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Personalizing Adjuvant Therapy for Stage II/III Colorectal Cancer
Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.
Abstract
This review focuses on three areas of interest with respect to the treatment of stage II and III colon and rectal cancer, including (1) tailoring adjuvant therapy for the geriatric population, (2) the controversy as to the optimal adjuvant therapy strategy for patients with locoregional rectal cancer and for patients with colorectal resectable metastatic disease, and (3) discussion of the microenvironment, molecular profiling, and the future of adjuvant therapy. It has become evident that age is the strongest predictive factor for receipt of adjuvant chemotherapy, duration of treatment, and risk of treatment-related toxicity. Although incorporating adjuvant chemotherapy for patients who have received neoadjuvant chemoradiation and surgery would appear to be a reasonable strategy to improve survivorship as an extrapolation from stage III colon cancer adjuvant trials, attempts at defining the optimal rectal cancer population that would benefit from adjuvant therapy remain elusive. Similarly, the role of adjuvant chemotherapy for patients after resection of metastatic colorectal cancer has not been clearly defined because of very limited data to provide guidance. An understanding of the biologic hallmarks and drivers of metastatic spread as well as the micrometastatic environment is expected to translate into therapeutic strategies tailored to select patients. The identification of actionable targets in mesenchymal tumors is of major interest.
KEY POINTS
Age is the strongest predictive factor for receipt of adjuvant chemotherapy, duration of treatment, and risk of treatment-related toxicity.
Available data support disease-free and overall survival benefit after adjuvant therapy among older adults age 70–74 years with colon cancer, but variable outcomes for those age 75 years or older.
Attempts at defining the optimal rectal cancer population that would benefit from adjuvant therapy remain elusive.
In stage II disease, microsatellite instability and/or high “immunoscores” associate with very good prognosis and support a no-adjuvant-treatment approach. On the other hand, empirical evidence for the addition of supervised gene expression classifiers to the clinical decision-making paradigm is scarce.
Irrespective of tumor stage, activation of a gene expression signature of epithelial-mesenchymal transition correlates with an invasive-inflamed microenvironment infiltrated with stromal and immunosuppressive cells, which confers poor prognosis and limited benefit with standard adjuvant chemotherapies.
Although there is no uniform number at which physiologic aging occurs, there is little known about optimal treatment of colon cancer involving lymph nodes following surgical resection for adults age 75 or older.1,2 A substantial number of patients with colorectal cancer (CRC; 40%) are adults age 75 or older.3 Standards for adjuvant chemotherapy following resection of colon cancer were established based on results of three large randomized clinical trials: MOSAIC (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer), NSABP C-07 (National Surgical Adjuvant Breast and Bowel Project), and XELOXA NO16968 (XELOX in Adjuvant Colon Cancer Treatment). Yet with less than 1% (MOSAIC) and 5% (NSABP C-07), respectively, of those trials including older adults, it proves difficult to extrapolate standards of adjuvant chemotherapy to older adults in the real-world setting (the proportion age 75 or older is not reported in XELOXA NO16968). Several pooled analyses show potential for survival benefit among some older adults; however, nearly two-thirds do not receive adjuvant treatment.3,4 Nonreceipt of systemic chemotherapy is particularly prevalent among those older adults diagnosed with colon cancer who also have geriatric syndromes (e.g., delirium, frailty) or active comorbid medical conditions.5 Expertise in delivering care to this growing subset of patients is predominantly driven by provider experience and possible bias, given the limited clinical trial data available to guide use of adjuvant chemotherapy in the older adult population. Here, we review the available data and recommendations for adjuvant treatment recommendations for adults age 75 or older diagnosed with stage III colon cancer.
