PARP Inhibitors in Colorectal Malignancies: A 2023 Update.

BACKGROUND: Colorectal carcinoma (CRC) is one of the most common malignancies in the Western world, and metastatic disease is associated with a dismal prognosis. Poly-ADpribose polymerase (PARP) inhibitors gain increasing attention in the field of medical oncology, as they lead to synthetic lethality in malignancies with preexisting alterations in the DNA damage repair (DDR) pathway. As those alterations are frequently seen in CRC, a targeted approach through PARP inhibitors is expected to benefit these patients, both alone and in combination with other agents like chemotherapy, immunotherapy, antiangiogenics, and radiation. OBJECTIVE: This review article aims to better clarify the role of PARP inhibitors as a treatment option in patients with metastatic CRC with alterations in the DDR pathway. METHODS: We used the PubMed database to retrieve journal articles and the inclusion criteria were all human studies that illustrated the effective role of PARP inhibitors in patients with metastatic CRC with homologous repair deficiency (HRD) and the correct line of therapy. RESULTS: Current evidence supports the utilization of PARP inhibitors in CRC subgroups, as monotherapy and in combination with other agents. Up to now, data are insufficient to support a formal indication, and further research is needed. CONCLUSION: Efforts to precisely define the homologous repair deficiency (HRD) in CRC - and eventually the subgroup of patients that are expected to benefit the most - are also underway. REGISTRATION NUMBER: DOI: dx.doi.org/10.17504/protocols.io.dm6gp3ey8vzp/v1.

Identification of a Novel TSC2 c.170G>A Missense Variant: A Case Report and Elaboration on the Yield of Targeted Options against Tuberous Sclerosis Complex Manifestations.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare genetic disease that affects multiple organs and affects the quality of life. Mutations in TSC1 and TSC2 genes are causing dysregulations in the mammalian target of the rapamycin (mTOR) pathway, inducing mostly benign but also malignant tumors, including renal cell carcinoma (RCC). The diagnosis of TSC, based on established clinical and genetic criteria, is essential for the optimal surveillance and management of patients. CASE PRESENTATION: With the current report, we present the case of two sisters who were consequently diagnosed with early-stage chromophobe-like RCC, possibly familial given their young age. The younger sister also had a previous diagnosis of differentiated thyroid carcinoma, for which she had been treated properly. Genetic testing of both revealed the same heterozygous TSC2 variant that is currently regarded as a variant of unknown significance, while both patients did not fulfill the clinical criteria for the diagnosis of TSC. Owing to these data, we opted to manage and surveil both sisters as TSC patients, while we also considered the specific TSC2 variant to be pathogenic - but of low penetrance - based on clinical judgment and functional analyses. Furthermore, we discussed the implementation of mTOR inhibitors for the treatment of TSC complications. CONCLUSION: As novel pathogenic variants of TSC genes are constantly being explored, the identification of TSC variants of unknown significance in combination with absent clinical diagnostic criteria cannot exclude a TSC diagnosis. We support the implementation of clinical judgment in assisting the diagnosis of TSC, as well as the enrollment of patients in clinical trials due to the rarity of the disease.

Is the Patient Actually Failing on Enzalutamide? A Case Report and Issues to Consider in Enzalutamide-Resistant Oligoprogressive Metastatic Castrate-Resistant Prostate Cancer.

BACKGROUND: Metastatic castrate-resistant prostate cancer (mCRPC) is a challenging disease, especially in heavily pretreated patients. Androgen pathway inhibitors have contributed to a notable improvement in the overall survival and quality of life in patients with mCRPC during the last decade. Still, a considerable percentage of patients are unable to draw benefits from this drug category and are deprived of a treatment that offers limited toxicity and preserves a good quality of life. The mechanisms leading to this pre-existing or acquired resistance, as well as the possible strategies to overcome this resistance have been put at the center of scientists' attention. CASE PRESENTATION: With the present report we present the case of a 70-year-old patient with mCRPC, who was apparently an enzalutamide non-responder, but a multimodal approach with enzalutamide continuation and irradiation to his symptomatic oligoprogressive disease converted him to a responder with clinical, biochemical and imaging response; furthermore, we discuss the existing data providing evidence for the use of metastasis-directed therapy in combination with androgen pathway inhibitors in order to overcome drug resistance in patients with oligoprogressive disease. CONCLUSION: A considerable proportion of patients with oligometastatic or oligoprogressive prostate cancer who seem not to respond to androgen pathway inhibitors, such as enzalutamide, due to preexisting or acquired resistance, could benefit from MDT with a multimodal treatment approach. This strategy allows androgen pathway inhibitor continuation beyond biochemical progression and delays the switch to next-line systemic treatment.

Immune checkpoint inhibitors and combinations with other agents in cholangiocarcinoma.

Cholangiocarcinoma consists of a heterogeneous group of malignancies with generally poor prognoses. Immunotherapy has emerged in the treatment landscape of many tumors, offering survival benefits, but data regarding the use of immunotherapy for cholangiocarcinoma remain vague. In this review, the authors analyze differences in the tumor microenvironment and various immune escape mechanisms and discuss available immunotherapy combinations with other agents among completed and ongoing clinical trials, such as chemotherapy, targeted agents, antiangiogenic drugs, local ablative therapies, cancer vaccines, adoptive cell therapy and PARP and TGF-ß inhibitors. Ongoing research to identify appropriate biomarkers is warranted.

Cholangiocarcinomas are a group of rare tumors. Survival time is limited, due to late diagnosis and advanced symptoms. The small number of patients makes it difficult to carry out clinical trials and find new medicines. Another issue is that there are many different subtypes of this tumor. Each one requires a different approach. Despite these setbacks, new treatment choices have appeared. Medicines that stimulate the immune system to fight cancer cells have changed the current treatment landscape for many tumor types and are very promising in cholangiocarcinomas.