Pathological complete response achieved with FLOT chemotherapy in two patients with MSI-H esophagogastric junction and gastric adenocarcinoma.

Globally, more than 1 million new cases of gastric cancer were estimated in 2020, ranking fourth in cancer mortality. Currently although in resectable gastric cancer and esophagogastric junction (EGJ) adenocarcinoma a perioperative triplet chemotherapy regimen including a fluoropyrimidine, a platinum compound and docetaxel (FLOT) demonstrated a better overall survival, the survival rate is still very low, and a massive effort is still required to improve clinical prognosis. High microsatellite instability (MSI-H) status in gastric cancer is a favorable prognostic factor but poor data are available on its predictive role for perioperative FLOT chemotherapy in resectable gastric cancer. Here, we presented the case of two patients with advanced MSI-H gastric cancer/EGJ adenocarcinoma who had no residual tumor following neoadjuvant FLOT chemotherapy maintaining a complete response for more than 30 months, suggesting MSI-H status to be a positive prognostic marker also in patients treated with a taxane-containing triplet in this setting. We also discuss the future perspectives including the opportunity to achieve excellent clinical outcomes with immune checkpoint inhibitor (ICI)-based regimens.

Evaluation of Fruquintinib in the Continuum of Care of Patients with Colorectal Cancer.

The management of patients with metastatic colorectal cancer (mCRC) has the continuum of care as the treatment paradigm. To date, trifluridine/tipiracil, a biochemically modulated fluoropyrimidine, and regorafenib, a multi-kinase inhibitor, remain the main options for the majority of patients who progressed to standard doublet- or triplet-based chemotherapies, although a tailored approach could be indicated in certain circumstances. Being highly selective for vascular endothelial growth factor receptor (VEGFR)-1, -2 and -3, fruquintinib demonstrated a strong anti-tumor activity in preclinical models and received approval from China's National Medical Products Administration (NMPA) in 2018 for the treatment of patients with chemo-refractory mCRC. The approval was based on the results of the phase III FRESCO trial. Then, in order to overcome geographic differences in clinical practice, the FRESCO-2 trial was conducted in the US, Europe, Japan, and Australia. In a heavily pretreated patient population, the study met its primary endpoint, demonstrating an advantage of fruquintinib over a placebo in overall survival (OS). Here, we review the clinical development of fruquintinib and its perspectives in gastrointestinal cancers. Then, we discuss the introduction of fruquintinib in the continuum of care of CRC paying special attention to unmet needs, including the identification of cross-resistant and potentially susceptible populations, evaluation of radiological response, and identification of novel biomarkers of clinical benefit.

Perioperative Tailored Treatments for Gastric Cancer: Times Are Changing.

Resectable gastric or gastroesophageal (G/GEJ) cancer is a heterogeneous disease with no defined molecularly based treatment strategy. Unfortunately, nearly half of patients experience disease recurrence despite standard treatments (neoadjuvant and/or adjuvant chemotherapy/chemoradiotherapy and surgery). In this review, we summarize the evidence of potential tailored approaches in perioperative treatment of G/GEJ cancer, with a special focus on patients with human epidermal growth factor receptor-2(HER2)-positive and microsatellite instability-high (MSI-H) tumors. In patients with resectable MSI-H G/GEJ adenocarcinoma, the ongoing INFINITY trial introduces the concept of non-operative management for patients with complete clinical-pathological-molecular response, and this could be a novel and potential practice changing strategy. Other pathways involving vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), claudin18 isoform 2 (CLDN18.2), and DNA damage repair proteins are also described, with limited evidence until now. Although tailored therapy appears to be a promising strategy for resectable G/GEJ cancer, there are several methodological issues to address: inadequate sample size for pivotal trials, underestimation of subgroup effects, and choice of primary endpoint (tumor-centered vs. patient-centered endpoints). A better optimization of G/GEJ cancer treatment allows maximizing patient outcomes. In the perioperative phase, although caution is mandatory, times are changing and tailored strategies could introduce new treatment concepts. Overall, MSI-H G/GEJ cancer patients possess the characteristics to be the subgroup that could receive the most benefit from a tailored approach.

