Mutational analysis of microsatellite-stable gastrointestinal cancer with high tumour mutational burden: a retrospective cohort study.

BACKGROUND: Genomic signatures contributing to high tumour mutational burden (TMB-H) independent from mismatch-repair deficiency (dMMR) or microsatellite instability-high (MSI-H) status are not well studied. We aimed to characterise molecular features of microsatellite stable (MSS) TMB-H gastrointestinal tumours. METHODS: Molecular alterations of 48 606 gastrointestinal tumours from Caris Life Sciences (CARIS) identified with next-generation sequencing were compared among MSS-TMB-H, dMMR/MSI-H, and MSS-TMB-low (L) tumours, using χ2 or Fisher's exact tests. Antitumour immune response within the tumour environment was predicted by analysing the infiltration of immune cells and immune signatures using The Cancer Genome Atlas database. The Kaplan-Meier method and the log-rank test were used to evaluate the impact of gene alterations on the efficacy of immune checkpoint inhibitors in MSS gastrointestinal cancers from the CARIS database, a Memorial Sloan Kettering Cancer Center cohort, and a Peking University Cancer Hospital cohort. FINDINGS: MSS-TMB-H was observed in 1600 (3·29%) of 48 606 tumours, dMMR/MSI-H in 2272 (4·67%), and MSS-TMB-L in 44 734 (92·03%). Gene mutations in SMAD2, MTOR, NFE2L2, RB1, KEAP1, TERT, and RASA1 might impair antitumour immune response despite TMB-H, while mutations in 16 other genes (CDC73, CTNNA1, ERBB4, EZH2, JAK2, MAP2K1, MAP2K4, PIK3R1, POLE, PPP2R1A, PPP2R2A, PTPN11, RAF1, RUNX1, STAG2, and XPO1) were related to TMB-H with enhanced antitumour immune response independent of dMMR/MSI-H, constructing a predictive model (modified TMB [mTMB]) for immune checkpoint inhibitor efficacy. Patients with any mutation in the mTMB gene signature, in comparison with patients with mTMB wildtype tumours, showed a superior survival benefit from immune checkpoint inhibitors in MSS gastrointestinal cancers in the CARIS cohort (n=95, median overall survival 18·77 months [95% CI 17·30-20·23] vs 7·03 months [5·73-8·34]; hazard ratio 0·55 [95% CI 0·31-0·99], p=0·044). In addition, copy number amplification in chromosome 11q13 (eg, CCND1, FGF genes) was more prevalent in MSS-TMB-H tumours than in the dMMR/MSI-H or MSS-TMB-L subgroups. INTERPRETATION: Not all mutations related to TMB-H can enhance antitumour immune response. More composite biomarkers should be investigated (eg, mTMB signature) to tailor treatment with immune checkpoint inhibitors. Our data also provide novel insights for the combination of immune checkpoint inhibitors and drugs targeting cyclin D1 or FGFs. FUNDING: US National Cancer Institute, Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Gene Gregg Pancreas Research Fund, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund, Victoria and Philip Wilson Research Fund, Fong Research Project, Ming Hsieh Research Fund, Shanghai Sailing Program, China National Postdoctoral Program for Innovative Talents, China Postdoctoral Science Foundation, National Natural Science Foundation of China.

Overcoming the hurdles: surmounting acquired resistance to anti-EGFR therapy in metastatic colorectal cancer.

Colorectal cancer is the third most prevalent cancer type in the United States, with an alarming incidence and mortality rate, especially among individuals younger than 50 years. The epidermal growth factor receptor (EGFR), essential for cell proliferation and survival, has surfaced as a promising therapeutic target for metastatic colorectal cancer and has demonstrated success in various clinical trials. Monoclonal antibodies such as cetuximab and panitumumab have proven to be effective against EGFR by blocking vital downstream signaling pathways and inhibiting gene transcription and cell proliferation. Despite this promise, most patients eventually develop resistance to anti-EGFR treatment, thereby limiting its long-term efficacy. Genomic alterations, such as mutations in KRAS, NRAS, and BRAF, often bypass the EGFR receptor, promoting resistance to therapy. Although our understanding of primary resistance to anti-EGFR therapy has improved, acquired resistance remains a significant hurdle. This review explores the potential mechanisms underpinning this acquired resistance and strategies to overcome it.

A Randomized Phase II Trial of mFOLFOX6 + Bevacizumab Alone or with AdCEA Vaccine + Avelumab Immunotherapy for Untreated Metastatic Colorectal Cancer.

