Focus on RAS Codon 61 Mutations in Metastatic Colorectal Cancer: A Retrospective Analysis.

RAS mutations involving codon 61 are rare in metastatic colorectal cancer (mCRC), accounting for only 1-4%, but they have recently been identified with high frequency in the circulating tumor DNA (ctDNA) of patients with secondary resistance to anti-EGFRs. This retrospective monocentric study aimed to investigate the clinical phenotype and prognostic performance of codon 61 RAS-mutated mCRC. Fifty patients with codon 61 RAS-mutated mCRC treated at our institution between January 2013 and December 2021 were enrolled. Additional datasets of codon 61 RAS wild-type mCRCs (648 patients) were used as comparators. The endpoint for prognostic assessment was overall survival (OS). Metastatic involvement of the peritoneum or ovary was significantly more frequent in codon 61 RAS-mutated mCRC compared to codon 61 RAS wild-type (54 vs. 28.5%), non-codon 61 RAS-mutated (35.6%), BRAF V600E-mutated (25%), and RAS/BRAF wild-type (20.5%) cohorts. At a median follow up of 96.2 months, the median OS for codon 61 RAS-mutated patients was significantly shorter compared to RAS/BRAF wild-type (26.9 vs. 36.0 months, HR 0.56) patients, while no significant difference was observed compared to non-codon 61 RAS-mutated and BRAF V600E-mutated patients. We showed a negative prognostic impact and a statistically significant correlation between codon 61 RAS mutations and metastatic involvement of the peritoneum and ovary.

Pemigatinib for patients with previously treated, locally advanced or metastatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements: A joint analysis of the French PEMI-BIL and Italian PEMI-REAL cohort studies.

BACKGROUND: Pemigatinib is approved for patients with pretreated, locally advanced or metastatic CCA harboring FGFR2 rearrangements or fusions. We aim to assess the effectiveness and safety of pemigatinib in real-world setting. MATERIAL AND METHODS: A joint analysis of two multicentre observational retrospective cohort studies independently conducted in France and Italy was performed. All consecutive FGFR2-positive patients affected by CCA and treated with pemigatinib as second- or further line of systemic treatment in clinical practice, within or outside the European Expanded Access Program, were included. RESULTS: Between July 2020 and September 2022, 72 patients were treated with pemigatinib in 14 Italian and 25 French Centres. Patients had a median age of 57 years, 76% were female, 81% had ECOG-PS 0-1, 99% had intrahepatic CCA, 74% had ≥ 2 metastatic sites, 67% had metastatic disease at diagnosis, while 38.8% received ≥ 2 previous lines of systemic treatment. At data cut-off analysis (April 2023), ORR and DCR were 45.8% and 84.7%, respectively. Median DoR was 7 months (IQR: 5.8-9.3). Over a median follow-up time of 19.5 months, median PFS and 1-year PFS rate were 8.7 months and 32.8%. Median OS and 1-year OS rate were 17.1 months and 60.6%. Fatigue (69.4%), ocular toxicity (68%), nail toxicities (61.1%), dermatologic toxicity (41.6%) hyperphosphataemia (55.6%), stomatitis (48.6%), and diarrhea (36.1%) were the most frequent, mainly G1-G2 AEs. Overall incidence of G3 AEs was 22.2%, while no patient experienced G4 AE. Dose reduction and temporary discontinuation were needed in 33.3% and 40.3% of cases, with 1 permanent discontinuation due to AEs. CONCLUSIONS: These results confirm the effectiveness and safety of pemigatinib in a real-world setting.

An Immune-Related Gene Expression Signature Predicts Benefit from Adding Atezolizumab to FOLFOXIRI plus Bevacizumab in Metastatic Colorectal Cancer.

