Pharmacotherapy of Neoplastic Disease PDF

VIII Section Pharmacotherapy of Neoplastic Disease Section Editor: Anton Wellstein Chapter 69. General Principles in the Pharmacotherapy of Cancer / 1337 Chapter 70. Cytotoxics and Antimetabolites / 1343 Chapter 71. Protein Kinase Inhibitors and Pathway-Targeted Small Molecule...

VIII Section Pharmacotherapy of Neoplastic Disease Section Editor: Anton Wellstein Chapter 69. General Principles in the Pharmacotherapy of Cancer / 1337 Chapter 70. Cytotoxics and Antimetabolites / 1343 Chapter 71. Protein Kinase Inhibitors and Pathway-Targeted Small Molecules / 1381 Chapter 72. Antibodies, CAR T Cells, and Proteins to Treat Cancer / 1415 Chapter 73. Hormones, Hormone Receptor Antagonists, and Related Agents in the Therapy of Cancer / 1435 https://ebooksmedicine.net/ This page intentionally left blank  69 Chapter THE CELL CYCLE CANCER EVOLUTION AND DRUG DISCOVERY General Principles in the Pharmacotherapy of Cancer Anton Wellstein MOLECULAR TESTING TO SELECT APPROPRIATE DRUGS Molecular Analysis and Tumor Heterogeneity Liquid Biopsies DRUG RESISTANCE ACHIEVING THERAPEUTIC INTEGRATION AND EFFICACY A CAUTIONARY NOTE Cancer pharmacology has changed dramatically during the recent past, with the improved understanding of cancer biology and an The Cell Cycle ever-expanding set of new drugs that target vulnerabilities in specific An understanding of the cell cycle is essential for the rational use of cyto- cancers. Effective treatments had been developed earlier for some fatal toxic anticancer drugs that target proliferating cells (Figure 69–2). Many malignancies, including testicular cancer, lymphomas, and leukemia. cytotoxic agents act by damaging DNA. Their efficacy is thus greatest Adjuvant chemotherapy and hormonal therapy can extend overall sur- during S phase, the DNA synthetic phase of the cell cycle. Other agents, vival and prevent disease recurrence following surgical resection of local- such as the vinca alkaloids and taxanes, block the formation of a func- ized breast, colorectal, and lung cancers. Chemotherapy is also employed tional mitotic spindle in the M phase. These agents are most effective on as part of the multimodal treatment of locally advanced head and neck, cells entering mitosis, the most vulnerable phase of the cell cycle. Accord- breast, lung, and esophageal cancers; soft-tissue sarcomas; and pediatric ingly, human cancers most susceptible to chemotherapy are those hav- solid tumors, thereby allowing for neoadjuvant surgery that is more lim- ing a high percentage of proliferating cells. However, normal tissues that ited and results in favorable outcomes (Chabner and Roberts, 2005). proliferate rapidly (bone marrow, hair follicles, and intestinal epithelium) In the past 10 years, the ability to harness the power of the immune sys- are thus also susceptible to damage from cytotoxic drugs. In addition, tem in the treatment of cancer has brought about a paradigm shift whereby slowly growing tumors with a small growth fraction (e.g., carcinomas of some of the most feared diseases, such as melanoma and lung cancer and the colon or NSCLC) are less responsive to cell cycle–specific drugs. even late-stage metastatic disease, can be eradicated. For some cancers, Although cells from different tumors display differences in the dura- response rates are surprisingly high: 87% in Hodgkin lymphoma even in tion of their transit through the cell cycle and in the fraction of cells in heavily pretreated patients (Ansell et al., 2015), and 50% in patients with active proliferation, all cells display a similar pattern of cell cycle progres- metastatic melanoma treated with combinations of anti-PD-1 and -CTLA4 sion (Figure 69–2): immune checkpoint antibodies. Immune checkpoint inhibitors are cur- A phase that precedes DNA synthesis (G1) rently approved for the treatment of over a dozen different cancers that A DNA synthesis phase (S) include melanoma and cancers of the bladder, kidneys, liver, lungs as well An interval following the termination of DNA synthesis (G2) as Hodgkin lymphoma. In addition to these histologically defined malig- The mitotic phase (M) in which the cell, containing a double comple- nancies, any cancers with deficient DNA mismatch repair (e.g., colorec- ment of DNA, divides into two daughter G1 cells tal, ovarian, pancreatic, endometrial cancers) were also approved for A probability of moving into a quiescent state (G0) for long periods treatment. of time Despite these major therapeutic successes, few categories of medication have a narrower therapeutic index and greater potential for causing harmful Some