Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and sensitize tumors to checkpoint blockade immunotherapy. However, many POLE mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we. prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with specific single base substitution signature, high T-cell infiltrates, and high response rate to anti-PD1 monotherapy. This study illustrates how specific DNA repair defects can sensitize to immunotherapy, POLE proofreading deficiency representing a novel tumor agnostic biomarker for response to PD-1 checkpoint blockade therapy.

Hepatoid adenocarcinoma (HAC) is a rare and aggressive cancer subtype with a poor prognosis under metastatic conditions. Currently, there is no specific chemotherapy treatment protocol for advanced stages of the disease. This review evaluates two cases of HAC of gastric cardia with synchronous liver metastasis, which were successfully treated by chemotherapy with cisplatin (25 mg/m2 each day) (day 1 to day 3) and etoposide (100 mg/m2) (day 1 to day 3), every three weeks. A structured literary evaluation and reviewed pertinent articles are additionally presented to analyse the different approaches for the treatment of metastatic HAC (mHAC). The two described case reports demonstrated good partial responses to treatment and one of the two patients exhibited a good prognosis after a 9-year follow-up. A total of 20 case reports concerning the use of chemotherapy in mHAC were presented in the literature, 11 of which were regarding gastric HACs. The two aforementioned cases result in a total of 22 reports, 11 of which exhibited objective responses to chemotherapy, 8 patients demonstrated a partial response and 3 a complete response. The cisplatin-based regimen concerned 55% (12/22) patients and enabled 9 (75%) to exhibit a partial or complete response. A total of three patients exhibited a good prognosis in the long-term follow-up, all of them treated with a cisplatin-based regimen. It was demonstrated that the usual digestive regimens were not efficient in the treatment of HAC. In the absence of prospective trials, it may be hypothesized that cisplatin-based chemotherapy may be the most efficient first-line treatment in mHAC, with a 75% patient response, in accordance with the literature and follow-up cases.

The cancer armamentarium is evolving with evidence of the efficacy of oral treatments. Their mode of administration is simple and convenient, but absorption is influenced by diet and gastric pH.Moreover, the efficacy of checkpoint inhibitors (CPIs) depends on the gut microbiome. Proton pump inhibitors (PPIs), which are among the most widely prescribed drugs, decrease the bioavailability of oral cancer treatments, lowering their efficacy, 1-4 and induce major microbial alterations in the gut. 4 We conducted a study to evaluate the prevalence of PPI prescribing, to identify the factors associated with PPI prescription, and to focus on patients receiving tyrosine kinase inhibitors (TKIs), CPIs, and capecitabine. MethodsThis cross-sectional study was conducted in 4 French Comprehensive Cancer Centers from June 15 to 19 and from June 22 to 26, 2020. It was approved by the ethics committee of Angers University, which waived the need for informed consent in accordance with university policy. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.Volunteer physicians collected data from patients with cancer seen in consultation or in the Same Day Unit. An information sheet (explaining the goals of the study, that patients could refuse to participate, and that all data would be anonymized) was given to patients; those who accepted were included. The physicians then completed a form (with scrolling menu) based on the patient's medical records and answers to a few questions.Parameters were compared using Welch t test, χ 2 test, or Fisher exact test as appropriate.Significant parameters were entered into a multivariable logistic regression with a stepwise procedure. All P values were 2-sided with P < .05 considered significant. Statistical analyses were performed with R statistical software version 4.0.2 (R Project for Statistical Computing). ResultsIn total, 872 complete and verified (data manager) forms corresponding to 566 women ( 64.9%) and 306 men (35.1%) (median [range] age, 63 [20-91] years) (Table 1) were recorded. Among these, 229 patients (26.3%) were taking PPIs on the day of inclusion. Most patients who used PPIs did so on a regular basis (163 patients [71.1%]), at normal dosage (154 patients [67.2%]), for epigastric pain (114 patients [50.0%]), retrosternal pain (32 patients [14.0%]), proven esophageal or gastric ulcer (18 patients [8.0%]), or gastroprotection (34 patients [15.0%]).

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Multikinase inhibitors (MKIs), and particularly tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (CPIs), are currently some of the major breakthroughs in cancer treatment. Proton pump inhibitors (PPIs) revolutionised the treatment of acid-related diseases, but are frequently overused for epigastric pain or heartburn. However, long-term acid suppression from using PPIs may lead to safety concerns, and could have a greater impact in cancer patients undergoing therapy, like bone fractures, renal toxicities, enteric infections, and micronutrient deficiencies (iron and magnesium). Moreover, acid suppression may also affect the pharmacokinetics of drugs (at least during acid suppression) and decrease the absorption of many molecularly-targeted anticancer therapies, which are mostly weak bases with pH-dependent absorption. This type of drug-drug interaction may have detrimental effects on efficacy, with major clinical impacts described for some orally administrated targeted therapies (erlotinib, gefitinib, pazopanib, palbociclib), and conflicting results with many others, including capecitabine. Furthermore, the long-term use of PPIs results in severe alterations to the gut microbiome and recent retrospective analyses have shown that the benefit of using CPIs was suppressed in patients treated with PPIs. These very expensive drugs are of great importance because of their efficacy. As the use of PPIs is not essential, we must apply the precautionary principle. All these data should encourage medical oncologists to refrain from prescribing PPIs, explaining to patients the risks of interaction in order to prevent inappropriate prescription by another physician.