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Issues in Oncology cytotoxic chemotherapies, targeted or precision therapies, and immunotherapies. e Predictive assays identify the subset of patients who will or will not benefit from an intervention, whereas Traditional Cancer Therapies prognostic assays can identify the subset of patients at For tumors that are localized, surgical resection remains at the higher or lower risk but do not offer guidance in select- center of treatment. After a complete resection, the patient is at ing treatment to mitigate that risk. risk from microscopic tumors that may remain. Neoadjuvant (preoperative) or adjuvant (postoperative) treatment with irra- diation, chemotherapy, or both may be used to eradicate resid- Precision Medicine ual microscopic disease and increase the chance for cure. The Current developments in chemotherapy are centered on creat- nature of the treatment, in terms of chemotherapy, irradiation, ing agents that target specific driver mutations in a particular or both, depends on the type of tumor and its characteristic cancer. Although in theory, these agents should be more selec- pattern of spread. Randomized trials are crucial in determining tive and have fewer toxicities than older, conventional chemo- whether, for any given population of patients, neoadjuvant or therapies, this has not always turned out to be the case. Many adjuvant therapy improves an important outcome, such as of the signaling pathways that are hyperactive in tumor cells cure, or disease-free interval, without unacceptable toxicity. remain at least somewhat active in normal cells, and so dis- Conversion therapy seeks to convert an unresectable tumor to ruption of these pathways can produce considerable adverse one that is resectable by shrinking it away from critical struc- effects. tures and creating a plane for resection that was previously The goal of precision medicine is to identify specific muta-

Conversion therapy seeks to convert an unresectable tumor to ruption of these pathways can produce considerable adverse one that is resectable by shrinking it away from critical struc- effects. tures and creating a plane for resection that was previously The goal of precision medicine is to identify specific muta- lacking. This type of treatment differs from neoadjuvant che- tions or alterations that are driving growth and survival in a motherapy, which targets micrometastases of an already particular tumor and to treat with agents designed to inhibit resectable tumor. that aberrant pathway. Markers can be either inclusionary, in Balancing therapy efficacy and toxicity—in particular, the that they include a patient in a therapy that otherwise might need for adjuvant or neoadjuvant therapy or the desired not be considered, or exclusionary, in that they exclude a aggressiveness of the primary chemotherapy, radiation ther- patient from a treatment that otherwise might have been used. apy, or surgical therapy for populations of patients—has tradi- An example of an inclusionary marker is the V600 BRAF tionally been based on stage, pathology, and understanding mutation in melanoma. Specific BRAF inhibitors, such as the tumor’s overall behavior. Currently available imaging and vemurafenib, dabrafenib, or encorafenib, would only be laboratory studies are somewhat limited in terms of their abil- appropriate for use in melanomas that harbor this specific ity to identify which patients will be at risk for cancer recur- mutation. Melanomas lacking this mutation would not be rence after definitive surgery. Numerous tumor markers, gene treated with these agents. Trastuzumab, a monoclonal anti- panels, and other technologies are available, but few are defin- body against the human epidermal growth factor receptor 2 itive. The preferred assay would be predictive, meaning that it (HER2) on the cell surface, is only active in breast or gastro- could identify the subset of patients at risk for recurrence who esophageal tumors that overexpress HER2. will benefit from an intervention such as adjuvant chemo- Examples of exclusionary markers are RAS mutations.

itive. The preferred assay would be predictive, meaning that it (HER2) on the cell surface, is only active in breast or gastro- could identify the subset of patients at risk for recurrence who esophageal tumors that overexpress HER2. will benefit from an intervention such as adjuvant chemo- Examples of exclusionary markers are RAS mutations. therapy. An example of this is a commercially available 21-gene The anti-epidermal growth factor receptor monoclonal anti- assay for breast cancer that identifies a patient population who bodies cetuximab and panitumumab were initially thought to is at risk for recurrence and will have that risk lowered by be appropriate for treatment of all colorectal cancers. chemotherapy. Such predictive tools are highly useful because Subsequently, it was determined that any tumors harboring they provide actionable information in terms of who to treat mutations in either the KRAS or NRAS gene were not only and who not to treat. A similar multigene assay in colorectal highly resistant to responding to these agents, but in fact, the cancer is prognostic in that it can quantitate a patient’s risk of growth of the RAS-mutated tumors may even be accelerated recurrence but fails to identify which patients will have their by these agents. All metastatic colorectal cancers now require risk lowered by chemotherapy. Therefore, it does not provide tumor genotyping for KRAS, NRAS, and BRAF mutations, and information that is useful for decision making. Predictive tests only tumors lacking all three of these mutations are appropri- are of high value in that they provide clear, actionable infor- ate for treatment with cetuximab or panitumumab. mation. Prognostic tests add no value in dictating therapy, as Circulating tumor DNA can often be isolated from the

