Real-world treatment outcomes in HR+ HER2- metastatic breast cancer patients treated with CDK4/6 inhibitors: Results from a reference center in Brazil.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have been recently developed and introduced into clinical practice. METHODS: We retrospectively analyzed data from patients with confirmed HR+/HER2 metastatic breast cancer treated with hormonal therapy in combination with ribociclib (R), palbociclib (P), or abemaciclib (A). OUTCOMES: median progression-free survival (mPFS), time to treatment discontinuation (mTTD), and objective response rate (ORR). RESULTS: Between January 2016 - June 2021, 142 patients were treated with an CDK4/6i (79 P, 42 R, 21 A). The median age was 59 years and 67.6% had recurrent disease. Roughly 35.2%, 36.6%, 28.2% of the patients had 1, 2 or 3+ metastatic sites, respectively, and 55.6% of the patients received CDK4/6i as a first-line treatment. The mPFS was 28m(R) vs. 14m(P) vs. 6m(A) (P = 0.002), with a higher proportion of patients receiving R in the first-line setting. However, no difference was seen when the analysis was restricted to the first-line scenario (P = 0.193). Sixty-four patients required one dose reduction, and 19 patients required two. ORR was 76.2% (R) vs 62% (P) vs 42.9% (A). More patients achieved a complete response with R and P, with no difference in the incidence of partial response and stable disease. Adverse events occurred in 94.4% of the population, with the most common grade 3-4 AE being neutropenia (59.1%). CONCLUSIONS: Our results confirm the efficacy and tolerability of CDK4/6i in routine clinical practice. This is the first real-world data describing and comparing the efficacy and toxicity of CDK4/6i in the Brazilian population.

What can we learn from more than 1,000 Brazilian patients at risk of hereditary cancer?

Background: Identifying individuals at a higher risk of developing cancer is a major concern for healthcare providers. Cancer predisposition syndromes are the underlying cause of cancer aggregation and young-onset tumors in many families. Germline genetic testing is underused due to lack of access, but Brazilian germline data associated with cancer predisposition syndromes are needed. Methods: Medical records of patients referred for genetic counseling at the Oncogenetics Department at the Hospital Sírio-Libanês (Brasília, DF, Brazil) from July 2017 to January 2021 were reviewed. The clinical features and germline findings were described. Detection rates of germline pathogenic/likely pathogenic variant (P/LPV) carriers were compared between international and Brazilian guidelines for genetic testing. Results: A total of 1,091 individuals from 985 families were included in this study. Most patients (93.5%) had a family history of cancer, including 64% with a family member under 50 with cancer. Sixty-six percent of patients (720/1091) had a personal history of cancer. Young-onset cancers (<50 years old) represented 62% of the patients affected by cancer and 17% had multiple primary cancers. The cohort included patients with 30 different cancer types. Breast cancer was the most prevalent type of cancer (52.6%). Germline testing included multigene panel (89.3%) and family variant testing (8.9%). Approximately 27% (236/879) of the tested patients harbored germline P/LPVs in cancer susceptibility genes. BRCA2, BRCA1, and TP53 were the most frequently reported genes, corresponding to 18.6%, 14.4%, and 13.5% of the positive results, respectively. Genetic testing criteria from international guidelines were more effective in identifying carriers than the Brazilian National Agency of Supplementary Health (ANS) criteria (92% vs. 72%, p<0.001). Forty-six percent of the cancer-unaffected patients who harbored a germline P/LPV (45/98) would not be eligible for genetic testing according to ANS because they did not have a family variant previously identified in a cancer-affected relative. Conclusion: The high detection rate of P/LPVs in the present study is possibly related to the genetic testing approach with multigene panels and cohort's characteristics, represented mainly by individuals with a personal or family history of young-onset cancer. Testing asymptomatic individuals with suspicious family history may also have contributed to a higher detection rate. A significant number of carriers would not have been identified using ANS criteria for genetic testing.

Targeting PARP1 to Enhance Anticancer Checkpoint Immunotherapy Response: Rationale and Clinical Implications.

Reinvigorating the antitumor immune response using immune checkpoint inhibitors (ICIs) has revolutionized the treatment of several malignancies. However, extended use of ICIs has resulted in a cancer-specific response. In tumors considered to be less immunogenic, the response rates were low or null. To overcome resistance and improve the beneficial effects of ICIs, novel strategies focused on ICI-combined therapies have been tested. In particular, poly ADP-ribose polymerase inhibitors (PARPi) are a class of agents with potential for ICI combined therapy. PARPi impairs single-strand break DNA repair; this mechanism involves synthetic lethality in tumor cells with deficient homologous recombination. More recently, novel evidence indicated that PAPRi has the potential to modulate the antitumor immune response by activating antigen-presenting cells, infiltrating effector lymphocytes, and upregulating programmed death ligand-1 in tumors. This review covers the current advances in the immune effects of PARPi, explores the potential rationale for combined therapy with ICIs, and discusses ongoing clinical trials.

Cost-effectiveness analysis of Oncotype DX from a Brazilian private medicine perspective: a GBECAM multicenter retrospective study.

