The clinical challenges of homologous recombination proficiency in ovarian cancer: from intrinsic resistance to new treatment opportunities.

Ovarian cancer is the most lethal gynecologic cancer. Optimal cytoreductive surgery followed by platinum-based chemotherapy with or without bevacizumab is the conventional therapeutic strategy. Since 2016, the pharmacological treatment of epithelial ovarian cancer has significantly changed following the introduction of the poly (ADP-ribose) polymerase inhibitors (PARPi). BRCA1/2 mutations and homologous recombination deficiency (HRD) have been established as predictive biomarkers of the benefit from platinum-based chemotherapy and PARPi. While in the absence of HRD (the so-called homologous recombination proficiency, HRp), patients derive minimal benefit from PARPi, the use of the antiangiogenic agent bevacizumab in first line did not result in different efficacy according to the presence of homologous recombination repair (HRR) genes mutations. No clinical trials have currently compared PARPi and bevacizumab as maintenance therapy in the HRp population. Different strategies are under investigation to overcome primary and acquired resistance to PARPi and to increase the sensitivity of HRp tumors to these agents. These tumors are characterized by frequent amplifications of Cyclin E and MYC, resulting in high replication stress. Different agents targeting DNA replication stress, such as ATR, WEE1 and CHK1 inhibitors, are currently being explored in preclinical models and clinical trials and have shown promising preliminary signs of activity. In this review, we will summarize the available evidence on the activity of PARPi in HRp tumors and the ongoing research to develop new treatment options in this hard-to-treat population.

Prognostic Value of Thyroid Hormone Ratio in Patients With Advanced Metastatic Renal Cell Carcinoma: Results From the Threefour Study (Meet-URO 14).

BACKGROUND: Thyroid hormone impairment, represented as an alteration in levels of thyroid hormones and a lower fT3/fT4 ratio, has been correlated with a worse prognosis for both cancer and non-cancer patients. The role of baseline thyroid function in patients with metastatic renal cell carcinoma (mRCC) however, has not been studied yet. MATERIALS AND METHODS: We recorded clinical data, baseline biochemical results, and oncological outcomes from 10 Oncology Units in Italy. We stratified patients into three groups according to the fT3/fT4 ratio value and subsequently analyzed differences in progression-free survival (PFS) and overall survival (OS) in the three groups. We also performed univariate and multivariate analyses to find prognostic factors for PFS and OS. RESULTS: We analyzed 134 patients treated with systemic treatment for mRCC. Median PFS in the low, intermediate, and high fT3/fT4 ratio group were 7.5, 12.1, and 21.7 months respectively (p<0.001); median OS in the three groups were 36.5, 48.6, and 70.5 months respectively (p =0.006). The low fT3/fT4 ratio maintained its prognostic role at the multivariate analysis independently from IMDC and other well-established prognostic factors. The development of iatrogenic hypothyroidism was not associated with a better outcome. CONCLUSION: We found that baseline thyroid hormone impairment, represented by a low fT3/fT4 ratio, is a strong prognostic factor in patients treated for mRCC in first line setting and is independent of other parameters currently used in clinical practice.

Clinical Impact of COVID-19 Outbreak on Cancer Patients: A Retrospective Study.

BACKGROUND: Coronavirus disease (COVID-19), an acute respiratory syndrome caused by a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), has rapidly spread worldwide, significantly affecting the outcome of a highly vulnerable group such as cancer patients. The aim of the present study was to evaluate the clinical impact of COVID-19 infection on outcome and oncologic treatment of cancer patients. PATIENT AND METHODS: We retrospectively enrolled cancer patients with laboratory and/or radiologic confirmed SARS-CoV-2 infection, admitted to our center from February to April 2020. Descriptive statistics were used to summarize the clinical data and univariate analyses were performed to investigate the impact of anticancer treatment modifications due to COVID-19 outbreak on the short-term overall survival (OS). RESULTS: Among 61 patients enrolled, 49 (80%) were undergoing anticancer treatment and 41 (67%) had metastatic disease. Most patients were men; median age was 68 years. Median OS was 46.6 days (40% of deaths occurred within 20 days from COVID-19 diagnosis). Among 59 patients with available data on therapeutic course, 46 experienced consequences on their anticancer treatment schedule. Interruption or a starting failure of the oncologic therapy correlated with significant shorter OS. Anticancer treatment delays did not negatively affect the OS. Lymphocytopenia development after COVID was significantly associated with worst outcome. CONCLUSIONS: COVID-19 diagnosis in cancer patients may affect their short-term OS, especially in case of interruption/starting failure of cancer therapy. Maintaining/delaying cancer therapy seems not to influence the outcome in selected patients with recent COVID-19 diagnosis.

Afatinib therapy in case of EGFR G724S emergence as resistance mechanism to osimertinib.

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) used both as the first-line treatment of EGFR-mutated non-small cell lung cancer patients and in second-line after T790M-positive disease progression to first- or second-generation TKIs. Unfortunately, patients unavoidably experience disease progression to osimertinib and the current research is focused on resistance mechanisms and the relative therapeutic strategy. We report the case of a patient with advanced EGFR-mutated (exon 19 deletion and T790M-positive) non-small cell lung cancer who developed disease progression to osimertinib characterized by the loss of T790M concurrently with the emergence of G724S EGFR mutation, which was tackled by subsequent afatinib treatment. Next-generation sequencing molecular study of rebiopsy at time of progression to osimertinib revealed the persistence of EGFR exon 19 deletion, loss of T790M with a new G724S EGFR mutation; other concomitant mechanisms were excluded. Retrospective analysis of cell-free DNA revealed the emergence of G724S EGFR mutation four months before the radiologically-proven disease progression. The patient, after chemotherapy, was treated with afatinib with clinical and radiological benefit. Our case report contributes to increase the knowledge on acquired resistance mechanisms to osimertinib treatment, and it shows, for the first time, the efficacy of afatinib in the case of T790M loss and emergence of G724S EGFR mutation.