PURPOSE: AtezoTRIBE phase II randomized study demonstrated that adding atezolizumab to first-line FOLFOXIRI (5-fluorouracil, oxaliplatin, irinotecan) plus bevacizumab prolongs progression-free survival (PFS) of patients with metastatic colorectal cancer (mCRC), with a modest benefit among proficient mismatch repair (pMMR). DetermaIO is an immune-related 27-gene expression signature able to predict benefit from immune checkpoint inhibition in triple-negative breast cancer. In this analysis of AtezoTRIBE, we investigated the predictive impact of DetermaIO in mCRC. EXPERIMENTAL DESIGN: Patients with mCRC unselected for MMR status were randomly assigned (1:2) to FOLFOXIRI plus bevacizumab (control arm) or the same regimen with atezolizumab (atezolizumab arm). qRT-PCR by DetermaIO was performed on RNA purified from pretreatment tumors of 132 (61%) of 218 enrolled patients. A binary result (IOpos vs. IOneg) adopting the preestablished DetermaIO cut-off point (0.09) was obtained, and an exploratory optimized cut-off point (IOOPT) was computed in the overall population and in pMMR subgroup (IOOPTpos vs. IOOPTneg). RESULTS: DetermaIO was successfully determined in 122 (92%) cases, and 23 (27%) tumors were IOpos. IOpos tumors achieved higher PFS benefit from atezolizumab arm than IOneg (HR: 0.39 vs. 0.83; Pinteraction = 0.066). In pMMR tumors (N = 110), a similar trend was observed (HR: 0.47 vs. 0.93; Pinteraction = 0.139). In the overall population, with the computed IOOPT cut-off point (0.277), 16 (13%) tumors were IOOPTpos and they derived higher PFS benefit from atezolizumab than IOOPTneg (HR: 0.10 vs. 0.85, Pinteraction = 0.004). Similar results were found in the pMMR subgroup. CONCLUSIONS: DetermaIO may be useful to predict benefit of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in mCRC. The exploratory IOOPT cut-off point should be validated in independent mCRC cohorts.

The role of the multidisciplinary tumor board (MDTB) in the assessment of pancreatic cancer diagnosis and resectability: A tertiary referral center experience.

Background: The introduction of multidisciplinary tumor boards (MDTBs) for the diagnostic and therapeutic pathway of several oncological disease significantly ameliorated patients' outcomes. However, only few evidences are currently present on the potential impact of the MDTB on pancreatic cancer (PC) management. Aim of this study is to report how MDTB may influence PC diagnosis and treatment, with particular focus on PC resectability assessment and the correspondence between MDTB definition of resectability and intraoperative findings. Methods: All patients with a proven or suspected diagnosis of PC discussed at the MDTB between 2018 and 2020 were included in the study. An evaluation of diagnosis, tumor response to oncological/radiation therapy and resectability before and after the MDTB was conducted. Moreover, a comparison between the MDTB resectability assessment and the intraoperative findings was performed. Results: A total of 487 cases were included in the analysis: 228 (46.8%) for diagnosis evaluation, 75 (15.4%) for tumor response assessment after/during medical treatment, 184 (37.8%) for PC resectability assessment. As a whole, MDTB led to a change in treatment management in 89 cases (18.3%): 31/228 (13.6%) in the diagnosis group, 13/75 (17.3%) in the assessment of treatment response cohort and 45/184 (24.4%) in the PC resectability evaluation group. As a whole, 129 patients were given indication to surgery. Surgical resection was accomplished in 121 patients (93.7%), with a concordance rate of resectability between MDTB discussion and intraoperative findings of 91.5%. Concordance rate was 99% for resectable lesions and 64.3% for borderline PCs. Conclusions: MDTB discussion consistently influences PC management, with significant variations in terms of diagnosis, tumor response assessment and resectability. In this last regard, MDTB discussion plays a key role, as demonstrated by the high concordance rate between MDTB resectability definition and intraoperative findings.

Efficacy of third-line anti-EGFR-based treatment versus regorafenib or trifluridine/tipiracil according to primary tumor site in RAS/BRAF wild-type metastatic colorectal cancer patients.

Background: Right- (R) and left-sided (L) metastatic colorectal cancer (mCRC) exhibit different clinical and molecular features. Several retrospective analyses showed that survival benefit of anti-EGFR-based therapy is limited to RAS/BRAF wt L-sided mCRC patients. Few data are available about third-line anti-EGFR efficacy according to primary tumor site. Methods: RAS/BRAF wt patients mCRC treated with third-line anti-EGFR-based therapy versus regorafenib or trifluridine/tipiracil (R/T) were retrospectively collected. The objective of the analysis was to compare treatment efficacy according to tumor site. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), response rate (RR) and toxicity. Results: A total of 76 RAS/BRAF wt mCRC patients, treated with third-line anti-EGFR-based therapy or R/T, were enrolled. Of those, 19 (25%) patients had a R-sided tumor (9 patients received anti-EGFR treatment and 10 patients R/T) and 57 (75%) patients had a L-sided tumor (30 patients received anti-EGFR treatment and 27 patients R/T). A significant PFS [7.2 vs 3.6 months, HR 0.43 (95% CI 0.2-0.76), p= 0.004] and OS benefit [14.9 vs 10.9 months, HR 0.52 (95% CI 0.28-0.98), p= 0.045] in favor of anti-EGFR therapy vs R/T was observed in the L-sided tumor group. No difference in PFS and OS was observed in the R-sided tumor group. A significant interaction according to primary tumor site and third-line regimen was observed for PFS (p= 0.05). RR was significantly higher in L-sided patients treated with anti-EGFR vs R/T (43% vs. 0%; p <0.0001), no difference was observed in R-sided patients. At the multivariate analysis, third-line regimen was independently associated with PFS in L-sided patients. Conclusions: Our results demonstrated a different benefit from third-line anti-EGFR-based therapy according to primary tumor site, confirming the role of L-sided tumor in predicting benefit from third-line anti-EGFR vs R/T. At the same time, no difference was observed in R-sided tumor.