BACKGROUND: FOLFOX plus bevacizumab is a standard of care (SOC) for first-line treatment of microsatellite-stable metastatic colorectal cancer (MSS mCRC). This study randomized patients to SOC or SOC plus avelumab (anti-PD-L1) plus CEA-targeted vaccine. METHODS: Patients with untreated MSS mCRC enrolled to a lead-in arm assessing safety of SOC + immuno-oncology agents (IO). Next, patients were randomized to SOC or SOC + IO. The primary endpoint was progression-free survival (PFS). Multiple immune parameters were analyzed. RESULTS: Six patients enrolled to safety lead-in, 10 randomized to SOC, and 10 to SOC + IO. There was no difference in median PFS comparing SOC versus SOC + IO (8.8 months (95% CI: 3.3-17.0 months) versus 10.1 months (95% CI: 3.6-16.1 months), respectively; hazard ratio 1.061 [P = .91; 95% CI: 0.380-2.966]). The objective response rate was 50% in both arms. Of patients analyzed, most (8/11) who received SOC + IO developed multifunctional CD4+/CD8+ T-cell responses to cascade antigens MUC1 and/or brachyury, compared to 1/8 who received SOC alone (P = .020). We detected post-treatment changes in immune parameters that were distinct to the SOC and SOC + IO treatment arms. Accrual closed after an unplanned analysis predicted a low likelihood of meeting the primary endpoint. CONCLUSIONS: SOC + IO generated multifunctional MUC1- and brachyury-specific CD4+/CD8+ T cells despite concurrent chemotherapy. Although a tumor-directed immune response is necessary for T-cell-mediated antitumor activity, it was not sufficient to improve PFS. Adding agents that increase the number and function of effector cells may be required for clinical benefit.

Therapeutic Potential of Afatinib in NRG1 Fusion-Driven Solid Tumors: A Case Series.

BACKGROUND: Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors. PATIENTS AND METHODS: This report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib. RESULTS: The six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day. CONCLUSION: This report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors. KEY POINTS: NRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.

Molecular Profiling in Metastatic Colorectal Cancer.

Colorectal cancer (CRC) is a commonly diagnosed malignancy. Although chemotherapy remains the backbone of treatment, the landscape of treating metastatic CRC (mCRC) is changing with the understanding of its heterogeneity and molecular blueprint. Colon cancer sidedness has proven to hold prognostic implications, with right-sided tumors having higher incidence of BRAF and KRAS mutations and being microsatellite instability-high (MSI-H); overall, they have a worse prognosis compared with left sided-tumors. Results of molecular research have demonstrated the need to profile each mCRC patient for RAS and BRAF mutations, MSI-H status, HER2 amplifications, and NTRK fusions. Ongoing clinical trials using targeted agents aim to further improve survival outcomes. We emphasize the epidemiology, knowledge of primary tumor location, and mutational landscape of mCRC, as well as novel treatment options for patients harboring unique subtypes of these characteristics.

Impact of Patient Age on Molecular Alterations of Left-Sided Colorectal Tumors.

