been categorized into three groups: diagnostic, predictive and prognostic. Few but promising data are available about the use of liquid biopsy for early diagnosis of RC, with the main limitation of sensitivity due to low concentrations of ctDNA in this setting. In terms of prediction of response to chemoradiation, still inconclusive data are available about the utility of a pre-treatment liquid biopsy, whereas some studies report a positive correlation with a dynamic (pre/post-treatment) monitoring. The presence of minimal residual disease by ctDNA was consistently associated with worse prognosis across studies. Conclusions The use of liquid biopsy for monitoring response to chemoradiation and assess the risk of disease recurrence are the most advanced potential applications for liquid biopsy in RC, with implications also in the context of non-operative management strategies.

The RAS oncogene is among the most commonly mutated in cancer. RAS mutations are identified in about half of patients diagnosed with metastatic colorectal cancer (mCRC), conferring poor prognosis and lack of response to anti-epidermal growth factor receptor (EGFR) antibodies. In the last decades, several investigational attempts failed in directly targeting RAS mutations, thus RAS was historically regarded as ‘undruggable’. Recently, novel specific KRASG12C inhibitors showed promising results in different solid tumors, including mCRC, renewing interest in this biomarker as a target. In this review, we discuss different strategies of RAS targeting in mCRC, according to literature data in both clinical and preclinical settings. We recognized five main strategies focusing on those more promising: direct RAS targeting, targeting the mitogen-activated protein kinase (MAPK) pathway, harnessing RAS through immunotherapy combinations, RAS targeting through metabolic pathways, and finally other miscellaneous approaches. Direct KRASG12C inhibition is emerging as the most promising strategy in mCRC as well as in other solid malignancies. However, despite good disease control rates, tumor response and duration of response are still limited in mCRC. At this regard, combinational approaches with anti-epidermal growth factor receptor drugs or checkpoint inhibitors have been proposed to enhance treatment efficacy, based on encouraging results achieved in preclinical studies. Besides, concomitant therapies increasing metabolic stress are currently under evaluation and expected to also provide remarkable results in RAS codon mutations apart from KRASG12C. In conclusion, based on hereby reported efforts of translational research, RAS mutations should no longer be regarded as ‘undruggable’ and future avenues are now opening for translation in the clinic in mCRC., Highlights • RAS mutations were historically considered ‘undruggable’ despite their high prevalence in colorectal cancer. • Many strategies targeting RAS mutations were attempted in the past with poor results across all histologies. • Novel inhibitors of the KRASG12C mutation recently obtained encouraging results in early-phase clinical trials. • Combining KRASG12C inhibition with anti-EGFR drugs or immunotherapy may provide further opportunities in colorectal cancer.