Background: Oncotype DX (ODX) is a validated assay for the prediction of risk of recurrence and benefit of chemotherapy (CT) in both node negative (N0) and 1-3 positive nodes (N1), hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early breast cancer (eBC). Due to limited access to genomic assays in Brazil, treatment decisions remain largely driven by traditional clinicopathologic risk factors. ODX has been reported to be cost-effective in different health system, but limited data are available considering the reality of middle-income countries such as Brazil. We aim to evaluate the cost-effectiveness of ODX across strata of clinical risk groups using data from a dataset of patients from Brazilian institutions. Methods: Clinicopathologic and ODX information were analyzed for patients with T1-T3, N0-N1, HR+/HER2- eBC who had an ODX performed between 2005 and 2020. Projections of CT indication by clinicopathologic criteria were based on binary clinical risk categorization based on the Adjuvant! Algorithm. The ODX score was correlated with the indication of CT according to TAILORx and RxPONDER data. Two decision-tree models were developed. In the first model, low and high clinical risk patients were included while in the second, only high clinical risk patients were included. The cost for ODX and CT was based on the Brazilian private medicine perspective. Results: In all, 645 patients were analyzed; 411 patients (63.7%) had low clinical risk and 234 patients (36.3%) had high clinical risk disease. The ODX indicated low (<11), intermediate (11-25), and high (>25) risk in 119 (18.4%), 415 (64.3%), and 111 (17.2%) patients, respectively. Among 645 patients analyzed in the first model, ODX was effective (5.6% reduction in CT indication) though with an incremental cost of United States Dollar (US$) 2288.87 per patient. Among 234 patients analyzed in the second model (high clinical risk only), ODX led to a 57.7% reduction in CT indication and reduced costs by US$ 4350.66 per patient. Conclusions: Our study suggests that ODX is cost-saving for patients with high clinical risk HR+/HER2- eBC and cost-attractive for the overall population in the Brazilian private medicine perspective. Its incorporation into routine practice should be strongly considered by healthcare providers.

Second-Line Treatment of HER2-Positive Salivary Gland Tumor: Ado-Trastuzumab Emtansine (T-DM1) after Progression on Trastuzumab.

Patients with salivary duct cancer (SDC) and HER2 overexpression could receive trastuzumab in combination with chemotherapy for metastatic disease. No standard treatment exists for patients with HER2-positive metastatic SDC after progression. We report an excellent patient response to second-line treatment with T-DM1 after progression on paclitaxel plus trastuzumab. CASE REPORT: In June 2014, a 79-year-old male patient underwent right parotidectomy and ipsilateral radical neck dissection after the diagnosis of parotid carcinoma. Pathological staging demonstrated locally advanced disease with the involvement of 13 lymph nodes (levels I, II, III, and IV), with extracapsular extravasation. He underwent adjuvant radiotherapy ending in December 2014. A PET scan in March 2015 diagnosed recurrent and systemic disease, with bone lesions, neck lymph node involvement, and hepatic metastasis. The immunohistochemistry showed HER2 receptor overexpression (+3/+3). The patient received first-line trastuzumab plus paclitaxel beginning in April 2015. After 6 cycles, his response was confirmed by PET scan. In February 2016, he had symptoms of disease progression, and a PET scan revealed disease progression in the neck, bones, and liver. He started T-DM1 in April 2016. The neck skin lesions disappeared after 6 cycles, with low toxicity. PET scans performed every 3 months showed response in the liver and bone lesions. CONCLUSIONS: We report the case of a patient with SDC treated with T-DM1, with a very good response. Salivary carcinoma is a rare disease for which no randomized clinical trials are available. The maintenance of HER2 blockage might be important in this disease.

Hepatocellular Carcinoma: Review of Targeted and Immune Therapies.

BACKGROUND: Hepatocellular carcinoma is the fifth most common cancer globally and the second leading cause of cancer-related mortality worldwide. Despite the established efficacy of screening programs for at-risk individuals, most patients are diagnosed at later stages of disease, wherein the tumor characteristics or liver disease progressions do not allow for curative interventions. Many cytotoxic chemotherapeutic agents have been tested in patients with advanced disease with disappointing outcomes and poor tolerance; therefore, no standard systemic therapy emerged until the approval of sorafenib in 2006. CONCLUSION: Despite the toxicity and low response rate, sorafenib had shown a significant survival benefit in phase III clinical trials, thus encouraging clinical research aimed at advancing the field of molecular therapy. Disrupted signaling pathways related to hepatocellular carcinoma (HCC) include the Wnt/ß-catenin, Ras/Raf/MAPK, phosphatidyl inositol 3-kinase/Akt/mechanistic target of rapamycin, hepatocyte growth factor/c-mesenchymal-epithelial transition, IGF, vascular endothelial growth factor, and platelet-derived growth factor pathways, and a variety of agents targeting these pathways are currently under investigation. Additionally, better comprehension of the complex mechanisms underlying the ability of tumor cells to escape immune surveillance has led to impressive results with immunotherapy in many types of cancer, and this treatment strategy is currently being developed for HCC patients. Previous and ongoing targeted therapy and immunotherapy trials for HCC are discussed in this review.