BACKGROUND: The incidence of colorectal cancer (CRC) in younger patients is rising, mostly due to tumors in the descending colon and rectum. Therefore, we aimed to explore the molecular differences of left-sided CRC between younger (≤45 years) and older patients (≥65). SUBJECTS, MATERIALS, AND METHODS: In total, 1,126 CRC tumor samples from the splenic flexure to (and including) the rectum were examined by next-generation sequencing (NGS), immunohistochemistry, and in situ hybridization. Microsatellite instability (MSI) and tumor mutational burden (TMB) were assessed by NGS. RESULTS: Younger patients (n = 350), when compared with older patients (n = 776), showed higher mutation rates in genes associated with cancer-predisposing syndromes (e.g., Lynch syndrome), such as MSH6 (4.8% vs. 1.2%, p = .005), MSH2 (2.7% vs. 0.0%, p = .004), POLE (1.6% vs. 0.0%, p = .008), NF1 (5.9% vs. 0.5%, p < .001), SMAD4 (14.3% vs. 8.3%, p = .024), and BRCA2 (3.7% vs. 0.5%, p = .002). Genes involved in histone modification were also significantly more mutated: KDM5C (1.9% vs. 0%, p = .036), KMT2A (1.1% vs. 0%, p = .033), KMT2C (1.6% vs. 0%, p = .031), KMT2D (3.8% vs. 0.7%, p = .005), and SETD2 (3.2% vs. 0.9%, p = .039). Finally, TMB-high (9.7% vs. 2.8%, p < .001) and MSI-high (MSI-H; 8.1% vs. 1.9%, p = .009) were more frequent in younger patients. CONCLUSION: Our findings highlight the importance of genetic counseling and screening in younger CRC patients. MSI-H and TMB-high tumors could benefit from immune-checkpoint inhibitors, now approved for the treatment of MSI-H/deficient mismatch repair metastatic CRC patients. Finally, histone modifiers could serve as a new promising therapeutic target. With confirmatory studies, these results may influence our approach to younger adults with CRC. IMPLICATIONS FOR PRACTICE: The increasing rate of colorectal cancers (CRC), primarily distal tumors, among young adults poses a global health issue. This study investigates the molecular differences between younger (≤45 years old) and older (≥65) adults with left-sided CRCs. Younger patients more frequently harbor mutations in genes associated with cancer-predisposing syndromes. Higher rates of microsatellite instability-high and tumor mutational burden-high tumors occur in younger patients, who could benefit from immune-checkpoint inhibitors. Finally, histone modifiers are more frequently mutated in younger patients and could serve as a new promising therapeutic target. This study provides new insights into mutations that may guide development of novel tailored therapy in younger CRC patients.

Colon Cancer in Young Adults: Trends and Their Implications.

PURPOSE OF REVIEW: The recent rise of young individuals under age 50 with colorectal cancer (CRC) is a startling trend in need of greater focus and research. The etiology of young-onset CRC is unexplained as efforts to blame obesity or diabetes as causative factors are simplistic and inadequate. RECENT FINDINGS: We describe the epidemiologic shifts of CRC incidence and mortality across age groups as well as the differences in clinicopathologic, molecular, treatment, and survival characteristics between young and older patients. Novel studies of the microbiome may elucidate bacterial causes of CRC carcinogenesis in younger individuals. Moving up the colonoscopy screening to age 45 in normal-risk individuals should prove beneficial in detecting more patients with early-onset CRC. We favor the development of risk-adaptive screening decision algorithms and flexible sigmoidoscopy screening at age 40 given the predilection for left-sided primaries in this age group. More awareness and attention to young-onset CRC will be critical to improve outcomes in this patient population.

Biomarkers for immune therapy in gastrointestinal cancers.

Immunotherapy with checkpoint blockade of pro-grammed death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has substantially increased the number of anticancer agents in our arsenal. However, these therapies are not effective in all cancer types, benefitting only a subset of patients with susceptible, immunogenic cancers. This problem is especially significant in gastrointestinal malignancies, which infrequently respond to immunotherapy. Although we clearly need more accurate biomarkers to predict response to immune checkpoint inhibition in gastrointestinal cancers, the established markers of mismatch repair deficiency, microsatellite instability, programmed death ligand 1 (PD-L1) expression, and tumor mutational burden are good starting points to identify patients who may benefit. Tumor-infiltrating lymphocytes, Epstein-Barr virus, and the stool microbiome are candidates for future immuno-oncology biomarkers in gastrointestinal malignancies. The availability of better biomarkers will improve patient selection for immunotherapy; it will also improve the design of clinical trials of agents intended for this population of patients, who require more effective treatment options.

Immuno-Oncology Biomarkers for Gastric and Gastroesophageal Junction Adenocarcinoma: Why PD-L1 Testing May Not Be Enough.