The benefit of adjuvant chemotherapy has been clearly established in the adjuvant setting for node-positive colon cancer. Standard treatment options include fluorouracil (FU) or capecitabine with or without oxaliplatin (Table 1). The addition of FU to surgical resection led to 17% improvement in disease-free survival and 13% improvement in overall survival among patients with node-positive colon cancer.6 The addition of capecitabine led to similar improvements in disease-free (hazard ratio [HR], 0.87; 95% CI, 0.75–1.00) and overall survival (HR, 0.84; 95% CI, 0.69–1.01) compared with bolus FU/leucovorin (p for equivalence < .001, with median follow-up of 3.8 years).7 The addition of oxaliplatin to FU further leads to an absolute improvement in disease-free and overall survival at 10 years by an additional 8%.8 The addition of oxaliplatin to capecitabine results in a similar improvement, with reductions of 20% and 17% in the relative risk of recurrence or death (95% CI, 0.69–0.93; p = .004) and risk of death (95% CI, 0.70–0.99; p = .04), respectively.9 The extent to which older adults derive benefit from adjuvant chemotherapy was not established in these trials, given that most trials limited participation to those younger than age 757,10 or limited the number of adults age 75 or older.3,4
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A number of pooled and subpopulation analyses have been conducted to fill the gap in knowledge regarding survival benefit of older adults receiving adjuvant chemotherapy for stage III colon cancer (refer to Table 123,24). In a pooled analysis of seven randomized clinical trials of adjuvant chemotherapy included in the ACCENT (Adjuvant Colon Cancer End Points) study, older adults did not experience substantial benefit from adjuvant fluoropyrimidine or combination chemotherapy regimens regarding disease-free survival (HR, 1.05; 95% CI, 0.94–1.19), overall survival (HR, 1.08; 95% CI, 0.95–1.23), or time to recurrence survival (HR, 1.06; 95% CI, 0.93–1.22).22 Older adults seemed to have a reduced overall survival benefit from oxaliplatin-based chemotherapy with a similar disease-free survival benefit compared with younger adults receiving oxaliplatin-based chemotherapy. There was no difference in rates of death within experimental or control arms, suggesting that it is unlikely that the substantial interaction noted between treatment and age would be explained by early deaths attributable to treatment-related toxicity.22
In contrast, comorbidity and age did not appear to affect disease-free or overall survival among older adults enrolled in four randomized clinical trials evaluating adjuvant fluoropyrimidine with or without oxaliplatin including comorbidity data defined by the Charlson Comorbidity Index or the National Cancer Institute Combined Index.15 The ACCORE study evaluated 191 patients age 70 or older and 338 patients younger than 70 receiving adjuvant 5-fluorouracil (5-FU) or capecitabine with or without oxaliplatin for CRC in Denmark from 2001 to 2012.25 Older adults experienced similar 10-year CRC-specific overall survival compared with younger patients but did experience higher rates of mortality owing to other causes after controlling for performance status and presence of comorbid medical conditions. Older adults received equivalent doses of capecitabine but fewer doses of oxaliplatin and 5-FU compared with younger patients. Disease-free survival and CRC-specific mortality were not affected by reductions in chemotherapy dose intensity. This and other pooled analyses from clinical trials are limited by the relatively small number of older adults enrolled. Despite this, rates of use of oxaliplatin found in the Surveillance, Epidemiology and End Results (SEER) database increased rapidly in adults age 65 or older diagnosed with stage III colon cancer (from 52% in 2004 to 73% in 2007, albeit at reduced rates among individuals older than 85 and those with comorbid medical conditions).26
In the general population of 5,489 adults 75 or older, 2,395 (44%) received chemotherapy within 120 days of surgery and 3,096 (56%) did not.3 Rates of chemotherapy administration were higher in academic centers (75% in a National Comprehensive Cancer Network assessment [61% oxaliplatin]) versus nonacademic and community sites (42% in a SEER-Medicare analysis [42% oxaliplatin], 45% in a New York State Cancer Registry-Medicare study [28% oxaliplatin], and 52% in the CanCORS study). Oxaliplatin receipt decreased with increasing age, from 46% of adults age 75–79 to 7% among those age 85 or older. However, the benefit of adjuvant chemotherapy in this heterogeneous older population was comparable to that observed in pooled analyses of selected fit older adults participating in clinical trials, suggesting retention of survival benefit among subsets of older adults amenable to and receiving adjuvant chemotherapy within 120 days of surgical resection.