anticancer drugs act at specific phases in the cell cycle, mainly at effects than anticancer drugs. A thorough understanding of their mecha- the S and M phases; other drugs are cytotoxic at any point in the cell cycle nisms of action, including clinical pharmacokinetics, drug interactions, and and are termed cell cycle phase nonspecific. adverse effects, is essential for their safe and effective use. Anticancer drugs Each transition point in the cell cycle requires the activation of specific are quite varied in structure and mechanism of action. The group includes cyclin-dependent kinases (CDKs), which, in their active forms, couple alkylating agents; antimetabolite analogues of folic acid, pyrimidine, and with corresponding regulatory proteins called cyclins. The proliferative purine; natural products; hormones and hormone antagonists; and a variety impact of CDKs is, in turn, dampened by inhibitory proteins such as of small-molecule drugs and antibodies directed at specific molecular tar- p16INK4A, a tumor suppressor named for its molecular mass (protein of gets, such as extracellular receptors, intracellular kinases, or the checkpoints 16 kDa) and inhibition of CDK4. Tumor cells often exhibit changes in of immune surveillance. Figure 69–1 depicts the cellular targets of these cell cycle regulation that lead to relentless proliferation (e.g., mutations or classes of drugs, and Chapters 70 to 73 provide information about them. loss of p16INK4A or of other inhibitory components of the so-called retino- Anticancer drugs are increasingly used in a variety of nonmalignant blastoma pathway, enhanced cyclin, or enhanced CDK activity). diseases and have become treatment standards, for example, for autoim- The CDK family consists of over 20 serine/threonine protein kinases mune diseases (rituximab); rheumatoid arthritis (methotrexate and cyclo- that have been among the first pathway targets pursued for the treat- phosphamide); Crohn’s disease (6-mercaptopurine); organ transplantation ment of cancer. However, different tissue selectivities and distinct cell (methotrexate and azathioprine); sickle cell anemia (hydroxyurea); pso- cycle–specific activity periods of the various CDKs provide a challenge riasis (methotrexate); and wet macular degeneration (ranibizumab and for the development of CDK inhibitors. CDK4/6 have become attractive aflibercept). targets because they control cell cycle progression from the G1 to the https://ebooksmedicine.net/  1338 Abbreviations S phase. Interaction of cyclin D with CDK4/6 enhances phosphoryla- tion and inactivation of the retinoblastoma (Rb) protein, followed by the transcription of factors that control transition into the S phase. CDK4/6 ABL: Abelson murine leukemia viral oncogene homolog inhibition will thus cause a G1 arrest in susceptible cells that utilize this ALK: anaplastic lymphoma kinase pathway. CDK4/6 inhibitors were recently approved for the treatment of BCR: breakpoint cluster region breast cancer (see Chapter 71). BRAF: B-Raf proto-oncogene ser/thr protein kinase Because of the central importance of DNA to the identity and func- CAR(T): chimeric antigen receptor T cell tionality of a cell, elaborate cellular mechanisms (“cell cycle checkpoints”) CDK: cyclin-dependent kinase have evolved to monitor DNA integrity. At each transition point in the ctDNA: circulating, cell-free mutant tumor DNA cell cycle, specific proteins, such as p53 and chk-1 and-2, monitor the integrity of DNA and, upon detection of DNA damage, may initiate DNA CTLA4: cytotoxic T lymphocyte–associated protein 4 repair processes, or in the presence of massive damage, direct cells down EGF(R): epidermal growth factor (receptor) [HER1, ErbB-1] a pathway of cell death (apoptosis). If a cell possesses normal checkpoint CHAPTER 69 GENERAL PRINCIPLES IN THE PHARMACOTHERAPY OF CANCER ER: estrogen receptor function, drug-induced DNA damage will activate apoptosis when the FDA: Food and Drug Administration cell reaches the G1/S or G2/M boundary. However, if the p53 gene prod- GI: gastrointestinal uct or other checkpoint proteins are mutated or absent or the checkpoint HER1: human EGFR (ErbB-1) function fails, damaged cells will not divert to the apoptotic pathway but HER2: human EGFR 2 (ErbB-2) will proceed through the S phase and mitosis. The cell progeny will then MEK: mitogen-activated protein kinase kinase emerge as a mutated and potentially drug-resistant subpopulation (see MHC: major histocompatibility class (protein) Figure 69–3A). NCCN: National Comprehensive Cancer Network NSCLC: non–small cell lung cancer PARP: poly(ADP-ribose) polymerase Cancer Evolution