PURPOSE: The treatment of patients with advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinomas has been transformed by the U.S. Food and Drug Administration approval of pembrolizumab. Tumor and adjacent tissue must stain positively for the programmed cell death ligand 1 (PD-L1) protein by companion diagnostic testing. However, some patients with PD-L1-negative tumors also benefit from pembrolizumab. High microsatellite instability (MSI) and tumor mutational load (TML) are positive predictive biomarkers for immune checkpoint inhibition (ICI) in other tumors. We sought to identify more patients who could benefit from ICI using alternative PD-L1 thresholds, MSI, and TML. METHODS: Tumor specimens underwent next-generation sequencing (NGS) and PD-L1 testing using immunohistochemistry. NGS was used to determine TML and MSI. RESULTS: We profiled 581 G/GEJ adenocarcinoma specimens. PD-L1 staining was scored for intensity (0, none; 1+, weak; 2+, moderate; 3+, strong). Using 2+ staining at a 5% threshold, 9.3% of tumors were PD-L1 positive, and using 1+ staining at 1%, 16.2% were PD-L1 positive. 6.9% of tumors had high MSI. High TML (≥17 mutations per megabase) was seen in 6.9%, and medium TML (≥7) was seen in 56.5% of tumors. Thirty (5.2%) PD-L1-negative tumors at the 1+, 1% threshold had high TML or high MSI. Primary tumors had higher rates of high TML (8.8% vs. 3.9%; p = .0377) and high MSI (8.5% vs. 3.9%; p = .0471) than metastases. CONCLUSION: PD-L1 testing alone fails to detect patients who may benefit from ICI. Lower PD-L1 thresholds and TML testing should be considered in future clinical trials. IMPLICATIONS FOR PRACTICE: Pembrolizumab is approved by the U.S. Food and Drug Administration for patients with refractory gastric and gastroesophageal cancers if the tumor and adjacent tissue stain positively for the programmed cell death ligand 1 (PD-L1) protein by companion diagnostic testing. Tumor mutational load, microsatellite instability (MSI), and alternative PD-L1 testing thresholds may serve as predictive biomarkers for response to immune checkpoint inhibition, and standard PD-L1 testing will not identify all patients who may benefit from this therapy.

Comprehensive Genomic Profiling Aids in Distinguishing Metastatic Recurrence from Second Primary Cancers.

BACKGROUND: Metastatic recurrence after treatment for locoregional cancer is a major cause of morbidity and cancer-specific mortality. Distinguishing metastatic recurrence from the development of a second primary cancer has important prognostic and therapeutic value and represents a difficult clinical scenario. Advances beyond histopathological comparison are needed. We sought to interrogate the ability of comprehensive genomic profiling (CGP) to aid in distinguishing between these clinical scenarios. MATERIALS AND METHODS: We identified three prospective cases of recurrent tumors in patients previously treated for localized cancers in which histologic analyses suggested subsequent development of a distinct second primary. Paired samples from the original primary and recurrent tumor were subjected to hybrid capture next-generation sequencing-based CGP to identify base pair substitutions, insertions, deletions, copy number alterations (CNA), and chromosomal rearrangements. Genomic profiles between paired samples were compared using previously established statistical clonality assessment software to gauge relatedness beyond global CGP similarities. RESULTS: A high degree of similarity was observed among genomic profiles from morphologically distinct primary and recurrent tumors. Genomic information suggested reclassification as recurrent metastatic disease, and patients received therapy for metastatic disease based on the molecular determination. CONCLUSIONS: Our cases demonstrate an important adjunct role for CGP technologies in separating metastatic recurrence from development of a second primary cancer. Larger series are needed to confirm our observations, but comparative CGP may be considered in patients for whom distinguishing metastatic recurrence from a second primary would alter the therapeutic approach. The Oncologist 2017;22:152-157Implications for Practice: Distinguishing a metastatic recurrence from a second primary cancer can represent a difficult clinicopathologic problem but has important prognostic and therapeutic implications. Approaches to aid histologic analysis may improve clinician and pathologist confidence in this increasingly common clinical scenario. Our series provides early support for incorporating paired comprehensive genomic profiling in clinical situations in which determination of metastatic recurrence versus a distinct second primary cancer would influence patient management.

The Growing Challenge of Young Adults With Colorectal Cancer.

Although the incidence of colorectal cancer is declining in the overall US population, the rates of colorectal cancer are rising among adolescent and young adult (AYA) patients-defined as individuals under 45 years of age. This population includes patients deemed too young for routine colorectal cancer screening, which in the United States is typically initiated at age 50 for men and women at average risk. Clinicopathologic differences have long been observed between AYAs and older patients with colorectal cancer. In addition, recently available high-throughput DNA sequencing techniques have revealed different rates of genetic alterations between these two groups, indicating potential molecular differences in the disease state and suggesting the need for alternative treatment strategies in younger patients. AYA patients with colorectal cancer often receive more aggressive treatment regimens than their older counterparts, without a corresponding improvement in survival. Furthermore, these younger patients have particular survivorship issues that warrant attention from the oncology community. In this review, we address specific issues pertaining to AYA patients with colorectal cancer, including evaluation for hereditary colorectal cancer syndromes, clinicopathologic and biologic features unique to AYA patients with colorectal cancer, treatment outcomes, and survivorship.

