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When Tissue Is No Longer the Issue: Tissue-Agnostic Cancer Therapy Comes of Age

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When Tissue Is No Longer the Issue: Tissue-Agnostic Cancer Therapy Comes of Age

Matching unique features of cancer types with effective therapies is a cornerstone of precision medicine. Clinical success has been seen in inhibiting specific molecular alterations that drive the growth of cancer cells and targeting molecules whose elevated expression is confined to cancer cells. In addition, cancer cells can have vulnerabilities induced by somatic mutations they carry; attacks on these vulnerabilities range from specific molecular alterations pointing to direct drug strategies to harnessing immune recognition of genetically altered epitopes produced by the cancer cells. Recent advances have found that the success of biomarker-driven cancer therapy may be relevant across sites of origin. For example, cancer types that show DNA mismatch repair deficiency, such as colon, biliary, and endometrial cancer, are more sensitive to immune checkpoint inhibition. Several large, ongoing clinical trials with a “basket” design are combining tumor tissue genomics with potential off-the-shelf therapies in drug development, and more tissue-agnostic biomarker therapies are reaching the bedside.

Cytotoxic chemotherapy has been the mainstay of cancer therapy for several decades. Success is evidenced by our ability to use it to cure patients with advanced testicular germ cell tumors and diffuse large B-cell lymphoma. However, chemotherapy is relatively nonselective and may affect noncancerous tissues, resulting in side effects. This is partly because cytotoxic chemotherapy affects structure and physiology essential for both cancerous and noncancerous tissues. In addition, biomarkers that reliably predict responsiveness to cytotoxic chemotherapy remain elusive.

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