As novel treatments are developed that either directly target or rely on genetics and genomics, the role and timing of surgery in the multidisciplinary care of patients with solid tumors is constantly evolving. In the current era, it is critical that surgeons are aware of the role of genetic and genomic testing and when it is appropriate, so as to guide surgeons in appropriate and optimal care. The "poster child" for this principle is molecular oncology, which has identified novel immunotherapy treatment paradigms that, with chemotherapy, can inform surgical decision-making.1 In this article, we examine key mutations identified in gastric cancer, colorectal cancer (CRC), and cholangiocarcinoma (CCA) and corresponding available therapies. We also discuss how tumor-agnostic microsatellite instability high (MSI-H) tumors benefit from immunotherapy.
Gastric Cancer
Gastric cancer is the fourth-most common cancer globally, and 90 percent of gastric cancers are adenocarcinoma.2 There is significant variance in prevalence geographically, with especially high rates in Asia, Eastern Europe, and South America. Globally, only 25 percent of patients have resectable disease at time of presentation.3 The landmark 2014 study from the Cancer Genome Atlas Research Network identified four molecular subtypes of gastric cancer: EBV positive cancers with recurrent PIK3CA mutations, DNA hypermethylation, JAK2, PD-L1 and PD-L2 amplification; microsatellite unstable tumors; genomically stable tumors; and tumors with chromosomal instability.4 This classification has been demonstrated to be predictive of patients' response to adjuvant chemotherapy, as well as overall prognosis.5 For example, the presence of microsatellite instability, as seen in approximately 10 to 20 percent of gastric cancers, determines the need for perioperative chemotherapy; specifically, perioperative chemotherapy confers no survival benefit, or may result in decreased survival, in these patients.6
Molecular testing, namely for HER2 overexpression, is standard of care, although several molecular targets have been identified (see Table 1). Approximately 10 to 20 percent of gastric cancers are HER2 positive, and trastuzumab, a HER2-specific antibody, has been shown to confer an overall survival benefit when given in addition to cisplatin and fluoropyrimidine and is first-line therapy for HER2 positive gastric cancers in addition to chemotherapy.7 Anti-PD-1 antibodies such as pembrolizumab and nivolumab have also shown efficacy as second- or third-line agents for patients who have failed standard chemotherapy; nivolumab has shown to improve overall survival in combination with standard chemotherapy.8 VEGF-targeting monoclonal antibodies, namely ramucirumab, have additionally demonstrated improved overall survival when given in addition to paclitaxel compared to paclitaxel alone, as well as in patients who have failed initial first-line chemotherapy.9 Of note, ramucirumab has demonstrated a synergistic effect when given with paclitaxel, by enhancing paclitaxel's ability to halt cell cycle progression.10 More recently, 20 microRNAs have been found to be prognostic biomarkers for survival amongst patients who had undergone radical gastrectomy. Of these, 14 were independently informative.11 The higher expression of most of these microRNAs was associated with shorter survival. The presence and levels of these miRNAs were found to be more predictive than TNM staging.12
In summary, when treating patients with gastric cancer, surgeons should test for biomarkers with established therapies, namely HER2 positivity, PD-L1 expression and MSI-H status. Large scale studies assessing additional tumor mutations are ongoing.