Older adults appear to receive a benefit from adjuvant chemotherapy in some, but not all, studies. Survival seems to differ across age categories, with decreasing survival benefit with increasing age. A review of the National Cancer Institute SEER database linked to the Medicare database (SEER-Medicare) noted a predicted increased 5-year survival benefit of 14% among patients age 70–74 compared with 8% among those age 80–84.17 Survival benefit persists in older adults age 80–89, despite only 43% of the 8,141 octogenarians included in the National Cancer Database from 2006 to 2011.4 Regardless of potential benefit for some older adults, older age remains the strongest determinant of initiation, duration, and completion of adjuvant chemotherapy.3,27-29 Older adults are also more likely to have delays in initiation of adjuvant chemotherapy and are less likely to complete the full 6 months of adjuvant therapy, factors that also increase mortality risk.25,30,31
Could a molecular profile determine those older adults unlikely to benefit from adjuvant chemotherapy? We sought to identify a subset of molecular markers unique to older adults diagnosed with colon or rectal cancer. We examined the presence of the CpG island methylator phenotype; microsatellite instability (MSI); KRAS, BRAF, and PIK3CA mutations; and nuclear CTNNβ1 expression status by age at CRC diagnosis within a large prospective cohort study. Tumor nuclear CTNNβ1 appeared to be associated with higher mortality among older adults diagnosed with CRC.32 However, subsequent examination of the impact of nuclear CTNNβ1 and a host of additional molecular factors on prognosis for older adults diagnosed with colon or rectal cancer did not confirm a particular molecular phenotype among older adults diagnosed with colon or rectal cancer (N. J. McCleary, MD, MPH, and A. J. Bass, manuscript in preparation, 2017). Additional study is underway to examine whether a particular molecular phenotype predicts survival among a cohort of older adults receiving chemotherapy for colon or rectal cancer.
Potential benefit from adjuvant chemotherapy in older adults must be balanced by the potential for risk attributable to increased toxicity, reduced organ function, sarcopenia, limited social support, or unanticipated decline in physical function.33 Although prospective clinical trials cannot delineate patients most at risk for poor clinical or physical outcomes from specific adjuvant chemotherapy regimens, doses, or duration of treatment, we can glean recommendations for treatment decisions from a few notable studies.
First, we can predict treatment-related toxicity across multiple cancer types for older adults. Moving beyond the limitations of the Eastern Cooperative Oncology Group or Karnofsky performance status, the comprehensive geriatric assessment has been shown to predict those older adults at risk for toxicity across a number of cancer types and stages, including colon cancer.34,35 The comprehensive geriatric assessment is a feasible, validated instrument that allows both patient and provider evaluation of functional status, medications, social support, cognition, nutrition, psychologic state, and comorbidity to better assess overall fitness. This assessment may identify issues affecting treatment decision making for both patient and provider. The geriatric assessment can predict overall morbidity and mortality but, more specifically, it can anticipate chemotherapy-related toxicity.36-39 A cancer-specific comprehensive geriatric assessment has shown benefit in treatment selection for older adults diagnosed with lung cancer in the ambulatory setting40 and for hospitalized older adults.41 It is now being embedded within a prospective multicenter treatment clinical trial to assess its ability to risk-stratify patients (A. Hurria, personal communication, ALLIANCE meeting, Chicago, IL, November 2016). This and other indices of frailty,42 or risk of increased morbidity and mortality associated with chemotherapy, will not only provide parameters for discussion with older adults regarding the additive risks versus benefits of adjuvant chemotherapy, but they will also potentially inform provider decision making regarding initiation and dosing of treatment.43-45
Second, we can consider the potential impact of particular adjuvant chemotherapy regimens on organ function and physical function absent from any specific comorbid medical condition. Common measures of performance status underestimate the physiologic changes in organ function occurring with aging.24 Bone marrow reserves decrease with increasing age. Chemotherapy treatment can lead to depletion of the bone marrow, thereby increasing the risk of cytopenias and subsequent risks of bleeding or infection. Aging is also associated with decreases in renal and hepatic function, bone and muscle mass, and risks of altered cognition, potentially increasing the risk of treatment-related toxicity.24 Exercise is recommended for secondary cancer prevention following resection of colon cancer and may serve as a useful adjunct during the postoperative treatment course.46,47 However, older adults receiving chemotherapy are susceptible to a decline in physical function, potentially limiting their ability to exercise. Oxaliplatin-induced neuropathy further affects this physical decline and increases the potential risk of falls and limits independence.24,48-50
Third, we can discuss the relative benefit of adjuvant chemotherapy among those older adults with active, unmanaged comorbid medical conditions and competing risk of death or disability. Comorbid medical conditions appear to have a greater effect on older adults diagnosed with advanced CRC.51 Comorbid medical conditions may impact drug absorption and clearance. The presence of comorbid medical conditions predict for concomitant medications and risk of drug interactions.52 Regular careful review of patient medications, as promoted by geriatric assessment, can limit the potential risk of drug-drug interactions.53 In the adjuvant setting, renal excretion of both capecitabine and oxaliplatin requires dose adjustment for creatinine clearance below 50 mL/min.24 Capecitabine also requires dose adjustment for patients taking warfarin. Cognitive impairment increases the risk of nonadherence to capecitabine.
