![]() Approval of pembrolizumab for treating MSI-H/dMMR cancers While this can potentially become an alternative molecular test, with the advantage of simultaneous testing of TMB and other actionable gene mutations and optimization of tumor tissue usage, it is important to highlight that these tests should be performed at validated laboratories. More recently, the use of NGS panels has been validated for MSI-H diagnosis, and the reported concordance rates between NGS testing and IHC or PCR are both high 17, 18. Frequently, clinical trials that assessed MSI/MMR status used both IHC and PCR methodologies. In fact, pentaplex PCR is the preferred panel given its higher sensitivity and specificity 13, 16. Tumors with instability at 2 or more of these markers are defined as MSI-H 10, 12, 14, 15. This can be done using two panels: The National Cancer Institute (NCI) panel, which evaluates two single nucleotide repeat loci, BAT-25 and BAT-26, and three dinucleotide repeat loci, D2S123, D5S346 and D17S250 and pentaplex PCR, using five poly-A mononucleotide repeats (BAT-25, BAT-26, NR-21, NR-24, and NR-27). The assessment of microsatellite alterations using classical PCR-based methodology combined with fragment length analysis is usually performed with DNA samples from tumors and paired normal DNA. In cases of indeterminate IHC results, a molecular test preferentially based on PCR is indicated 13. Importantly, while there is a strong recommendation for performing IHC for all tumors belonging to the spectrum of Lynch syndrome, there are insufficient data for definitive recommendations in breast cancer. If IHC expression of at least one of those proteins is lost, the diagnosis of dMMR is established. dMMR by IHC is defined by the absence of nuclear staining of some of the abovementioned MMR proteins in the tumor with preserved internal positive cell controls 10. IHC for the MMR proteins MLH1, MSH2, MSH6, and PMS2 is a practical and widely available methodology among pathology laboratories. #Treatment with the designated agnostic therapy should be started during the course of therapy for patients with the target biomarker who have progressed following prior treatment, and no satisfactory alternative treatment options are available. †NGS should be performed preferentially at validated laboratories. *In cases of negative IHC for dMMR in breast cancer, confirmatory PCR or NGS could be performed. IHC: immunohistochemistry FFPE: formalin-fixed, paraffin-embedded FISH: fluorescence in situ hybridization MBC: metastatic breast cancer NGS: next-generation sequencing PCR: polymerase chain reaction. For those patients harboring any of these three biomarkers who have progressed following prior treatment and who have no satisfactory alternative treatment options, we recommend the use of the appropriate tissue-agnostic approved therapy. In the case of TMB, blood samples can be collected to perform liquid biopsy-based NGS panels. 1).įollowing the diagnosis of metastatic breast cancer, formalin-fixed, paraffin-embedded (FFPE) tissue blocks from archival tissue or from a new tumor biopsy should be used to evaluate the status of one of the three discussed biomarkers: MSI, TMB-H, or NTRK fusions. In 2020, the FDA expanded pembrolizumab approval to a new tissue-agnostic indication: high tumor mutational burden (TMB-H) 5 (Fig. The first tissue-agnostic treatment approval was granted by the FDA to pembrolizumab in patients with high microsatellite instability (MSI-H) tumors in 2017, followed by larotrectinib and entrectinib for the treatment of cancers harboring NTRK fusions in 20, respectively 4. Novel oncogenic drivers and biomarkers have been described across different tumor types, leading to the development of targeted therapies and the design of innovative trials, many of which are evaluating tissue-agnostic therapies 3. With the emergence of next-generation sequencing (NGS) tools, cancer genomic data have become more widely available, and cancer therapy has shifted from a purely histology-based approach toward incorporating a precision medicine-based approach. Although substantial progress in treatment has been made, metastatic breast cancer (MBC) remains an incurable disease, and the 5-year survival rate for stage IV breast cancer is approximately 25% 2. Breast cancer (BC) represents the most frequently occurring cancer and is the leading cause of cancer-related deaths among female patients worldwide 1.
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