and Drug Discovery PD-1: programmed cell death 1 The rapidly expanding knowledge of cancer biology and the ability to PD-L1: programmed cell death ligand 1 analyze cancer genome alterations in thousands of patient samples have SARS-CoV-2: severe acute respiratory syndrome–coronavirus 2 led to a better understanding of the molecular evolution of cancer and TMB: tumor mutational burden the discovery of cancer-specific drug targets: growth factor receptors, intracellular signaling pathways, epigenetic processes, tumor vascularity, 6-MERCAPTOPURINE Purine Pyrimidine HYDROXYUREA 6-THIOGUANINE synthesis synthesis Inhibits ribonucleotide reductase Inhibit purine ring biosynthesis 5-FLUOROURACIL Inhibit DNA synthesis Ribonucleotides Inhibits thymidylate synthesis PEMETREXED METHOTREXATE GEMCITABINE Deoxyribo- CYTARABINE Inhibit dihydrofolate reduction, nucleotides FLUDARABINE block thymidylate and 2-CHLORODEOXYADENOSINE purine synthesis CLOFARABINE Inhibit DNA synthesis CAMPTOTHECINS ETOPOSIDE PLATINUM ANALOGUES TENIPOSIDE ALKYLATING AGENTS DAUNORUBICIN DNA MITOMYCIN DOXORUBICIN TEMOZOLOMIDE Block topoisomerase function Form adducts with DNA L-ASPARAGINASE RNA Deaminates asparagine (transfer, messenger, ribosomal) PROTEIN KINASE INHIBITORS Inhibits protein synthesis ANTIBODIES EPOTHILONES Block activities of signaling pathways Proteins TAXANES VINCA ALKALOIDS IMMUNE CHECKPOINT ESTRAMUSTINE INHIBITORS Enzymes Micro- Inhibit function of microtubules Receptors tubules Block immune evasion Response Differentiation ATRA to antigens ARSENIC TRIOXIDE HORMONE ANTAGONISTS HISTONE DEACETYLASE INHIBITORS Hormone Inhibit receptor function & expression receptors Induce differentiation Figure 69–1 Mechanisms and sites of action of some of the drugs used in the treatment of cancer.  G1 to S PHASE Clinically detectable cancer lesions represent approximately 1 g of 1339 CDK4/6 INHIBITOR tumor tissue or 109 cells and can contain a multitude of subpopulations palbociclib, abemaciclib, ribociclib and a wide variety of genetic alterations (see legend of Figure 69–3). The S PHASE– dynamic evolution of individual cancer genomes and its implications for SPECIFIC DRUGS the development of therapies were established from the analyses of speci- cytosine arabinoside, mens from diverse cancers (Yates and Campbell, 2012). This dynamic was S hydroxyurea, irinotecan, exemplified in a detailed analysis of a series of multiple parallel biopsies topotecan from different sites in patients with metastatic melanoma during treat- G1 ment with inhibitors of mutant BRAF. The genomic analysis of the biop- S PHASE–SPECIFIC sies revealed complex and distinct evolutionary branching architectures Checkpoints SELF-LIMITING due to the selection of drug-resistant subpopulations during treatment 6-mercaptopurine, (Shi et al., 2014). SECTION VIII PHARMACOTHERAPY OF NEOPLASTIC DISEASE G1 G2 G2 methotrexate Nevertheless, in many tumors, proliferation and survival of the major- ity of subpopulations depend on a shared (ancestral) constitutive activ- ity of a single growth factor pathway, or so-called oncogene addiction. Inhibition of that pathway leads to cell death of the sensitive populations. M Thus, imatinib attacks the unique and specific bcr-abl translocation in chronic myelocytic leukemia. Imatinib also inhibits c-kit and produces M PHASE–SPECIFIC DRUGS extended control of GI stromal tumors that express a mutated and consti- G0 vincristine, vinblastine, paclitaxel tutively activated form of c-kit. Monoclonal antibodies effectively target tumor-associated antigens such as the amplified HER2 receptor in breast cancer cells (Slamon et al., 2001). Protein kinase inhibitors targeting CELL CYCLE–NONSPECIFIC DRUGS mutant EGFR or mutant ALK in lung cancers improve disease outcomes alkylating agents, nitrosoureas, over the use of conventional chemotherapy. antitumor antibiotics, procarbazine, These examples emphasize that new strategies for drug discovery and cisplatin, dacarbazine development, and advances in patient care, will result from new knowl- edge of cancer biology. One response to the oncogene addiction para- Figure 69–2 Cell cycle specificity of drugs used in the treatment of cancer. digm has been to group cancers by shared vulnerabilities, include patients DNA repair defects, cell death pathways, and immune escape mecha- in so-called basket trials that evaluate a drug based on its target rather nisms (Hanahan and Weinberg, 2011). Human malignancies are a highly than particular disease entities, and consider sensitivity and resistance to diverse group of diseases that vary even within defined classifications