information that is useful for decision making. Predictive tests only tumors lacking all three of these mutations are appropri- are of high value in that they provide clear, actionable infor- ate for treatment with cetuximab or panitumumab. mation. Prognostic tests add no value in dictating therapy, as Circulating tumor DNA can often be isolated from the they do not provide actionable information. blood of patients with metastatic cancer, and molecular profil- ing of the tumor can therefore be accomplished on a blood sample. This technique, referred to as a liquid biopsy, may be e Treatment with irradiation, chemotherapy, or both, in useful to avoid an unnecessary invasive procedure when addition to definitive surgery, is called neoadjuvant if archived tumor tissue is not available. Ongoing research will administered preoperatively or adjuvant if administered determine whether circulating tumor DNA may be useful postoperatively. either for surveillance after surgery or to identify at-risk (Continued) patients for adjuvant therapy.

Breast Cancer Breast Cancer e Precision medicine refers to agents that target specific mutations or alterations that are driving growth and Introduction survival in a particular tumor. Breast cancer is the most common type of cancer in women in the e¢ Tumor markers of mutations or alterations can be United States, excluding skin cancers. In 2019, there were approx. inclusionary, in that they include a patient in a therapy imately 268,600 new invasive breast cancer cases and 48,100 in that otherwise might not be considered, or exclusion- situ cases diagnosed. The lifetime risk of developing invasive ary, in that they exclude a patient from a treatment that breast cancer is 12.4% (about 1 in 8) for women in the United otherwise might have been used. States. There were an estimated 40,610 deaths from breast cancer in the United States in 2017—the second leading cause of cancer death in women. The lifetime risk of dying from breast cancer for Immunotherapy women in the United States is 2.76%. Breast cancer is rare in men. Immunotherapy agents are drugs that do not attack the can-

ary, in that they exclude a patient from a treatment that breast cancer is 12.4% (about 1 in 8) for women in the United otherwise might have been used. States. There were an estimated 40,610 deaths from breast cancer in the United States in 2017—the second leading cause of cancer death in women. The lifetime risk of dying from breast cancer for Immunotherapy women in the United States is 2.76%. Breast cancer is rare in men. Immunotherapy agents are drugs that do not attack the can- cer directly but rather mobilize the patient’s own immune Epidemiology and Risk Factors system to do so. This has become possible through the identi- Breast cancer incidence increases with age. The median age of fication of immune checkpoints, which serve as “brakes” on diagnosis in women is 61 years. Incidence rates are highest in the immune system in order to prevent the immune system non-Hispanic White and Black women. Other risk factors for from attacking itself and causing autoimmune diseases. breast cancer are listed in Table 2. Antibodies that block these checkpoints release the brakes on Patients with deleterious BRCA1 or BRCA2 gene muta- the immune system and allow it to aggressively attack the tions have a 50% to 85% lifetime risk of breast cancer. Patients tumor. Adverse effects are related to resultant autoimmunity who received chest wall irradiation between ages 10 and from the less-regulated immune system and can be severe. 30 years for treatment of Hodgkin lymphoma have a 30% to The first immune checkpoint identified was the antigen-4 50% risk of breast cancer. Atypical breast lesions, such as (A-4) molecule on the surface of the cytotoxic lymphocyte (T atypical hyperplasia or lobular carcinoma in situ, result in a cell), hence its designation cytotoxic T-lymphocyte antigen-4. cumulative 30-year breast cancer risk of up to 35%. Antibodies that block cytotoxic T-lymphocyte antigen-4, such Patients with possible hereditary breast cancer syn- as ipilimumab, have been successful in mobilizing the dromes should be referred to a genetic counselor for assess- immune system against melanoma, renal cell carcinoma, and ment and possible genetic testing. The U.S. Preventive Services other malignancies. The other immune checkpoint that has Task Force recommends assessment of women with a personal been successfully exploited is the programmed death 1 (PD-1) or family history of breast, ovarian, tubal, or peritoneal cancer receptor. Anti-PD-1 agents, such as nivolumab or pembroli- or those who have a family history of BRCA1/2 gene mutations zumab, have shown substantial and durable activity against with an appropriate brief familial risk assessment tool. melanoma and non-small cell lung cancers, as well as other Validated tools are available at https://www.uspreventiveser- tumors. Agents against the ligand of PD-1, PD-L1, such as vicestaskforce.org/uspstf/recommendation/brea-related-cancer- atezolizumab or durvalumab, have also shown important risk-assessment-genetic-counseling-and-genetic-testing. clinical activity. Combinations of these agents are showing Women with a positive result on the risk assessment tool further effectiveness but with increased toxicity and also con- should receive genetic counseling and, if indicated after coun- siderable expense. Many other checkpoints in the immune seling, genetic testing. The National Comprehensive Cancer system are now being explored by numerous drugs in Network criteria for genetic testing are outlined in Table 3. development. Further progress in immunotherapy has occurred in the use of cellular immunity, particularly the development and e Breast cancer incidence increases with age, with the commercialization of chimeric antigen receptor T cells, which highest incidence in non-Hispanic White women and have demonstrated striking activity in selected B-cell leuke- second highest in Black women. mias and lymphomas, albeit with substantial clinical and e¢ Women with possible hereditary breast cancer syn- financial toxicity. Investigations into development of this tech- dromes should be referred to a genetic counselor for nology for other liquid and some solid tumors are ongoing. possible genetic testing for breast cancer susceptibility genes, such as BRCA1 and BRCA2.

