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Principles of CancerTreatment

Chapter 78 | Harrison's 22e

KEY CLINICAL POINTS

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RAW CONTENT

[PAGE 551] Principles Cancer Treatment 551 CHAPTER proteins, and many are in clinical development for cancer therapy. therapy. Furthermore, it has become clear that specific molecular fac- In addition, various combinations targeting more than one protein tors detected in individual tumors (gene mutations, gene expression involved in modulating the immune response against cancers or with profiles, miRNA expression, overexpression of specific proteins) can be other anticancer approaches (targeted agents, chemotherapy, radia- used to tailor therapy and maximize antitumor effects. tion therapy) that may lead to enhanced antitumor activity are also Potentially of even greater impact on decreasing deaths from can- being explored. An important aspect of these approaches is balancing cer, better understanding of the biology of early cancer development sufficient release of the negative control of the immune response to should ultimately lead to better approaches for prevention. And tech- allow immune-mediated attack on the tumors while not allowing too nologic development to improve sensitivity and specificity in detect- much of an immune response against normal tissues and thus induc- ing cancer-specific molecules (e.g., mutated genes) provide hope that ing severe autoimmune effects (e.g., against lung, liver, skin, thyroid, approaches for earlier detection of cancer can be developed. pituitary gland, gastrointestinal tract, or other organs). As is true for other immunotherapeutic approaches against cancer, major efforts are I FURTHER READING ongoing to better understand the mechanism of immune toxicity from Agudo J et al: Targeting cancer cell dormancy. Nat Rev Cancer 24:97, these approaches and, therefore, ways of controlling this while not 2024. abrogating the antitumor effects. Improved knowledge of the biology Bhullar KS et al: Kinase-targeted cancer therapies: Progress, chal- of the interactions between the immune system and cancers continues lenges and future directions. Mol Cancer 17:48, 2018. to be rapid with the promise for additional significant improvements de Visser KE, Joyce JA: The evolving tumor microenvironment: From in use of immunotherapy to treat cancer. cancer initiation to metastatic outgrowth. Cancer Cell 41:374, 2023. Given the success of vaccines against multiple viruses, many efforts Finley LWS: What is cancer metabolism? Cell 186:1670, 2023. have been made over decades to develop anticancer vaccines that would Fujii M et al: Decoding the basis of histological variation in human induce a sufficient immune response to lead to killing of cancer cells or cancer. Nat Rev Cancer 24:141, 2024. even potentially prevention. This has been largely unsuccessful for the Gacche RN: Changing landscape of anti-angiogenic therapy: Novel treatment of established cancers, although three vaccines are approved approaches and clinical perspectives. Biochim Biophys Acta Rev for use in cancer care: bacillus Calmette-Guérin (BCG) for intravesical Cancer 1878:189020, 2023. treatment of superficial bladder cancer, sipuleucel-T for prostate can- Gerstberger S et al: Metastasis. Cell 186:1564, 2023. cer, and talimogene laherparepvec for direct injection into melanoma. Hanahan D: Hallmarks of cancer: New dimensions. Cancer Discov Except for BCG, and then only for superficial bladder cancer, these 12:31, 2022. have had relatively limited effectiveness. Perhaps more promising Matthews HK et al: Cell cycle control in cancer. Nat Rev Mol Cell are vaccines combined with other forms of immunotherapy. Benefit Biol 23:74, 2022. may be enhanced by using a vaccine in combination with immune Pottier C et al: Tyrosine kinase inhibitors in cancer: Breakthrough checkpoint inhibition therapy to delay recurrence of resected high-risk and challenges of targeted therapy. Cancers (Basel) 12:731, 2020. melanoma and provides hope that this approach may be effective in the Prager BC et al: Cancer stem cells: The architects of the tumor ecosystem. future. However, further studies are needed to confirm this. Cell Stem Cell 24:41, 2019. Reiter JG et al: An analysis of genetic heterogeneity in untreated cancers. IMPACT OF UNDERSTANDING CANCER Nat Rev Cancer 19:639, 2019. BIOLOGY ON PREVENTION AND EARLY Romesser PB, Lowe SW: The potent and paradoxical biology of cellular DETECTION senescence in cancer. Annu Rev Cancer Biol 7:207, 2023. Sharma P, et al: Immune checkpoint therapy: Current perspectives The biggest impacts on decreasing cancer mortality come from pre- and future directions. Cell 186:1652, 2023. vention followed by early detection. In addition to the critical role Tomuleasa C et al: Therapeutic advances of targeting receptor tyro- that new knowledge about cancer biology has in developing improved sine kinases in cancer. Sig Transduct Target Ther 9:201, 2024. treatment approaches, it is also critical in enhancing preventative and Yang K et al: Antigen presentation in cancer: Mechanisms and clinical early detection approaches. Examples in prevention include using implications for immunotherapy. Nat Rev Clin Oncol 20:604, 2023. knowledge about the roles of certain viruses in the development of Yuan J, Ofengeim D: A guide to cell death pathways. Nat Rev Mol Cell some cancers to create vaccines for viruses (e.g., hepatitis B virus and Biol 25:379, 2024. human papillomavirus) to decrease the risk of developing cancer from these infections and using knowledge about how certain carcinogens cause cancer to work on controlling or eliminating carcinogenic agents (e.g., cigarette smoking and asbestos). The development of sensitive methods for detecting circulating tumor DNA holds promise for earlier detection of cancer, although this has not yet been firmly established. Imaging agents for specific tissues (such as the use of proteins highly 78 Principles of Cancer expressed on specific cancer tissues including prostate-specific mem- brane antigen PET imaging to detect prostate cancer or HER2 to detect Treatment a subset of breast, gastric, and other cancers) or potentially against mutant proteins found in cancers (e.g., KRAS or p53 mutations) hold Edward A. Sausville, Dan L. Longo promise for earlier and more specific detection of cancer. As more is learned about cancer biology, this knowledge will also continue to be applied in preventative and early detection strategies. CANCER PRESENTATION SUMMARY Localized or systemic cancer is frequent in the differential diagnosis Just as human biology is complex, cancer biology is complex. Although of a variety of common complaints. Affording patients the greatest each of the biological aspects of cancers and examples of targeting opportunity for cure or meaningful prolongation of life is greatly aided them has been addressed individually, clearly there is complicated by diagnosis of cancer early in its natural history. The spectrum of cross-talk between these that occurs in all cancers that needs to be possible cancer-related interventions to make cure possible is shown better understood to optimally treat different cancers. The explosion in Table 78-1. of information on tumor cell biology, metastasis, and tumor-host interactions (including angiogenesis, other tumor-stromal interactions, I DETECTION OF A CANCER and immune evasion by tumors) has ushered in a new era of rational The term cancer, as used here, is synonymous with the term tumor, targeted therapy for cancers as well as the potential for individualized whose original derivation from Latin simply meant “swelling,” not [PAGE 552] 552 PART Oncology and Hematology TABLE 78-1 Spectrum of Cancer-Related Interventions TABLE 78-2 Diagnostic Biopsy: Standard-of-Care Molecular and Asymptomatic patient screening (breast, cervix, colon, some lung) Special Studies to Be Considered Consideration of cancer in a differential diagnosis All solid tumors Physical examination, imaging, or endoscopy to define a possible tumor Tumor mutational burden Phlebotomy for molecular studies and circulat