Primary versus secondary antiemetic prophylaxis with NK1 receptor antagonists in patients affected by gastrointestinal malignancies and treated with a doublet or triplet combination regimen including oxaliplatin and/or irinotecan plus fluoropyrimidines: A propensity score matched analysis.

Aim: The aim of the current study is to investigate the impact of primary compared to secondary chemotherapy-induced nausea and vomiting (CINV) prophylaxis with NK1 receptor antagonists (NK1-RA) in patients affected by gastrointestinal malignancies and treated with oxaliplatin- and/or irinotecan-based doublet or triplet regimens. Study design and methods: Clinical data of patients affected by gastrointestinal malignancies, treated with an oxaliplatin and/or irinotecan-based doublet or triplet regimen as neo/adjuvant or advanced-line treatment, and who received NK1-RA as primary (from the first cycle of treatment) or secondary (after the onset of CINV with a previous regimen with 5HT3-RA and dexamethasone) prophylaxis for CINV, were retrospectively collected in an observational study involving 16 Italian centers. A propensity score matching was performed by taking into account the following stratification factors: sex (male vs. female), age (< vs. ≥70 years old), overweight (body mass index, BMI < vs. ≥25), underweight (BMI < vs. ≥19), disease spread (early vs. advanced/metastatic), tumor type (esophagogastric cancer vs. the rest, hepatobiliary tumor vs. the rest, colorectal cancer vs. the rest), type of NK1-RA used as primary/secondary prophylaxis (netupitant-palonosetron vs. fosaprepitant/aprepitant), concomitant use of opioids (yes vs. no), concomitant use of antidepressant/antipsychotic drugs (yes vs. no), Eastern Cooperative Oncology Group (ECOG) performance status at the start of NK1-RA treatment (0 vs. 1-2), and intensity of chemotherapy regimen (doublet vs. triplet). Results: Among 409 patients included from January 2015 to January 2022 and eligible for analysis, 284 (69%) and 125 (31%) were treated with NK1-RA as primary and secondary antiemetic prophylaxis, respectively. After matching, primary NK1-RA use was not associated with higher rates of protection from emesis regardless the emesis phase (acute phase, p = 0.34; delayed phase, p = 0.14; overall phase, p = 0.80). On the other hand, a lower rate of relevant nausea (p = 0.02) and need for rescue antiemetic therapy (p = 0.000007) in the overall phase was found in primary NK1-RA users. Furthermore, a higher rate of both complete antiemetic response (p = 0.00001) and complete antiemetic protection (p = 0.00007) in the overall phase was more frequently observed in primary NK1-RA users. Finally, chemotherapy delays (p = 0.000009) and chemotherapy dose reductions (p = 0.0000006) were less frequently observed in primary NK1-RA users. Conclusion: In patients affected by gastrointestinal malignancies, a primary CINV prophylaxis with NK1-RA, 5HT3-RA, and dexamethasone might be appropriate, particularly in those situations at higher risk of emesis and in which it is important to avoid dose delays and/or dose reductions, keeping a proper dose intensity of chemotherapy drugs.

Role of Chemoradiation in the Adjuvant Treatment of Radically Resected Pancreatic Cancer Patients: A Mono-Institutional Retrospective Analysis.

INTRODUCTION: Pancreatic cancer (PC) represents an unfavorable prognosis condition, even in patients with resectable disease. The aim of this series was to investigate the role of treatment intensification with adjuvant chemoradiation (CRT) in radically resected PC patients. METHODS: Data from PC patients who underwent radical surgery, adjuvant chemotherapy (CT), and CRT throughout a 20-year period were retrospectively collected. Actuarial local control (LC) and the overall survival (OS) were the primary endpoints, with disease-free survival and metastasis-free survival (MFS) representing secondary endpoints. RESULTS: The analysis included 108 PC patients treated with adjuvant CRT and CT from January 2000 to August 2019. Median age was 66 years (range: 40-83), and all patients underwent radical surgical resection with adjuvant CT (88, 81.5%) plus concomitant CRT (101, 93.5%) or radiotherapy alone (7, 6.5%). The median dose delivered to the tumor bed was 50.4 Gy (range: 45-50.6 Gy), while median dose to regional lymphatic drainage stations was 39.6 Gy (range 39.6-45 Gy). Concomitant CT was a gemcitabine-based regimen in the vast majority of patients (87, 80.6%). Median follow-up time was 21 months; the 2- and 5-year LC rates were 75.8% and 59.1%, respectively. Perineural invasion at pathological assessment was found significantly associated with LC (p = 0.028). Median OS was 40 months with 2- and 5-year OS rates of 73.9% and 41.6%, respectively. CONCLUSIONS: The outcomes of this series suggest to investigate the possible impact of adding adjuvant CRT to CT in PC patients. Timing and combination of modern CRT with new systemic therapies need to be further investigated to personalize therapy and optimize clinical advantages.