treatments in that context. such as organ of origin (lung, breast, prostate, colon, etc.), histology, or However, in the foreseeable future, targeted drugs and cytotoxics will molecular marker. Also, the tumor cell population constituting a given continue to be used in combination. For instance, cytotoxics in combi- cancer at the time of diagnosis has evolved over many years from a few nation with monoclonal antibodies such as trastuzumab or bevacizumab precursor cells that accumulated mutations over time, generating hetero- improve efficacy. At the same time, the toxicities of cytotoxic drugs have geneity within the primary tumor and at metastatic sites (Figure 69–3). become more manageable with the development of better antinausea A B Metastatic spread 1000 Organ Somatic mutation prevalence metastasis 100 Tumor heterogeneity (per million bases) 10 Primary tumor 1 0.1 Organ Diagnosis metastasis Initiation Adeno - SCLC - Breast - Colorectal - Stomach - Prostate - Pancreas - SCC - Melanoma - Before detection Treatment A Treatment B Relapse Time line Lung Figure 69–3 Evolution of treatment resistance; mutational load of human cancers. A. Treatment resistance. Cancers accumulate mutations during their evolu- tion. Cancer cell subpopulations are selected based on their growth capacity, adaptation to the tumor microenvironment at the primary or metastatic site, and the evasion of immune surveillance. Drug treatment adds evolutionary pressure and selects for resistant subpopulations. Differently colored dots indicate tumor subpopulations of different genetic or epigenetic makeup. B. Mutational load. Data are median values ± range of numbers of somatic mutations per million bases observed for some major cancers. Note that the ordinate is a logarithmic scale. In 7042 cancer specimens, between 100 and 1,000,000 mutations were detected per tumor specimen, with a 30- to 1000-fold range among individual specimens from a single cancer type (see original data in Alexandrov et al., 2013). A tumor mutational burden (TMB) of 10 somatic mutations per megabase (= 30,000 mutations in the human genome of 3 × 109 base pairs) results in approximately 150 mutations in amino acid sequences that can alter protein function, drug sensitivity, and antigenicity. In many cancer types, higher TMB is associated with poorer survival. On the other hand, the formation of tumor-specific neoantigens due to DNA mutations permits the immune system to distinguish between tumor and normal cells and contributes to the efficacy of cancer immunotherapy (Schumacher and Schreiber, 2015). Thus, in patients treated with immune checkpoint inhibitors, higher TMB is associated with longer survival. Adeno, adenocarcinoma; SCC, squamous cell carcinoma; SCLC, small cell lung cancer. https://ebooksmedicine.net/  1340 medications (see Chapter 54) and with granulocyte colony-stimulating clearance; and mutations, amplifications, or deletions in drug targets factor to restore bone marrow function (see Chapters 45 and 71). (Holohan et al., 2013). The processes of resistance are best understood Finally, targeted drugs are helping to overcome resistance to chemo- for pathway-targeted drugs. Tumors developing resistance to bcr-abl therapeutic agents by normalizing blood flow, promoting apoptosis, inhibitors and to inhibitors of the EGFR typically express mutations in and inhibiting prosurvival signals from growth factor pathways. Tumor the target enzyme. Cells exhibiting drug-resistant mutations preexist angiogenesis leads to increased interstitial pressure and diminishes deliv- in a patient’s tumor prior to drug treatment and are selected by drug ery of drugs to tumor cells; inhibitors of angiogenesis (e.g., bevacizumab) exposure (see Figure 69–3A). Resistance to inhibitors of the EGFR may normalize blood flow and interstitial pressure, improve drug delivery, also develop through expression of an alternative receptor, c-met, which and can thus synergize with cytotoxic drugs in the treatment of lung, bypasses EGFR blockade and stimulates proliferation (Engelman et al., colon, and other cancers. It is also thought that the combination of cyto- 2007). Defects in recognition of DNA breaks and overexpression of spe- toxic drugs or pathway inhibitors can induce tumor cell death and anti- cific repair enzymes may contribute to resistance to cytotoxic drugs, and gen release and thus enhance responses to immune checkpoint inhibitors a loss of apoptotic pathways can lead to resistance to both cytotoxic and or other immune modulators. This concept is part of a recommendation pathway-targeted drugs. CHAPTER 69 GENERAL PRINCIPLES IN THE