ABSTRACT
Modern advancements in targeted therapy and immunotherapy have significantly improved survival outcomes for advanced melanoma; however, there remains a need for novel approaches to overcome disease progression and treatment resistance. In recent years, PARPi therapy has shown great promise both as a single regimen and in combination with other therapeutics in melanoma. Here, we describe three unique cases of advanced BRAF V600 mutated melanoma that progressed on targeted BRAF/MEK agents that subsequently exhibited partial to near-complete responses to combinatory PARPi and BRAF/MEK inhibitors. This highlights both a potential synergy underlying this combinatory approach and its efficacy as a treatment option for patients with advanced melanoma refractory to targeted and/or immunotherapies. Prospective clinical trials are needed to explore this synergic effect in larger melanoma cohorts to investigate this combination for treating refractory advanced melanoma.
ABSTRACT
Background: Shwachman-Diamond syndrome (SDS) is a rare inherited bone marrow failure syndrome associated with cytopenia and the development of hematologic malignancies. Solid tumor occurrence is rare and, historically, these patients have had poor outcomes due to chemotherapy-induced myelosuppression and increased susceptibility to infections. We report the administration of cytotoxic systemic therapy with granulocyte colony-stimulating factor (G-CSF) in a patient with SDS and metastatic breast cancer. We describe the risk-benefit profile of utilizing G-CSF in managing this patient to improve her therapeutic outcome and review the prior literature. Case Description: A 41-year-old Caucasian female with SDS developed stage IV triple-positive [estrogen positive, progesterone positive, and human epidermal growth factor receptor 2 (HER2) positive] invasive ductal carcinoma of the left breast with liver metastases. She had lifelong thrombocytopenia with other hematologic parameters within normal limits, no tumor protein 53 (TP53) mutation, and no history of marrow dysplasia. Based on her underlying SDS, paclitaxel was favored over docetaxel due to the reduced risk of myelosuppression and weekly dosing schedule. Her regimen included weekly paclitaxel with trastuzumab and pertuzumab every 21 days. She experienced chemotherapy-induced neutropenia with an absolute neutrophil count of less than 1,500 leading to the utilization of G-CSF support. She received chemotherapy with twice-weekly G-CSF and did not experience severe infections. After nine cycles of therapy, she had no evidence of metastatic disease on imaging. The patient has an ongoing complete response at 18 months since treatment initiation. Conclusions: This case report describes the treatment of a patient with SDS and metastatic breast cancer with cytotoxic chemotherapy and G-CSF. G-CSF facilitated ongoing chemotherapy administration and reduced the risk of infection leading to an optimal therapeutic outcome. There should be careful consideration of early G-CSF use in patients with SDS to optimize continuous chemotherapy dosing.
ABSTRACT
Immunotherapy is the first-line option for treating advanced cutaneous squamous cell carcinoma (cSCC). However, up to half of patients experience no benefit and treatment resistance, warranting newer therapeutic approaches. Combinatory approaches, including cetuximab, may help overcome immunotherapy resistance and improve response rates in advanced cSCC. We report three cases of metastatic cSCC that achieved significant clinical responses after cetuximab therapy following initial progression on pembrolizumab. We have retrospectively reviewed these cases at a single academic center between 2018 and 2023. All patients initially progressed on pembrolizumab, after which cetuximab (mono- or combination therapy) was added with two complete responses and one partial response. Initial responses were noted within 2 to 7 months of starting cetuximab. While the benefit of cetuximab and immunotherapy in head-and-neck squamous cell carcinoma has growing evidence, information regarding cSCC remains limited. This study adds three cases to the underreported literature on treating advanced cSCC with cetuximab after initially failing immunotherapy.
ABSTRACT
Skin cancers, including basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (SCC), and melanoma, are the most common malignancies in the United States. Loss of DNA repair pathways in the skin plays a significant role in tumorigenesis. In recent years, targeting DNA repair pathways, particularly homologous recombination deficiency (HRD), has emerged as a potential therapeutic approach in cutaneous malignancies. This review provides an overview of DNA damage and repair pathways, with a focus on HRD, and discusses major advances in targeting these pathways in skin cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors have been developed to exploit HRD in cancer cells. PARP inhibitors disrupt DNA repair mechanisms by inhibiting PARP enzymatic activity, leading to the accumulation of DNA damage and cell death. The concept of synthetic lethality has been demonstrated in HR-deficient cells, such as those with BRCA1/2 mutations, which exhibit increased sensitivity to PARP inhibitors. HRD assessment methods, including genomic scars, RAD51 foci formation, functional assays, and BRCA1/2 mutation analysis, are discussed as tools for identifying patients who may benefit from PARP inhibitor therapy. Furthermore, HRD has been implicated in the response to immunotherapy, and the combination of PARP inhibitors with immunotherapy has shown promising results. The frequency of HRD in melanoma ranges from 18% to 57%, and studies investigating the use of PARP inhibitors as monotherapy in melanoma are limited. Further research is warranted to explore the potential of PARP inhibition in melanoma treatment.