Finally, it is incumbent on us as oncology providers to understand the full impact of adjuvant chemotherapy on older adults beyond disease-free and overall survival.54 Disease-free and overall survival are the primary outcomes used to determine the standards for adjuvant chemotherapy regardless of age at diagnosis. However, other clinical and quality outcomes may be of interest to patients. Although outcomes of interest have not yet been specifically identified for older adults, few clinical trials evaluate outcomes beyond traditional outcomes of disease-free and overall survival to include outcomes potentially pertinent to older adults, such as the impact of adjuvant chemotherapy on “quality of survival and functional independence.”34 Given this, we can consider the traditional outcomes as a measure of treatment response, but we cannot fully comment on other benefits that older adults may experience as a result of adjuvant chemotherapy. Adults age 65 or older reported greater decline in physical and mental health within the first 6 months of diagnosis of CRC compared with age-matched controls as part of the Medicare Health Outcomes Survey, particularly among patients diagnosed with stage III or IV CRC.55 How do we best define “functional independence” and “quality of survival” over the course of adjuvant chemotherapy administration and afterward? What is an acceptable threshold for additional outcomes beyond which treatment should not be recommended regardless of potential disease-free or overall survival benefit? We must begin exploring those additional outcomes of importance to older adults to determine the full impact of adjuvant chemotherapy on older adults and develop strategies to improve outcomes globally.
For many years, the standard of care for patients with locally advanced clinical stage II to III rectal cancer included surgery, often resulting in a permanent ostomy, followed by adjuvant chemotherapy and chemoradiation.11-14,16,18-21 This strategy improved both overall survival and the risk of locoregional failure. An example of the outcome benefits of combined adjuvant chemoradiation, published more than a decade ago, include the U.S. Intergroup 0144 trial, which evaluated the so-called sandwich approach of chemotherapy followed by chemoradiation followed by additional chemotherapy and compared bolus versus infusional 5-FU regimens for patients with T3-4N0M0 or T1-4N1,2M0 disease.56 The locoregional failure rate for those who received low anterior resection was between 3% and 5%. Three-year overall survival was between 81% and 83%. A pooled analysis of North American phase III combined modality adjuvant trials identified three different risk groups defined by TN stage, including T1-T2N1 and T3N0 (intermediate); T1-2N2, T3N1, and T4N0 (moderately high); and T3N2, T4N1, and T4N2 (high), which correlated with survival and disease control.57,58 Five-year overall survival rates for the intermediate group were 78%–85% compared with 25%–57% for those with high-risk lesions. Different treatment strategies depending upon risk were therefore implied. Subsequently there was a profound shift in the treatment approach for clinical stage II to III rectal cancer as data emerged supporting the use of neoadjuvant chemoradiation; however, this therapeutic evolution generated considerable controversy as to the role of adjuvant chemotherapy, a controversy that has persisted.
