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Following initial successes in melanoma treatment, immunotherapy has rapidly become established as a major treatment modality for multiple types of solid cancers, including a subset of colorectal cancers (CRCs). Two programmed cell death 1 (PD1)-blocking antibodies, pembrolizumab and nivolumab, have shown efficacy in patients with metastatic CRC that is mismatch-repair-deficient and microsatellite instability-high (dMMR–MSI-H), and have been granted accelerated FDA approval. In contrast to most other treatments for metastatic cancer, immunotherapy achieves long-term durable remission in a subset of patients, highlighting the tremendous promise of immunotherapy in treating dMMR–MSI-H metastatic CRC. Here, we review the clinical development of immune checkpoint inhibition in CRC leading to regulatory approvals for the treatment of dMMR–MSI-H CRC. We focus on new advances in expanding the efficacy of immunotherapy to early-stage CRC and CRC that is mismatch-repair-proficient and has low microsatellite instability (pMMR–MSI-L) and discuss emerging approaches for targeting the immune microenvironment, which might complement immune checkpoint inhibition.Ganesh et al. describe the rationale for using immunotherapy in select patients with colorectal cancer, discuss clinical findings supporting its use and highlight current strategies and future directions for expanding the scope of immunotherapy in this disease.

The FDA has approved immune checkpoint inhibitors for solid tumors of any histologic origin with more than 10 mutations per megabase of DNA. This study showed that in tumors with high mutational burden treated with an immune checkpoint inhibitor, improved overall survival was associated mainly with mutations in the POLE gene and with defective DNA mismatch repair, not overall mutational burden.

Colorectal cancer (CRC) is the second most common cause of cancer death in the United States. Every 3 years, the American Cancer Society provides an update of CRC occurrence based on incidence data (available through 2016) from population-based cancer registries and mortality data (through 2017) from the National Center for Health Statistics. In 2020, approximately 147,950 individuals will be diagnosed with CRC and 53,200 will die from the disease, including 17,930 cases and 3,640 deaths in individuals aged younger than 50 years. The incidence rate during 2012 through 2016 ranged from 30 (per 100,000 persons) in Asian/Pacific Islanders to 45.7 in blacks and 89 in Alaska Natives. Rapid declines in incidence among screening-aged individuals during the 2000s continued during 2011 through 2016 in those aged 65 years and older (by 3.3% annually) but reversed in those aged 50 to 64 years, among whom rates increased by 1% annually. Among individuals aged younger than 50 years, the incidence rate increased by approximately 2% annually for tumors in the proximal and distal colon, as well as the rectum, driven by trends in non-Hispanic whites. CRC death rates during 2008 through 2017 declined by 3% annually in individuals aged 65 years and older and by 0.6% annually in individuals aged 50 to 64 years while increasing by 1.3% annually in those aged younger than 50 years. Mortality declines among individuals aged 50 years and older were steep-est among blacks, who also had the only decreasing trend among those aged younger than 50 years, and excluded American Indians/Alaska Natives, among whom rates remained stable. Progress against CRC can be accelerated by increasing access to guideline-recommended screening and high-quality treatment, particularly among Alaska Natives, and elucidating causes for rising incidence in young and middle-aged adults.

Sixteen patients with mismatch repair–deficient, locally advanced rectal cancer were enrolled in a pilot study in which 6 months of neoadjuvant anti–PD-1 therapy was to be followed by surgical resection. Twelve patients have completed treatment and have had at least 6 months of follow-up; all 12 had a clinical complete response. All imaging tests and biopsies have shown no viable tumor.

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients’ tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.