PHARMACOTHERAPY OF CANCER for the treatment of patients with melanoma (Kaufman et al., 2013) and Resistance to immune checkpoint inhibitory drugs appears to follow should be relevant for a range of cancers (Sharma and Allison, 2015). The patterns that are distinct from those of other anticancer drugs, as evi- ongoing development of activating and inhibitory drugs for additional denced by their efficacy in some heavily pretreated patients. One recog- immune checkpoint pathways (Anderson et al., 2016) will provide new nized tumor variable of treatment sensitivity is the >30-fold range of the options for drug combinations. tumor mutational burden (TMB) among patient specimens from a given cancer type (Figure 69–3); TMB is thus used as one marker to assess the likelihood of response or resistance to immunotherapy (Table 69–1). Sur- prisingly, the composition of the gut microbiome as well as alterations by Drug Resistance antibiotic treatment were found to be related to the response of different Resistance remains the major obstacle to successful cancer treatment. cancers to immune checkpoint inhibitory drugs, suggesting a potential Resistance results from a variety of molecular changes acquired during vulnerability (Finlay et al., 2020; see also Chapter 6). Indeed, recent stud- evolution of a given cancer that can defeat the best-designed treatments. ies in patients with melanoma suggest that fecal microbiota transplant Mechanisms of drug resistance include poor drug absorption and deliv- from appropriate donors may overcome resistance to immunotherapy ery; genetically determined variability in drug transport, activation, and (Woelk and Snyder, 2021). A major challenge in immunotherapy is the TABLE 69–1 DIAGNOSTIC TESTS OF CANCER SPECIMENS TO GUIDE TREATMENT DECISIONS INDIVIDUAL MOLECULAR MARKER (DNA, mRNA, PROTEIN) TARGET: drugs CANCER INDICATION CHAPTER ALK translocation ALK: alectinib, ceritinib, crizotinib Lung NSCLC 71 BRAF V600 mutation BRAF: dabrafenib, vemurafenib Melanoma 71 BRAF V600 mutation MEK: trametinib Melanoma 71 BRCA mutation PARP: olaparib, rucaparib, talazoparib Breast, Ovarian, Pancreatic, 71 Prostate EGFR deletion of exon 19 or L858R mutationa EGFR: afatinib, dacomitinib, erlotinib, Lung NSCLC 71 gefitinib EGFR T790M mutationa EGFR: osimertinib Lung NSCLC 71 Estrogen receptor (ER) expression antiestrogens (tamoxifen, raloxifene, Breast 73 fulvestrant) or aromatase inhibitors (anastrozole, letrozole, exemestane) HER2 amplification; HER2: trastuzumab, ado-trastuzumab Breast, Gastric 71 HER2 overexpression emtansine, pertuzumab KRAS wild type EGFR: cetuximab, panitumumab Colorectal 71 PD-L1 expression PD-1, PD-L1: pembrolizumab Lung NSCLC, etc. 72 Panels of markers MSI-H (microsatellite instability high) or dMMR PD-1: pembrolizumab Solid tumors 72 (deficient mismatch repair) Tumor mutational burden (TMB) >10 DNA PD-1: pembrolizumab Solid tumors 72 mutations per million basesb mRNA expression of a panel of genes Chemotherapy Breast 73 (Risk of recurrence score) Next Generation DNA sequencing of tumor Genes sequenced include the above-named Solid tumors 71 samples for the presence of gene variants targets and their alterations. The respective (substitution, insertion, deletion), copy number, drugs are listed above rearrangement FDA-approved tests continuously updated: www.fda.gov “List of cleared or approved companion diagnostic devices.” (Accessed 19 March 2022) a Also detectable as circulating tumor DNA (ctDNA) in blood samples. b See Figure 69–3. poor predictability, in individual patients, of the immune responses that relapse. Thus, one can identify the patients at a high risk who will benefit 1341 govern the success of the treatment. mRNA-based vaccines that contain from adjuvant chemotherapy (Paik et al., 2004). the coding sequences of antigenic mutations detected in a given tumor are the most recently developed approach to elicit an immune response Molecular Analysis and Tumor Heterogeneity and enhance the efficacy of immune checkpoint inhibitor treatments One of the caveats to conclusions drawn from the molecular analysis of (Sahin and Türeci, 2018; Sahin et al., 2020). It is noteworthy that this tumor tissue specimens is the dynamic evolution of cancers noted above mRNA-based vaccine approach was also used to generate the first suc- (see Figure 69–3). Clinically important mutations in subclones may be cessful vaccines against SARS-CoV-2 (COVID-19). missed due to geographically inadequate sampling and may provide the Finally, T cells carrying chimeric antigen receptors (CARs) can be wrong guidance to treatment decisions. Treatment responses of