Neoadjuvant chemoradiation has become the preferred treatment of locally advanced rectal cancer because of evidence demonstrating improved outcomes, better tolerability, and, in many cases, considerable downstaging resulting in sphincter-preserving surgery and thus avoiding a permanent ostomy. A hallmark study from the Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society (CAO/ARO/AIO-94) compared preoperative chemoradiotherapy with postoperative chemoradiotherapy for locally advanced rectal cancer, demonstrating significant improvement in 5-year cumulative incidence of local relapse favoring a preoperative approach (6% vs. 13%; p = .006).59 There were considerably less acute and long-term toxic effects in the preoperative group, although 5-year overall survival rates were similar (76% vs. 74%). Patients also received four cycles of postoperative 5-FU. Long-term follow-up data showed improved outcomes for the preoperative patients who achieved complete and intermediate tumor regressions and the overall 10-year cumulative incidence of local relapse continued to favor the patients treated preoperatively (7.1% vs. 10.1%; p = .048); there was no change in overall survivorship (59.6% vs. 59.9%).60,61 A recent meta-analysis of more than 10,000 patients who participated in randomized controlled trials confirmed the improved rate of local control with neoadjuvant chemoradiation, including after total mesorectal excision, although there was no improvement in long-term survival.62
Although incorporating adjuvant chemotherapy for patients who have received neoadjuvant chemoradiation and surgery would appear to be a reasonable strategy to improve survivorship as an extrapolation from stage III colon cancer adjuvant trials, attempts at defining the optimal rectal cancer population that would benefit from adjuvant therapy remain elusive. This paucity of consistent evidence has resulted in variability in practice patterns. For example, a National Comprehensive Cancer Network CRC database assessment of nearly 2,000 patients with stage II/III rectal cancer who received neoadjuvant chemoradiation showed that a sizable minority of patients did not receive adjuvant chemotherapy.63 A SEER-Medicare database analysis noted that one in three patients did not receive adjuvant therapy after neoadjuvant chemoradiation and resection.64
Some investigations have attempted to select patients who may not require adjuvant therapy after neoadjuvant chemoradiation and surgery. For example, a study of 176 patients reported that those who achieved a complete response (15.3% of patients staged as ypT0M0) had 5-year disease-free and overall survival rates of 96% and 100%, respectively, suggesting that adjuvant therapy would provide no further meaningful benefit for these individuals.65 In a retrospective study of 851 patients, 330 received preoperative short-course radiation (2,500 cGy administered in five fractions without chemotherapy) and 123 received adjuvant chemotherapy.66 A subgroup analysis showed that adjuvant therapy improved disease-specific survival and overall survival only for those patients who had at least two high-risk features such as pT4 tumor, inadequate lymph node sampling, lymphovascular invasion, perineural invasion, poor differentiation, obstruction, or perforation.
EORTC 22921 was a randomized trial of 1,011 patients evaluating FU-based adjuvant chemotherapy after preoperative chemoradiation for patients with clinical stage T3 or T4 resectable rectal cancer.67 Patients were assigned to one of four treatment arms including preoperative radiotherapy with or without chemotherapy and preoperative radiotherapy with or without chemotherapy followed by adjuvant chemotherapy. There was relatively poor adherence to adjuvant chemotherapy, because only 43% of patients received the planned dose. At a median follow-up of 10.4 years, there was no substantial difference in overall survival among the four treatment groups (48.4%–51.9%), nor were there differences in disease-free survival rates and cumulative incidence of distant metastases. Most recurrences were noted within 5 years. A recently reported Italian study of 634 evaluable patients concluded that adjuvant 5-FU did not improve 5-year overall or disease-free survival, including among those who obtained a complete pathologic response and overall downstaging rates; 28% of patients, however, never received the assigned adjuvant chemotherapy.68 A Dutch study of 437 eligible patients closed prematurely for accrual reasons; however, there was no difference in 5-year cumulative incidence for either local regional recurrence or in 5-year distance recurrences after postoperative fluoropyrimidine monotherapy.69
Systematic reviews and meta-analyses also were recently reported to address the role of adjuvant chemotherapy after neoadjuvant therapy and surgery. An analysis of four phase III clinical trials of nearly 1,200 patients with ypTNM stage II and III rectal cancers and a R0 resection found no difference in overall survival comparing those who received adjuvant chemotherapy versus observation.70 There were patients with tumors located at 10 to 15 cm from the anal verge who had improved disease-free survival and fewer distant metastases when treated with adjuvant chemotherapy. Another analysis of randomized controlled trials in retrospective studies of nearly 5,500 patients reported improvement in both 5-year overall survival and disease-free survival for those patients treated with neoadjuvant chemoradiation, surgery, and adjuvant chemotherapy.71 The improvement in 5-year overall survival was largest among patients who were downstaged and in the retrospective series. A third systematic review and meta-analysis of five randomized trials including 2,398 patients did not show an advantage for those who received adjuvant chemotherapy although there was a substantial adjuvant chemotherapy effect for patients who were randomized after surgery (753 patients).72 In two trials, there was a difference in disease-free survival for those who received FU and oxaliplatin compared with single-agent 5-FU; however, in two other trials, FU and oxaliplatin did not show a substantial difference. Overall, the authors concluded that adjuvant chemotherapy provided no “strong scientific evidence” to support its use for those who received preoperative chemoradiation.