PD-L1 ≥ 50% lung cancer refractory to PD-1 inhibition: the role of salvage chemo-immunotherapy combination.

Novel treatment strategies incorporating PD-1/PD-L1 inhibitors in the first-line setting of advanced non-small-cell lung cancer (NSCLC) provided relevant improvements in survival outcomes. Among NSCLC patients with PD-L1 tumor proportion score ≥50%, identifying the ones to be addressed to pembrolizumab monotherapy or chemo-immunotherapy combinations is a matter of debate, taking into account the risks of overtreatment and toxicity. Here we report the clinical stories of four NSCLC patients with PD-L1 tumor proportion score ≥50% and good performance status, sharing high tumor burden including serosal involvement. After having rapidly progressed on first-line PD-1/PD-L1 inhibitors, they achieved major clinical and radiological response to pembrolizumab-chemotherapy combination. These cases prove the feasibility and effectiveness of salvage chemo-immunotherapy in pembrolizumab-refractory NSCLC patients.

Clinical impact of COVID-19 in a single-center cohort of a prospective study in cancer patients receiving immunotherapy.

Aim: Evaluating the incidence and course of COVID-19 in cancer patients treated with immunotherapy. Patients & methods: We reported the influenza-like illness events with diagnosis of COVID-19 within the patient cohort enrolled in the prospective observational multicenter INVIDIa-2 study in the single center of Parma. Results: Among 53 patients, eight experienced influenza-like illness during the influenza season 2019/2020, and three of them had diagnosis of COVID-19. They were males, elderly, with cardiovascular disease. Radiological features of COVID-19 pneumonitis were found in all of three cases, although the pharyngeal swab resulted positive in only two. Two of these three patients died due to respiratory failure. Conclusion: Cancer patients are at high risk of severe events from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Activity of lenvatinib plus everolimus combination in a heavily pretreated patient with papillary renal cell carcinoma: a case report.

BACKGROUND: Papillary renal cell carcinoma (pRCC) represents the second most common histologic subtype of renal cell carcinoma and comprises 2 subtypes. Prognosis for type 2 is associated with poor clinical outcome. Current guidelines are based on phase II trials, phase III trials in patients with clear cell histology, or retrospective data. CASE DESCRIPTION: To our knowledge, we describe for the first time a case of a patient with heavily pretreated metastatic pRCC who benefited from the combination of lenvatinib plus everolimus for more than 2 years. CONCLUSION: According to immunohistologic and biological findings in our patient both on primary tumor and liver metastasis, we hypothesize that selected patients with metastatic pRCC, progressed to standard/available treatments (including angiogenic drugs, mTOR inhibitors, and immunotherapy) and dissociated response to everolimus, could benefit from adding lenvatinib to everolimus.

Mechanism of Action and Clinical Efficacy of CDK4/6 Inhibitors in BRCA-Mutated, Estrogen Receptor-Positive Breast Cancers: Case Report and Literature Review.

Sensitivity to endocrine therapy of patients with estrogen receptor (ER)-positive metastatic breast cancer and germline BRCA1/2 mutations is not yet fully elucidated. Furthermore, the registration trials of CDK 4/6 inhibitors in combination with endocrine therapy lacked of a pre-specified subgroup analysis in BRCA1/2 mutation carriers. We report clinical history of two patients with BRCA-mutated, ER-positive metastatic breast cancer treated with letrozole plus the CDK 4/6 inhibitor palbociclib. Biological and clinical implications of the treatment outcome observed in the two cases are discussed with the knowledge of scientific evidence to date available. Overall, biological rationale, preclinical, and clinical data support the prominent role of CDK 4/6 inhibitors plus endocrine therapy, even in combination with PARP inhibitors, in the treatment of BRCA-mutated, ER-positive breast cancers. However, the interaction between Cyclin/CDK pathway, ER and BRCA is complex and evidences reported so far, albeit reliable, await confirmation in the context of future randomized clinical trials.

Meeting with triumph and disaster: Osimertinib in T790M-unknown CNS progression in EGFR-mutated non-small cell lung cancer.

INTRODUCTION: Treatment paradigms for EGFR-mutated non-small cell lung cancer (NSCLC) have successfully evolved since the introduction of osimertinib. The detection of EGFR T790M mutation in plasma or tumor samples obtained at disease progression to first-/second-generation EGFR inhibitors is mandatory for osimertinib prescription. Nevertheless, pharmacokinetics properties of osimertinib guarantee its usefulness in central nervous system (CNS) disease even in the case of T790M-negative or unknown status. PATIENTS AND METHODS: In this brief report, we share the clinical histories of two patients with CNS-preeminent progression under first-/second-generation EGFR inhibitors in which it was not possible to document the presence of T790M resistance mutation. RESULTS: Patient outcomes diverged dramatically due to the differential availability of off-label osimertinib. CONCLUSIONS: Waiting for the novel molecule to be approved and licensed in first-line treatment, our report of hope and frustration is intended to stress the opportunity of its administration in the case of CNS failure of first-line EGFR inhibition, even in the absence of T790M proof.