different directed against cancer cells that express specific antigens. CARs are subpopulations in a tumor or in different metastatic lesions present a fur- engineered to contain an antigen recognition domain of a monoclonal ther challenge and would require multiple-site tissue biopsies (Shi et al., antibody in the extracellular portion and intracellular signaling domains 2014). The molecular analysis of serially collected blood samples (“liquid SECTION VIII PHARMACOTHERAPY OF NEOPLASTIC DISEASE capable of activating T cells independently of the physiological pathway biopsies”) provides an alternative approach for treatment monitoring. of antigen presentation by an MHC molecule (see Figures 72–6, 38–2, and 38–4). CD19-targeted CAR T cells reached a 70% to 90% response rate in Liquid Biopsies patients with previously treated, relapsed B-cell leukemias (Khalil et al., More recent technology advances have made it possible to sequence and 2016), indicating a lack of cross-resistance with conventional therapies. quantitate circulating, tumor-derived DNA (ctDNA) in blood samples This result is consistent with the requirement for effective combination from patients with cancer (“liquid biopsies”), as first demonstrated for therapies, that is, complementary mechanisms of action and no overlap the changing abundance of mutant KRAS during colon cancer treat- in major toxicities. Combinations of immune modulating therapies with ment (Diehl et al., 2008). The analysis of ctDNA has shown that during pathway-targeted drugs and cytotoxic agents are currently evaluated in antiestrogen therapy of breast cancer the appearance of mutant estrogen national and international trials to generate effective treatment combina- receptor coincides with subsequent resistance to aromatase inhibitor tions (Hughes et al., 2016). treatment (Schiavon et al., 2015). Furthermore, mutant KRAS DNA in the circulation was increased during the treatment of patients with colon Molecular Testing to Select Appropriate Drugs cancer with EGFR antibodies but surprisingly reverted to baseline val- ues after cessation of the treatment. This observation demonstrates the Clinical trials and patient treatments increasingly employ results from dynamic evolution of cancer subpopulations during drug treatment, as biomarker analysis to identify patients likely to benefit from particular indicated in Figure 69–3 (Siravegna et al., 2015). As a consequence of treatments and individuals at the greatest risk of toxicity. Some of the these technological developments, the FDA approved a test for the pres- tests have been FDA-approved as “companion diagnostics” in conjunc- ence of mutant EGFR DNA in blood samples of patients with NSCLC to tion with specific drug therapies (see Table 69–1). Pretreatment testing select candidates for treatment with erlotinib or osimertinib and thus cir- of tumor specimens is standard practice in selecting patients for antihor- cumvent the need for a tissue biopsy. The incorporation of liquid biopsies monal therapy of breast cancer and for treatment with antibodies such as into treatment monitoring can provide additional molecular insights into trastuzumab (anti-HER2). Detection of a mutated KRAS gene indicates drug efficacy and adverse effects and reveal the onset of resistance to a that the tumor of a patient with colorectal cancer will not respond to anti- chosen treatment (Kilgour et al., 2020). EGFR antibodies; in patients with lung cancers and EGFR mutations, treatment with erlotinib, gefitinib, or afatinib results in response rates of 70%, and in patients with ALK translocations, the response rates are similar for treatment with the ALK inhibitors crizotinib and ceritinib. A Achieving Therapeutic Integration and Efficacy T790M “gatekeeper” mutation in EGFR (Kobayashi et al., 2005) accounts The clinical benefit of cytotoxic drugs has primarily been measured by for about 60% of acquired resistance to first- and second-generation radiological assessment of drug effects on tumor size. Pathway-targeted inhibitors but is sensitive to osimertinib, a third-generation EGFR inhib- agents, however, may only slow or halt tumor growth, so their effects itor (Thomas et al., 2015). Overall, introduction of molecular analysis may be measured in the assessment of time to disease progression; how- and appropriate choice of pathway-targeted inhibitors in the treatment of ever, for some immune checkpoint inhibitors, tumor lesions may ini- NSCLC has increased median survival of patients from less than 1 year to tially increase in size due to cytotoxic lymphocyte infiltration, so called over 3 years and the