A number of treatment strategies have been the subject of recent clinical trials and have informed current or planned global clinical trial portfolios73,74 (Table 2). For example, there is interest in the “wait and watch” approach for patients who have obtained a complete response after chemoradiation and in strategies to encompass neoadjuvant chemotherapy while reserving radiation for those with suboptimal response.73,74 The overall goal is to avoid more extensive intervention with the associated risk of toxicity and long-term sequelae for patients who may not need such an approach and to intensify therapy for those who are at highest risk for recurrence. Current National Comprehensive Cancer Network guidelines recommend a number of options for patients with clinical stage II and III rectal cancer, including (1) neoadjuvant therapy comprising long-course chemoradiation with either capecitabine or infusional 5-FU, short-course radiation, or a preferred chemotherapy regimen with oxaliplatin and a fluoropyrimidine followed by chemoradiation; or (2) adjuvant therapy is recommended after surgery for those who have received neoadjuvant oxaliplatin and a fluoropyrimidine followed by chemoradiation surveillance, whereas adjuvant chemotherapy with oxaliplatin and a fluoropyrimidine is recommended as the preferred regimen for those treated with chemoradiation or short-course radiation.75
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It has long been known that there is a subgroup of patients with colon or rectal cancer who have potentially resectable metastatic disease and can enjoy long-term survival after surgery. The introduction of combination chemotherapy for metastatic CRC has resulted in improvement in response, progression-free survival, and overall survival. In addition, there is a perceived benefit of combination chemotherapy for patients with resectable metastatic disease or those who obtain a substantial response to therapy rendering them with resectable disease. An advantage of preoperative chemotherapy for patients with resectable or potentially resectable metastatic disease is to determine “chemosensitivity” and also to identify those individuals who may be resistant to therapy and develop more rapid disease progression. For patients with rectal cancer and potentially resectable metastatic disease, preoperative chemoradiotherapy is often considered to reduce the risk of local regional recurrence, particularly when the goal of surgery is curative intent.
A perioperative approach for those with resectable metastatic disease incorporates a total chemotherapy treatment period of approximately 6 months including preoperative therapy followed by surgery and adjuvant chemotherapy. The role of adjuvant chemotherapy, however, has not been clearly defined because of very limited data to provide guidance. A systematic review of 642 evaluable patients with liver metastases evaluated surgery versus surgery and chemotherapy, demonstrating improvement in disease-free and progression-free survival favoring chemotherapy without a survival advantage.76 A meta-analysis of 10 studies including nearly 1,900 patients showed no survival benefit for patients who received perioperative chemotherapy for resectable liver metastases compared with surgery alone; however, a disease-free survival benefit was noted.77 Similar results were observed in additional analyses.78,79 EORTC 40983 evaluated six cycles of fluorouracil/leucovorin/oxaliplatin before and after surgical resection of liver metastases compared with surgery alone, demonstrating a 40% response to preoperative fluorouracil/leucovorin/oxaliplatin and improvement in progression-free survival for eligible patients who were resected with no overall survival benefit.80 There is consensus in the National Comprehensive Cancer Network guidelines that adjuvant chemotherapy after resection of metastatic disease remains an option of care.75
Retrospective biomarker analyses of multiple clinical trials in the adjuvant setting strongly support the feasibility of refining prognostic stratification in CRC by factoring in molecular features with pathologic tumor staging.81 However, validated predictive markers of adjuvant therapy benefit for stage II or III CRCs are still lacking.81 To date, the only molecular marker with proven clinical utility in early-stage CRC is MSI, which associates with very good prognosis in stage II disease irrespective of adjuvant chemotherapy, supporting a no-adjuvant-treatment approach.82 On the other hand, patients with MSI stage III CRC derive benefit from adjuvant chemotherapy, with no differential benefit compared with the microsatellite stability (MSS) population in clinical trials assessing 5-FU or oxaliplatin-based regimens.83 Interestingly, there is a possible interaction between MSI status and primary tumor location in stage III treated disease, with a better prognosis limited to right-sided tumors.84 This association reinforces the known intrinsic biologic differences between proximal and distal CRC.85