cer directly but rather mobilize the patient’s own immune Epidemiology and Risk Factors system to do so. This has become possible through the identi- Breast cancer incidence increases with age. The median age of fication of immune checkpoints, which serve as “brakes” on diagnosis in women is 61 years. Incidence rates are highest in the immune system in order to prevent the immune system non-Hispanic White and Black women. Other risk factors for from attacking itself and causing autoimmune diseases. breast cancer are listed in Table 2. Antibodies that block these checkpoints release the brakes on Patients with deleterious BRCA1 or BRCA2 gene muta- the immune system and allow it to aggressively attack the tions have a 50% to 85% lifetime risk of breast cancer. Patients tumor. Adverse effects are related to resultant autoimmunity who received chest wall irradiation between ages 10 and from the less-regulated immune system and can be severe. 30 years for treatment of Hodgkin lymphoma have a 30% to The first immune checkpoint identified was the antigen-4 50% risk of breast cancer. Atypical breast lesions, such as (A-4) molecule on the surface of the cytotoxic lymphocyte (T atypical hyperplasia or lobular carcinoma in situ, result in a cell), hence its designation cytotoxic T-lymphocyte antigen-4. cumulative 30-year breast cancer risk of up to 35%. Antibodies that block cytotoxic T-lymphocyte antigen-4, such Patients with possible hereditary breast cancer syn- as ipilimumab, have been successful in mobilizing the dromes should be referred to a genetic counselor for assess- immune system against melanoma, renal cell carcinoma, and ment and possible genetic testing. The U.S. Preventive Services other malignancies. The other immune checkpoint that has Task Force recommends assessment of women with a personal been successfully exploited is the programmed death 1 (PD-1) or family history of breast, ovarian, tubal, or peritoneal cancer receptor. Anti-PD-1 agents, such as nivolumab or pembroli- or those who have a family history of BRCA1/2 gene mutations zumab, have shown substantial and durable activity against with an appropriate brief familial risk assessment tool. melanoma and non-small cell lung cancers, as well as other Validated tools are available at https://www.uspreventiveser- tumors. Agents against the ligand of PD-1, PD-L1, such as vicestaskforce.org/uspstf/recommendation/brea-related-cancer- atezolizumab or durvalumab, have also shown important risk-assessment-genetic-counseling-and-genetic-testing. clinical activity. Combinations of these agents are showing Women with a positive result on the risk assessment tool further effectiveness but with increased toxicity and also con- should receive genetic counseling and, if indicated after coun- siderable expense. Many other checkpoints in the immune seling, genetic testing. The National Comprehensive Cancer system are now being explored by numerous drugs in Network criteria for genetic testing are outlined in Table 3. development. Further progress in immunotherapy has occurred in the use of cellular immunity, particularly the development and e Breast cancer incidence increases with age, with the commercialization of chimeric antigen receptor T cells, which highest incidence in non-Hispanic White women and have demonstrated striking activity in selected B-cell leuke- second highest in Black women. mias and lymphomas, albeit with substantial clinical and e¢ Women with possible hereditary breast cancer syn- financial toxicity. Investigations into development of this tech- dromes should be referred to a genetic counselor for nology for other liquid and some solid tumors are ongoing. possible genetic testing for breast cancer susceptibility genes, such as BRCA1 and BRCA2. ¢ Immune checkpoints prevent the immune system from attacking both normal tissues (self) and malignant cells; Chemoprevention and Other Risk immunotherapy can take advantage of this process by Reduction Strategies inhibiting the checkpoints and allowing the immune Breast cancer screening for average-risk women is dis- system to aggressively attack cancer cells. cussed in General Internal Medicine 2. The American