response rate from 30% to 80% (Ke and Wu, 2016). pseudo-progression. Thus, one of the great challenges is to assess efficacy Inherited differences in protein sequence polymorphisms or levels of and adjust drug regimens to achieve a therapeutic but nontoxic outcome. RNA expression can also influence toxicity and antitumor response. For Treatment of patients with cancer requires a skillful interdigitation of example, tandem repeats in the promoter region of the gene encoding pharmacotherapy with other modalities of treatment (e.g., surgery and thymidylate synthase, the target of 5-fluorouracil, determine the level radiation). Each treatment modality carries its own risks and benefits, of expression of the enzyme. Increased numbers of repeats are associ- with the potential for both antagonistic and synergistic interactions ated with increased gene expression, a lower incidence of toxicity, and a between modalities, particularly between drug treatment and radiation. decreased rate of response in patients with colorectal cancer (Pullarkat Individual patient characteristics determine the choice of modalities. et al., 2001). Polymorphisms of the dihydropyrimidine dehydrogenase Not all patients can tolerate drugs of the primary choice, and not all drug gene, the product of which is responsible for degradation of 5-fluorouracil, regimens are appropriate for a given patient. Renal and hepatic function, are associated with decreased enzyme activity and a significant risk of bone marrow reserve, general performance status, and concurrent med- overwhelming drug toxicity, particularly in the rare individual that is ical problems all come into consideration in making a therapeutic plan. homozygous for the polymorphic genes (Van Kuilenburg et al., 2002). Other less-quantifiable considerations, such as the natural history of the Gene expression profiling, in which the levels of messenger RNA from tumor, the patient’s willingness to undergo difficult and potentially dan- thousands of genes are surveyed using gene arrays, has revealed tumor gerous treatments, and the patient’s physical and emotional tolerance for profiles that are highly associated with poor outcomes and that warrant adverse effects enter the equation, with the goal of balancing the likely adjuvant chemotherapy (Sotiriou and Pusztai, 2009). As an alternative to long-term gains and risks in the individual patient. In particular, the long- this broad analysis, small sets of informative genes can be identified and term adverse effects of cytotoxic drugs have been related to the induction used clinically. One example is a set of 21 genes used in the analysis of of cellular senescence in different organs that resemble symptoms of samples from patients with early-stage breast cancer. Based on the known premature aging and can adversely affect organ function and the overall association between the expression pattern of the 21 genes and disease well-being of patients long after completion of the treatments (Childs et al., outcomes, the analysis of patient samples can predict the risk of disease 2015; Couzin-Frankel, 2019). The choice of treatment regimen should https://ebooksmedicine.net/  1342 take all of this into account. Finally, in terminally ill patients, the treat- Finlay BB, et al. Can we harness the microbiota to enhance the efficacy of ment choices must be weighed carefully; the maximal length and highest cancer immunotherapy? Nat Rev Immunol, 2020, 20:522–528. quality of life may be achieved with palliative care and may reduce the Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell, need for chemotherapy (Temel et al., 2010). 2011, 144:646–674. Holohan C, et al. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer, 2013, 13:714–726. A Cautionary Note Hughes PE, et al. Targeted therapy and checkpoint immunotherapy combinations for the treatment of cancer. Trends Immunol, 2016, Although advances in drug discovery and molecular profiling of tumors 37:462–476. offer great promise for improving the outcomes of cancer treatment, a Kaufman HL, et al. The Society for Immunotherapy of Cancer consensus final word of caution regarding all treatment regimen deserves emphasis: statement on tumour immunotherapy for the treatment of cutaneous The pharmacokinetics and toxicities of cancer drugs vary amongst individ- melanoma. Nat Rev Clin Oncol, 2013, 10:588–598. ual patients. It is imperative to recognize toxicities early, to alter doses or Ke EE, Wu YL. EGFR as a pharmacological target in EGFR-mutant non- CHAPTER 69 GENERAL PRINCIPLES IN THE PHARMACOTHERAPY OF CANCER discontinue offending medication to relieve symptoms