The impact of the histological classification of ampullary carcinomas on long-term outcomes after pancreaticoduodenectomy: a single tertiary referral center evaluation.

PURPOSE: Ampullary carcinomas (ACs) are classified as pancreatobiliary (Pb-AC), intestinal (Int-AC), or mixed (Mixed-AC). The influencing role of AC subtypes on long-term outcomes is still matter of debate. Aim of this study is to evaluate the prognostic role of the three histological variants on the overall (OS) and disease-free survival (DFS) after pancreaticoduodenectomy(PD). METHODS: All PDs for AC between 2004 and 2020 were included. Patients were classified according to the histological feature in Pb-AC, Int-AC, and Mixed-AC. Five-year OS and DFS were compared among the subtypes. Additionally, the prognostic role of the histological classification on OS and DFS was evaluated. RESULTS: Fifty-six (48.7%) Pb-ACs, 53 (46.1%) Int-ACs, and 6 (5.2%) Mixed-ACs were evaluated. A poorer 5-year OS was evidenced for the Pb-AC group (54.1%) as compared to the Int-AC cohort (80.7%) (p = 0.03), but similar to the Mixed-AC population (33%) (p = 0.45). Pb-AC presented a worse 5-year DFS (42.3%) in comparison to the Int-AC (74.8%) (p = 0.002), while no difference was evidenced in comparison to the Mixed-AC (16.7%) (p = 0.51). At the multivariate analysis, the Pb-/Mixed-AC histotype was recognized as negative prognostic factor for both OS (OR: 2.29, CI: 1.05-4.98; p = 0.04) and DFS (OR: 2.17, CI: 1-4.33; p = 0.02). CONCLUSION: Histological subtypes of AC play a relevant role in long-term outcomes after PD. Pb-ACs and Mixed-ACs show a more aggressive tumor biology and a consequent worse survival as compared to the Int-AC subtype.

Management of single pulmonary metastases from colorectal cancer: State of the art.

Colorectal cancer (CRC) is one of the most common causes of death from cancer. Lung seeding occurs in approximately 10% of patients surgically treated for primary CRC with radical intent: the lung is the most common site of metastases after the liver. While surgical treatment of liver metastases is widely accepted to affect long-term outcomes, more controversial and not standardized is the therapy for CRC patients developing lung metastases. Experience suggests the potential curative role of pulmonary metastasectomy, especially in oligometastatic disease. However, the optimal strategy of care and the definition of prognostic factors after treatment still need to be defined. This review focused on the uncommon scenario of single pulmonary metastases from CRC. We explored pertinent literature and provide an overview of the epidemiology, clinical characteristics and imaging of single pulmonary metastases from CRC. Additionally, we identified the best available evidence for overall management. In particular, we analyzed the role and results of locoregional approaches (surgery, radiotherapy or ablative procedures) and their integration with systemic therapy.

Clinical, Pathological and Prognostic Features of Rare BRAF Mutations in Metastatic Colorectal Cancer (mCRC): A Bi-Institutional Retrospective Analysis (REBUS Study).

Recently, retrospective analysis began to shed light on metastatic colorectal cancers (mCRCs) harboring rare BRAF non-V600 mutations, documenting a distinct phenotype and a favorable prognosis. This study aimed to confirm features and prognosis of rare BRAF non-V600 mCRCs compared to BRAF V600E and BRAF wild-type mCRCs treated at two Italian Institutions. Overall, 537 cases were retrospectively evaluated: 221 RAS/BRAF wild-type, 261 RAS mutated, 46 BRAF V600E and 9 BRAF non-V600. Compared to BRAF V600E mCRC, BRAF non-V600 mCRC were more frequently left-sided, had a lower tumor burden and displayed a lower grade and an MMR proficient/MSS status. In addition, non-V600 mCRC patients underwent more frequently to resection of metastases with radical intent. Median overall survival (mOS) was significantly longer in the non-V600 compared to the V600E group. At multivariate analysis, only age < 65 years and ECOG PS 0 were identified as independent predictors of better OS. BRAF V600E mCRCs showed a statistically significant worse mOS when compared to BRAF wild-type mCRCs, whereas no significant difference was observed between BRAF non-V600 and BRAF wild-type mCRCs. Our study corroborates available evidence concerning incidence, clinicopathologic characteristics and prognosis of BRAF-mutated mCRCs.