Gallbladder neuroendocrine neoplasm: a case report and critical evaluation of WHO classification.

Gallbladder neuroendocrine neoplasms (GB-NENs) are rare. The majority of GB-NENs are poorly differentiated, with increased mitotic activity and clinically aggressive course. Surgery is the only curative approach and the optimal medical treatment is uncertain. In this report we describe the case of a woman affected by metastatic well differentiated GB-NEN with increased Ki 67. The patient underwent surgical removal of the gallbladder neoplasm and showed disease recurrence with pulmonary and liver metastases. After achieving a partial chemotherapy response, the patient rapidly died due to progressive disease. This case raises important issues. Well differentiated NENs with a high proliferative index are not included as a specific entity in any of the most widely used nomenclature systems. Moreover considering the proliferative index of the disease, it is reasonable to consider the patient a candidate for chemotherapy. Nevertheless, recently published papers raise the possibility that well differentiated NENs and specific proliferative index cutoff can predict low chemosensitivity in patients with highly proliferative neuroendocrine carcinoma.

Biweekly sunitinib regimen reduces toxicity and retains efficacy in metastatic renal cell carcinoma: a single-center experience with 31 patients.

OBJECTIVES: Sunitinib is the standard care for first-line treatment of metastatic renal cell carcinoma. The aim of this study was to determine whether a sunitinib regimen of 50 mg/day 2-weeks on/1-week off could maintain the same dose-intensity as the standard 4-weeks on/2-weeks off schedule, and provide the same efficacy in terms of objective response, progression-free survival and overall survival, while reducing drug-related toxicity. METHODS: A total of 31 patients with metastatic renal cell carcinoma received sunitinib orally at the dose of 50 mg/day in a 2-weeks on/1-week off regimen until disease progression or intolerable toxicities occurred. RESULTS: All enrolled patients were assessable in terms of toxicity and response. They received treatment for a median of 16 months (range 2.0-36.0+ months). A total of 13 patients (42%) obtained an objective response; disease stabilization was achieved in 10 patients (32%), whereas eight patients (26%) experienced disease progression. The most important toxicities were anemia, gastrointestinal effects, fatigue and hypertension, but they were all controlled. CONCLUSIONS: Sunitinib 50 mg given orally in a 2-weeks on/1-week off regimen can provide a high response rate and avoid drug-related toxicities, achieving the same dose intensity as the standard schedule, and probably longer disease control.

Mutations matter: An observational study of the prognostic and predictive value of KRAS mutations in metastatic colorectal cancer.

Background: About half of metastatic colorectal cancers (CRCs) harbor Rat Sarcoma (RAS) activating mutations as oncogenic driver, but the prognostic role of RAS mutations is not fully elucidated. Interestingly, specific hotspot mutations have been identified as potential candidates for novel targeted therapies in several malignancies as per G12C. This study aims at evaluating the association between KRAS hotspot mutations and patient characteristics, prognosis and response to antiangiogenic drugs. Methods: Data from RAS-mutated CRC patients referred to Careggi University Hospital, between January 2017 and April 2022 were retrospectively and prospectively collected. Tumor samples were assessed for RAS mutation status using MALDI-TOF Mass Spectrometry, Myriapod NGS-56G Onco Panel, or Myriapod NGS Cancer Panel DNA. Results: Among 1047 patients with available RAS mutational status, 183 KRAS-mutated patients with advanced CRC had adequate data for clinicopathological and survival analysis. KRAS mutations occurred at codon 12 in 67.2% of cases, codon 13 in 23.5%, codon 61 in 2.2%, and other codons in 8.2%. G12C mutation was identified in 7.1% of patients and exon 4 mutations in 7.1%. KRAS G12D mutation, as compared to other mutations, was significantly associated with liver metastases (1-sided p=0.005) and male sex (1-sided p=0.039), KRAS G12C mutation with peritoneal metastases (1-sided p=0.035), KRAS G12V mutation with female sex (1-sided p=0.025) and no surgery for primary tumor (1-sided p=0.005). No associations were observed between specific KRAS variants and age, ECOG PS, site of primary tumor, pattern of recurrence for resected patients, and lung, distant lymph node, bone, or brain metastases.Overall survival (OS) was significantly longer in patients with KRAS exon 4 mutations than in those with other KRAS mutations (mOS 43.6 months vs 20.6 months; HR 0.45 [0.21-0.99], p=0.04). No difference in survival was observed for mutations at codon 12/13/61 (p=0.1). Treatment with bevacizumab (BV) increased significatively mPFS (p=0.036) and mOS (p=0.019) of the entire population with a substantial benefit in mOS for G12V mutation (p=0.031). Conclusions: Patterns of presentation and prognosis among patients with specific RAS hotspot mutations deserve to be extensively studied in large datasets, with a specific attention to the uncommon isoforms and the role of anti-angiogenic drugs.