Colorectal Cancer
CRC is the third-most common form of cancer in the U.S. and the third-most common cause of cancer death amongst men and women.13 22 percent of patients have metastatic disease at the time of diagnosis, with the most common site of metastasis being the liver.14,15 Genetic testing has become essential to treatment planning, especially in identification of tumor markers such as KRAS, BRAF and microsatellite instability status.16 Immunotherapy targeting additional pathways, such as PD-1, in the neoadjuvant setting has improved surgical resectability, supporting the increasing importance of immunotherapy in operative management of patients with CRC, especially timing systemic treatments with surgery (Table 2).17
Several genetic targets have been identified in CRC. Cetuximab, an EGFR-targeting monoclonal antibody, has demonstrated improved progression-free and overall survival when combined with FOLFOX compared to FOLFOX alone in patients with RAS wild-type metastatic CRC.18Of note, EGFR-targeted therapy is not effective in patients with mutations in KRAS, BRAF, HER2 or PICK3CA.13 BRAF overexpression is found in approximately 10 percent of colorectal cancers and has a notably poor prognosis, associated with a median survival of four to six months after failure of initial therapy and a two-fold increase in the risk of death. Combination therapy of encorafenib, a BRAF inhibitor; binimetinib, a MEK inhibitor; and cetuximab has demonstrated improved overall survival in this patient population to a median survival of nine months.19 In contrast, the presence of both SOX9 and BRAF oncogenic mutations in initially unresected colorectal liver metastases has been associated with successful conversion to resection.20 In regards to the HER2 oncogene, several therapies have been studied, including neratinib, pertuzumab, and trastuzumab; overall, monotherapy with any of these treatments has not shown to be effective in producing durable tumor regression.21 However, when administered in combination, such as trastuzumab and pertuzumab or trastuzumab and tucatinib, there is a significant increase in the overall response rate, which is notable in the setting of heavy pretreatment in the study populations.22,23
For MSI-H CRC, checkpoint inhibitors—specifically PD-1 targeted therapies—have become standard of care. Recently, a combination of PD-1 antibody therapies has demonstrated clinical success, such as nivolumab and ipilimumab following progression on pembrolizumab.24 PD-1 targeted therapies have additionally demonstrated improved efficacy in combination with other therapies. For example, PD-1 antibodies have demonstrated synergism when administered either simultaneously or immediately after FOLFOX chemotherapy by targeting and preventing tumor adaptive resistance to FOLFOX.25 Specifically in the neoadjuvant setting, immunoglobulins targeting PD-1 and CTLA-4, when used in combination, have demonstrated pathologic response in patients with both mismatch repair-deficient and proficient tumors.17,26
Several biomarkers should be assessed in patients with colorectal cancer, including EGFR and BRAF. Response to these therapies can be dependent on the presence of additional mutations, such as KRAS, HER2 and PICK3CA, for which other treatment regimens may be available.
Cholangiocarcinoma
Cholangiocarcinoma is an uncommon cancer, with approximately 8,000 new diagnoses per year. Its prognosis is poor, with an overall survival rate of less than 10 percent.27 The incidence of CCA has increased in the last 40 years in the U.S., the reasons for which remain unknown.28 CCA has been characterized both by etiology, such as fluke versus non-fluke, and location, such as intra- versus extrahepatic.29 The location of CCA—intrahepatic (iCCA), perihilar (pCCA), versus distal (dCCA)—has been associated with differences in genetic profiles. Amongst intrahepatic cancers, TP53, KRAS, ARID1A, IDH1, and MCL1 mutations have been identified as the most common; in contrast, amongst extrahepatic cancers, TP53, KRAS, ERBB2, SMAD4, FBXW7 and CDKN2A mutations are the most prevalent.30-32 Of note, molecular subtypes shared between iCCA and hepatocellular carcinoma have been identified.33
There are multiple relevant genetic mutations in cholangiocarcinoma that have been identified as therapeutic targets (Table 3). IDH1 mutations have been identified in approximately 13 percent of iCCAs, for which IDH1 targeted drugs, such as ivosidenib, have demonstrated improved progression-free survival.34,35 FGFR2 gene fusions have additionally been identified in approximately 13 to 14 percent of iCCA, for which FGFR inhibitors and monoclonal antibodies are presently being evaluated.27,36 In a phase II trial, FGFR inhibitor futibatinib demonstrated a 41.7 percent objective response rate with median progression-free survival of nine months.37 More recently, mucin 13 (MUC13) overexpression has been associated with metastasis via the EGFR/PI3K/AKT pathway.38 Unfortunately, treatments targeting EGFR has not shown clear clinical efficacy.39 One study of cancer cells resistant to EGFR-targeting therapies, namely erlotinib, found upregulation of the IR/IGF1R pathway; clinical trials assessing this pathway have yet to be tested.40 Of note, the incidence of MSI-H status in cholangiocarcinoma has been observed to be low.41,42 Although there are not approved neoadjuvant regimens, several upcoming trials will utilize targeted agents and immunotherapy in both the neoadjuvant and adjuvant settings.
Targetable mutations are being increasingly identified for cholangiocarcinoma, for which existing therapies developed for other malignancies may be applicable. Presently, key mutations include IDH1 and FGFR inhibitor status.
Conclusion
Treatments targeting specific genomic mutations and immunotherapies offer a more personalized and possibly more efficacious treatment modality compared to conventional chemotherapies. The timing and sequencing of these "precision" therapies with respect to surgery is rapidly evolving. With the ongoing innovations in these novel treatment paradigms, previously unresectable cancers may become resectable. Furthermore, multifocal disease may be controlled but develop "escape" lesions where resection may benefit patients. Understanding and appreciating these scenarios is critical to optimizing outcomes in patients with solid tumors. Furthermore, downstream analysis and research on tissues procured under IRB-approved protocols in many of these situations are led by, and dependent on, surgeons and their critical role in translational oncology research.