Mounting evidence indicates that an enhanced lymphocytic reaction in CRC is a critical determinant of the risk of dissemination to distant metastasis.86 A clinical translation of this finding was the establishment of a scoring system, called the “immunoscore,” based on the abundance of two distinct lymphocyte populations (CD8+ cytotoxic T cells and CD3+ T memory cells) at the tumor center and at its invasive margin. In a large validation study, time to recurrence and overall survival were significantly longer for patients with stage II and III colon cancer with immunoscore high tumors, independent of clinicopathological factors.87 MSI cancers characteristically exhibit strong infiltration of the tumor microenvironment with immune cells, which relates to hypermutation rates and higher neoantigen loads.88 However, a subset of MSS tumors also have increased intratumoral adaptive immune gene expression and high immunoscores. These “immune-activated” tumors, irrespective of stage, have improved survival outcomes and the immunoscore was shown to be superior to MSI in predicting patients’ disease-specific recurrence and survival in multivariable models.89 These data strengthen the concept that reduced immune cytotoxicity is a major factor driving metastases in CRC. However, most patients with early-stage CRC have MSS and/or a medium/low immunoscore, which associate with an intermediate to poor prognosis and do not help prioritize adjuvant chemotherapy in stage II or III disease. The same is true for tumors harboring BRAF V600E mutations, which are an independent prognostic factor of reduced overall survival in multiple studies, particularly in MSS left-sided disease, but not a marker of chemosensitivity/resistance to 5-FU or oxaliplatin-based regimens in the adjuvant setting.81
In addition to microsatellite status and gene mutations, which did not demonstrate predictive value for standard chemotherapy benefit in early-stage CRC, different groups explored the potential clinical utility of gene expression signatures in this context. The transcriptomic profile of a tumor, encompassing cancer cell, immune, and stromal signals, is intimately linked to its phenotype and clinical behavior. Gene expression profiling has been used extensively to identify biologically homogeneous subtypes of the disease through unsupervised clustering. An international effort dedicated to large-scale data sharing and coordinated analytics cross-compared independent transcriptomic-based CRC subtyping systems and resulted in a consensus molecular classification that allows the categorization of most CRC tumors into one of four robust intrinsic subtypes.90 The consensus molecular subtype (CMS) features are summarized in Table 3. There are striking differences in prognosis with this unsupervised gene expression signature, confirming that the biologic processes implicated in each subtype are clinically relevant.90 The CMS4 mesenchymal group is associated with a significantly higher risk of distant relapse and death for patients diagnosed with early-stage CRC, irrespective of validated clinicopathological features, MSI status, and BRAF V600E mutations.81 These tumors exert a proangiogenic and stromagenic influence on the microenvironment, which is highly infiltrated with endothelial cells and cancer-associated fibroblasts. In addition, CMS4 mesenchymal tumors are enriched with immunosuppressive cells, such as regulatory T cells, B cells, and myeloid-derived suppressor cells, which are negative regulators of cytotoxic T cells.91-93 This effect is explained in part by high expression of transforming growth factor-β and chemokines attracting myeloid cells (C-C motif chemokine ligand CCL2) and related cytokines (interleukin-23 and interleukin-17).92,93 The proangiogenic/stromagenic/immunosuppressive phenotype of CMS4 mesenchymal tumors, with their invasive-inflamed microenvironment, is intimately linked to higher chances of metastatic spread and resistance to therapy.94,95 Indeed, retrospective biomarker analysis of the NSABP C-07 randomized clinical trial showed poor prognosis and no benefit from adjuvant oxaliplatin-based chemotherapy in the subset of patients with stage III CRC whose tumors displayed a mesenchymal phenotype.96 However, the clinical utility of using intrinsic CRC subtyping to identify patients for oxaliplatin treatment requires validation in independent clinical trial cohorts.