and reduce risk, small-cell lung cancer: where do we stand now? Trends Pharmacol Sci, and to provide vigorous supportive care. Toxicities affecting the heart, 2016, 37:887–903. lungs, nervous system, or kidneys may be irreversible if recognized late in Khalil DN, et al. The future of cancer treatment: immunomodulation, their course, leading to permanent organ damage or death. Fortunately, CARs and combination immunotherapy. Nat Rev Clin Oncol, 2016, such toxicities can be minimized by early recognition and by adherence 13:273–290. to standardized protocols and to the guidelines for each drug’s use. Kilgour E, et al. Liquid biopsy-based biomarkers of treatment response and resistance. Cancer Cell, 2020, 37:485–495. Kobayashi S, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med, 2005, 352:786–792. A Note on Treatment Regimens Paik S, et al. A multigene assay to predict recurrence of tamoxifen-treated, Cancer treatment regimens change to reflect continuous advances node-negative breast cancer. N Engl J Med, 2004, 351:2817–2826. in basic and clinical science: new drugs, both small molecules and Pullarkat ST, et al. Thymidylate synthase gene polymorphism determines biologicals; improved methods of targeting and timing of drug response and toxicity of 5-FU chemotherapy. Pharmacogenomics J, delivery; agents with altered pharmacokinetic properties and 2001, 1:69–70. selectivities; the use of rational multidrug combinations; and greater Sahin U, et al. An RNA vaccine drives immunity in checkpoint-inhibitor- knowledge of the basic cell biology of tumorigenesis, metastasis, treated melanoma. Nature, 2020, 585:107–112. and immune function, among other advances. As a consequence, Sahin U, Türeci Ö. Personalized vaccines for cancer immunotherapy. this chapter and the four that follow present relatively few detailed Science, 2018, 359:1355–1360. treatment regimens; rather, we refer the reader to the web-based Schiavon G, et al. Analysis of ESR1 mutation in circulating tumor DNA resources of the U.S. FDA and the National Comprehensive Cancer demonstrates evolution during therapy for metastatic breast cancer. Sci Network (NCCN). Table 71–1 provides examples that illustrate the Transl Med, 2015, 7:313ra182. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. complexities of current therapeutic regimens for two cancers. Science (New York, NY), 2015, 348:69–74. Sharma P, Allison JP. The future of immune checkpoint therapy. Science (New York, NY), 2015, 348:56–61. Shi H, et al. Acquired resistance and clonal evolution in melanoma during Acknowledgment: Paul Calabresi and Bruce A. Chabner contributed to BRAF inhibitor therapy. Cancer Discov, 2014, 4:80–93. this chapter in earlier editions of this book. We have retained some of their Siravegna G, et al. Clonal evolution and resistance to EGFR blockade in text in the current edition. the blood of colorectal cancer patients. Nat Med, 2015, 21:795–801. Slamon DJ, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. Bibliography N Engl J Med, 2001, 344:783–792. Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl Alexandrov LB, et al. Signatures of mutational processes in human cancer. J Med, 2009, 360:790–800. Nature, 2013, 500:415–421. Temel JS, et al. Early palliative care for patients with metastatic non- Anderson AC, et al. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors small-cell lung cancer. N Engl J Med, 2010, 363:733–742. with specialized functions in immune regulation. Immunity, 2016, Thomas A, et al. Refining the treatment of NSCLC according to 44:989–1004. histological and molecular subtypes. Nat Rev Clin Oncol, 2015, Ansell SM, et al. PD-1 blockade with nivolumab in relapsed or refractory 12:511–526. Hodgkin’s lymphoma. N Engl J Med, 2015, 372:311–319. Van Kuilenburg ABP, et al. High prevalence of the IVS14 + 1G>A Chabner BA, Roberts TG. Timeline: chemotherapy and the war on mutation in the dihydropyrimidine dehydrogenase gene of patients cancer. Nat Rev Cancer, 2005, 5:69–72. with severe 5-fluorouracil-associated toxicity. Pharmacogenetics, 2002, Childs BG, et al. Cellular senescence in aging and age-related disease: 12:555–558. from mechanisms to therapy. Nat Med, 2015, 21:1424–1435. Woelk CH, Snyder A. Modulating gut microbiota to treat cancer. Science, Couzin-Frankel J. Beyond survival. Science, 2019, 363:1166–1169. 2021, 371:573–574. Diehl F, et al. Circulating mutant DNA to assess tumor dynamics. Nat Yates LR, Campbell PJ. Evolution of the cancer genome. Nat Rev Genet, Med, 2008, 14:985–990. 2012, 13:795–806. Engelman JA, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science, 2007, 316:1039–1043.