KRAS G12C Metastatic Colorectal Cancer: Specific Features of a New Emerging Target Population.

BACKGROUND: Kirsten rat sarcoma viral oncogene (KRAS) G12C mutation occurs in about 4% of colorectal cancers (CRCs). Recently, KRAS G12C was identified to be a potential drug target and predictor of response to the novel on AMG510 target treatment. We described the clinicopathologic features and prognosis of KRAS G12C-mutated metastatic CRCs compared to other KRAS mutation. PATIENTS AND METHODS: Clinicopathologic features and outcome data of KRAS-mutated metastatic CRC (mCRC) patients referred to 3 Italian oncology units from January 2010 to December 2018 were collected. A cohort of KRAS-mutant mCRC patients referred to the Department of Medical Oncology at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy) within the same time frame was included as external validation. RESULTS: A total of 839 KRAS-mutated mCRC cases were included in the main patient population. A total of 145 patients (17%) had KRAS G12C mutation. Our analyses showed that patients harboring KRAS G12C mutation were more likely to be men and to present lung and liver metastases, and were less likely to have peritoneal spread. KRAS G12C mutation was associated with shorter overall survival compared to other KRAS mutations (hazard ratio, 1.32; 95% confidence interval, 1.07-1.63; P = .009). Such results were confirmed in the external validation cohort. CONCLUSION: The knowledge of the distinctive traits of KRAS G12C-mutated CRC patients is crucial to future translational research studies, clinical trial design, and proper interpretation of results.

Retreatment With Anti-EGFR Antibodies in Metastatic Colorectal Cancer Patients: A Multi-institutional Analysis.

BACKGROUND: On the basis of retrospective analyses and phase 2 studies, metastatic colorectal cancer patients whose disease responded to a first-line regimen containing an anti-epidermal growth factor receptor (EGFR) agent may experience benefit from anti-EGFR readministration in later therapy lines. While the analysis of circulating tumor DNA seems a promising tool to select the best candidates for this strategy, identifying clinical predictors of anti-EGFR sensitivity would be useful to drive treatment choices in daily practice. PATIENTS AND METHODS: A real-life database of 5530 patients treated at 6 institutions was queried. Included were patients who were retreated with anti-EGFRs, who had RAS/BRAF wild-type-status tissue samples, who had received a first-line anti-EGFR-based regimen with at least stable disease as best response, and who had received at least one further line of therapy before anti-EGFR retreatment. The association with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of variables potentially related to anti-EGFR sensitivity was investigated. RESULTS: A total of 86 patients were identified. The ORR during anti-EGFR retreatment was 19.8%; median PFS and OS were 3.8 and 10.2 months, respectively. No significant association of clinical features of anti-EGFR sensitivity with ORR, PFS, and OS was observed. Among the 56 patients with a time from the last anti-EGFR administration to first-line progressive disease of < 3 months (rechallenge group), > 2 prior therapy lines and a longer anti-EGFR-free interval were associated with higher ORR, but not with longer PFS or OS. CONCLUSION: Clinical features we deemed surrogates of anti-EGFR sensitivity were not reliable predictors of benefit from anti-EGFR retreatment.

PTEN in Colorectal Cancer: Shedding Light on Its Role as Predictor and Target.

Molecular assessment of colorectal cancer (CRC) is receiving growing attention, beyond RAS and BRAF, because of its influence on prognosis and prediction in cancer treatment. PTEN (phosphatase and tensin homologue), a tumor suppressor, regulating cell division and apoptosis, has been explored, and significant evidence suggests a role in cetuximab and panitumumab resistance linked to the epidermal growth factor receptor (EGFR) signal transduction pathway. Factors influencing PTEN activity should be analyzed to develop strategies to maximize the tumor suppressor role and to improve tumor response to cancer treatment. Therefore, an in-depth knowledge of the PI3K-Akt pathway-one of the major cancer survival pathways-and the role of PTEN-a major brake of this pathway-is essential in the era of precision medicine. The purpose of this literature review is to summarize the role of PTEN as a predictive factor and possible therapeutic target in CRC, focusing on ongoing studies and the possible implications in clinical practice.