Molecular alterations in KRAS are associated with acquired resistance to anti-epidermal growth factor receptor (EGFR) treatment in colorectal cancer; resistant mutations can be identified in the blood of patients, months before clinical evidence of disease progression. Acquired resistance in anti-EGFR therapy Antibodies targeting epidermal growth factor receptor (EGFR) have become an established treatment for colorectal cancer, but they are contraindicated in patients carrying mutations in the KRAS oncogene. Drug resistance can also arise in initially responsive patients, and two papers in this issue of Nature present unequivocal evidence that mutations in KRAS underlie acquired resistance to anti-EGFR antibodies in many patients and that KRAS mutations can be detected in the serum of patients before the clinical emergence of resistance and relapse. Misale et al . show in cell-line models that KRAS mutations can confer resistance to cetuximab. And in colorectal cancer patients treated with cetuximab or panitumumab, resistance is associated with KRAS mutations selected from pre-existing subclones or acquired during treatment. Diaz et al . also find KRAS mutations accumulating in patients becoming resistant to panitumumab. Their mathematical models suggest that KRAS mutations pre-existed in tumour cells before therapy, which may explain why clinical recurrence is usually seen after about six months of treatment, by which time the resistant subpopulations of tumour cells with KRAS mutations has expanded. The apparent inevitability of resistance suggests that combinations of drugs targeting more than one oncogenic pathway will be needed if resistance is to be avoided. A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers 1 . After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug 2 . The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood 3 , 4 , 5 , 6 , 7 , 8 . Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.

In this issue of the Journal , Chalabi and colleagues 1 present findings from a large study showing impressive pathological responses of mismatch repair–deficient (dMMR) early-stage colon cancers to neoadjuvant dual immune checkpoint blockade followed by surgical resection. This study was started as a proof-of-principle pilot study with just 1 month of checkpoint blockade therapy followed by standard surgical resection. In the expanded cohort that is described in the current article, approximately two thirds of the patients had a pathological complete response (no residual viable tumor). The authors are to be congratulated on these results, which further highlight the sensitivity of dMMR . . .

Objective To interrogate the mesorectal fat using MRI radiomics feature analysis in order to predict clinical outcomes in patients with locally advanced rectal cancer. Methods This retrospective study included patients who underwent neoadjuvant chemoradiotherapy for locally advanced rectal cancer from 2009 to 2015. Three radiologists independently segmented mesorectal fat on baseline T2-weighted axial MRI. Radiomics features were extracted from segmented volumes and calculated using CERR software, with adaptive synthetic sampling being employed to combat large class imbalances. Outcome variables included pathologic complete response (pCR), local recurrence, distant recurrence, clinical T-category (cT), post-treatment T category (ypT), and post-treatment N category (ypN). A maximum of eight most important features were selected for model development using support vector machines and fivefold cross-validation to predict each outcome parameter via elastic net regularization. Diagnostic metrics of the final models were calculated, including sensitivity, specificity, PPV, NPV, accuracy, and AUC. Results The study included 236 patients (54 ± 12 years, 135 men). The AUC, sensitivity, specificity, PPV, NPV, and accuracy for each clinical outcome were as follows: for pCR, 0.89, 78.0%, 85.1%, 52.5%, 94.9%, 83.9%; for local recurrence, 0.79, 68.3%, 80.7%, 46.7%, 91.2%, 78.3%; for distant recurrence, 0.87, 80.0%, 88.4%, 58.3%, 95.6%, 87.0%; for cT, 0.80, 85.8%, 56.5%, 89.1%, 49.1%, 80.1%; for ypN, 0.74, 65.0%, 80.1%, 52.7%, 87.0%, 76.3%; and for ypT, 0.86, 81.3%, 84.2%, 96.4%, 46.4%, 81.8%. Conclusion Radiomics features of mesorectal fat can predict pathological complete response and local and distant recurrence, as well as post-treatment T and N categories. Key Points • Mesorectal fat contains important prognostic information in patients with locally advanced rectal cancer (LARC). • Radiomics features of mesorectal fat were significantly different between those who achieved complete vs incomplete pathologic response (accuracy 83.9%, 95% CI: 78.6–88.4%). • Radiomics features of mesorectal fat were significantly different between those who did vs did not develop local or distant recurrence (accuracy 78.3%, 95% CI: 72.0–83.7% and 87.0%, 95% CI: 81.6–91.2% respectively).