Two-point-NGS analysis of cancer genes in cell-free DNA of metastatic cancer patients.

BACKGROUND: Although the efficacy of molecularly target agents in vitro, their use in routine setting is limited mainly to the use of anti-HER2 and antiEGFR agents in vivo. Moreover, core biopsy of a single cancer site may not be representative of the whole expanding clones and cancer molecular profile at relapse may differ with respect to the primary tumor. METHODS: We assessed the status of a large panel of cancer driver genes by cell-free DNA (cfDNA) analysis in a cohort of 68 patients with 13 different solid tumors at disease progression. Whenever possible, a second cfDNA analysis was performed after a mean of 2.5 months, in order to confirm the identified clone(s) and to check the correlation with clinical evolution. RESULTS: The approach was able to identify clones plausibly involved in the disease progression mechanism in about 65% of cases. A mean of 1.4 mutated genes (range 1-3) for each tumor was found. Point mutations in TP53, PIK3CA, and KRAS and copy number variations in FGFR3 were the gene alterations more commonly observed, with a rate of 48%, 20%, 16%, and 20%, respectively. Two-points-Next-Generation Sequencing (NGS) analysis demonstrated statistically significant correlation between allele frequency variation and clinical outcome (P = .026). CONCLUSIONS: Irrespective of the primary tumor mutational burden, few mutated genes are present at disease progression. Clinical outcome is consistent with variation of allele frequency of specific clones indicating that cfDNA two-point-NGS analysis of cancer driver genes could be an efficacy tool for precision oncology.

Systemic therapies and cognitive impairment for breast cancer: an overview of the current literature.

Both endocrine and chemotherapy can be utilized for breast cancer patients' management, in multiple setting (i.e., primary systemic therapy, adjuvant, metastatic treatment). Health-related quality of life in breast cancer survivors can be significantly influenced by cognitive impairment, which has been related in several previously reported experiences to systemic therapies administration. However, although the growing body of literature, the impact of both chemo- and endocrine therapy on cognitive function is currently unclear, due to many confounding factors (i.e., multiple therapies, duration of therapy, comorbidity, age). The aim of the present review is to present an overview of the current literature concerning the possible influence of endocrine and systemic therapy on breast cancer patients' cognitive impairment.

SAFE trial: an ongoing randomized clinical study to assess the role of cardiotoxicity prevention in breast cancer patients treated with anthracyclines with or without trastuzumab.

Over the years, thanks to the addition of new generation systemic agents, as well as the use of more advanced and precise radiotherapy techniques, it was able to obtain a high curability rate for breast cancer. Anthracyclines play a key role in the treatment of breast disease, with a well-known benefit on disease-free survival of patients with positive nodal status. Trastuzumab have shown a significant outcome advantage after 1-year administration in case of HER2-positive disease. Unfortunately, significant increase in cardiotoxicity has been observed after anthracyclines and trastuzumab therapies. Even though the cardiology and oncology community strongly recommend a cardiotoxicity prevention strategy for this subset of patients, there is still no consensus on the optimal patient's approach. We aimed to review the published and ongoing researches on cardioprevention strategies and to present the SAFE trial (CT registry ID: NCT2236806; EudraCT number: 2015-000914-23). It is a randomized phase 3, four-arm, single-blind, placebo-controlled study that aims to evaluate the effect of bisoprolol, ramipril or both drugs, compared to placebo, on subclinical heart damage evaluated by speckle tracking cardiac ultrasound in non-metastatic breast cancer patients.