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Similarly, the value of supervised gene expression classifiers for adjuvant chemotherapy selection remains to be proven. Different prognostic signatures, such as Oncotype DX Colon Cancer, ColoPrint, Veridex, and GeneFx Colon, have been widely evaluated retrospectively in clinical cohorts.81 Irrespective of assay, gene panel size, and tissue source (fresh, frozen, formalin fixed, paraffin embedded), analysis of the various transcriptomes in CRC can effectively classify patients into subgroups at low and high risk of disease relapse. The original hypothesis was that patients whose tumors are categorized as high risk have increased benefit from adjuvant chemotherapy. In theory, the prognostic information provided by these signatures could have the greatest clinical utility when used as a complement to T stage and MSI status, specifically for patients who have pT3pN0 MSS disease.97 However, the relative chemotherapy benefit for Oncotype DX Colon Cancer was shown to be similar across risk groups.98,99 Despite the fact that gene expression–based risk scores seem to add little to risk models with known prognostic factors,100 incorporation of the signature results into clinical practice was associated with changes in treatment recommendation for nearly 50% of patients with pT3pN0 MSS CRC compared with traditional clinicopathological assessment variables alone.101 Prospective validation of these signatures has not yet been presented, and currently only one trial (PARSC [Prospective Study for the Assessment of Recurrence Risk in Stage II Colon Cancer Patients]) is comparing risk assessment using the ColoPrint profile versus a clinical risk assessment based on the investigator’s judgment and American Society of Clinical Oncology recommendations for high-risk disease. Furthermore, economic studies assessing the cost-effectiveness of using gene expression signatures to select patients with CRC who have a high risk of relapse (and to base adjuvant chemotherapy decision making on this criterion) are not yet available. Given the fact that high risk scores in supervised signatures have substantial overlap with a mesenchymal phenotype,102 it is understandable that these prognostic classifiers have limited predictive value for adjuvant chemotherapy selection. This finding is in stark contrast with prognostic gene expression classifiers in early-stage breast cancer, in which high risk scores associate with high proliferation rates and increased benefit from more aggressive adjuvant chemotherapy.103
In summary, pathways that coordinate the creation of an immunosuppressive microenvironment and stromal invasiveness are the key drivers of a prometastatic state in CRC.86 These processes are strongly enriched in the CMS4 mesenchymal CRC population,90 which is poorly responsive to standard chemotherapies.95,96 The following investigations should be pursued by the scientific community: (1) correlating response patterns of targeted agents and immunotherapies with the CMS classification in existing clinical trials; (2) adapting the design of future trials, such as adding stratification factors or increasing their power to allow these retrospective correlative analyses to be performed; and (3) designing prospective clinical trials in CRC that incorporate new biomarkers with drug repositioning and/or novel matched targeted agents and immunotherapies.91 Different academic groups are working on a practical and robust CMS classifier that works on formalin-fixed, paraffin-embedded primary CRC tissues (either gene expression or immunohistochemistry based).104 Molecular classifiers based on intrinsic tumor phenotypes are already being investigated in prospective clinical trials in the metastatic setting, such as in the MoTriColor project, a large pan-European effort pioneering novel molecularly guided trials in metastatic CRC, but the biologic differences between micro- and macrometastatic disease must be taken into account when translating data garnered from advanced-stage CRC into early-stage disease regarding treatment decisions.91 The recent failures with cetuximab and bevacizumab in adjuvant trials in stage III CRC exposed this challenge and call into question our traditional paradigm of drug development (namely, considering agents for testing in the curative setting only after they are found to be beneficial in the treatment of patients with metastatic disease). We believe that this new biologic understanding is expected to guide drug selection in future adjuvant clinical trials and is hoped to increase cure rates and survival in CRC.
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc.
No relationship to disclose
Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Boston Biomedical, Bristol-Myers Squibb, Celgene, EMD Serono, Exelixis, Genentech/Roche, Guardant Health, Guerbet, Halozyme, Helsinn, Immunogen, IntegraGen, Lexicon, Lilly, Novartis, Oncosil, Opsona Therapeutics, Pfizer, Purdue Pharma, Rafael Pharmaceuticals, Taiho Pharmaceutical, TRM Oncology
Research Funding: Acerta Pharma, advanced accelerator applications (Inst), Bristol-Myers Squibb, Celgene, Infinity Pharmaceuticals (Inst), MedImmune, Merck Sharp & Dohme (Inst), Novartis (Inst), Taiho Pharmaceutical (Inst), Xencor, Xencor
Travel, Accommodations, Expenses: Astellas Pharma, AVEO, Bayer, Boehringer Ingelheim, Boston Biomedical, Bristol-Myers Squibb, DAVAOncology, Genentech/Roche, Gilead Sciences, Guardant Health, guerbet, Helsinn, Lilly/ImClone, Sanofi, Spectrum Pharmaceuticals, TRM Oncology
Consulting or Advisory Role: Astellas Pharma, Novartis, Roche/Genentech
Research Funding: Merck
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