Precision Medicine in Metastatic Colorectal Cancer: Relevant Carcinogenic Pathways and Targets-PART 1: Biologic Therapies Targeting the Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor.

The survival of patients with metastatic colorectal cancer has improved dramatically in recent years, with overall survival exceeding 3 years in large randomized clinical trials. There are now several treatment options for patients with metastatic colorectal cancer. In addition to chemotherapy backbones utilizing fluoropyrimidine, oxaliplatin, and irinotecan combinations, biologic agents that target specific oncogenic pathways have contributed to the improved survival observed in this patient population. This class of medications includes epidermal growth factor receptor (EGFR)-targeted drugs (cetuximab and panitumumab) and vascular endothelial growth factor (VEGF)-targeted therapies (bevacizumab, ramucirumab, ziv-aflibercept, and regorafenib). Bevacizumab remains the only VEGF-targeted agent approved by the US Food and Drug Administration in the first-line metastatic setting. EGFR-directed treatment should be restricted to patients with extended RAS and BRAF wild-type tumors. Tumor sidedness may be a more powerful prognostic and predictive biomarker than tumor mutational profile. Patients with left-sided primary tumors derive greater benefit from EGFR-targeted therapies whereas patients with right-sided primary tumors benefit more from bevacizumab. Herein we review drugs that target the EGFR and VEGF pathways, focusing on patient selection, drug toxicities, and how to choose agents for first-line therapy.

Precision Medicine in Metastatic Colorectal Cancer: Relevant Carcinogenic Pathways and Targets-PART 2: Approaches Beyond First-Line Therapy, and Novel Biologic Agents Under Investigation.

A frequent quandary for oncologists is the selection of chemotherapy and biologic therapy for patients with metastatic colorectal cancer in second-line and higher treatment settings. While not approved by the US Food and Drug Administration (FDA) in the first-line setting, the vascular endothelial growth factor (VEGF)-targeting agents ziv-aflibercept and ramucirumab are appropriate treatment options in the second-line setting, as is continuation of first-line bevacizumab. Tumor RAS mutational status is helpful to determine which patients may benefit from epidermal growth factor receptor (EGFR)-directed therapies, and other novel biomarkers (BRAF, HER2, and mismatch repair deficiency) allow us to select patients who may benefit from biologic therapies that are FDA-approved for other malignancies. Maintenance therapy for patients with stable disease following first-line therapy is a unique clinical situation that warrants special attention. Immunotherapy has thus far been ineffective for patients with mismatch repair-proficient tumors, but novel combination strategies are being studied to break through this treatment barrier. Finally, several new biologic therapies with novel targets are under development and will likely contribute to the growing arsenal of treatment options for patients with metastatic colorectal cancer.

Evolving standards of care for resected pancreatic cancer.

Pancreatic cancer is a devastating illness, and surgical resection offers the only chance of a cure for patients with the disease. Relatively few patients have resectable disease at diagnosis, however, and the cancer frequently recurs even after complete surgical resection. This review discusses clinical trials in which adjuvant therapy with chemotherapy or chemoradiation has prolonged survival in patients following surgery. It also highlights new data from the ESPAC-4 and JASPAC 01 studies that may change the current treatment paradigm for adjuvant therapy. The ESPAC-4 results support the use of adjuvant gemcitabine plus capecitabine in preference to the previous standard of gemcitabine alone, demonstrating that in this instance, more may be better. Finally, the review discusses ongoing trials and new approaches that aim to improve outcomes further for patients with resectable pancreatic cancer.

Trifluridine/tipiracil and regorafenib: new weapons in the war against metastatic colorectal cancer.

Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Approximately 20% of patients have metastatic disease at diagnosis, and a vast number of these patients die within 5 years. The advent of modern chemotherapeutics has improved median overall survival for these patients; nonetheless, we must keep striving for better outcomes. Trifluridine/tipiracil (TAS-102) and regorafenib are agents newly approved by the US Food and Drug Administration that show promise in the treatment of metastatic colorectal cancer. These drugs have the benefit of being formulated for oral administration and have different side effect profiles. These differences are important in the selection of the best therapy for each patient, especially if the patient is prone to a side effect that is unique to just one of the treatments. In this review, we discuss the mechanism of action, side effect profile, and clinical efficacy of trifluridine/tipiracil, and compare them with those of regorafenib. Future trials will evaluate the use of these drugs in earlier lines of therapy, alone and in combination with other agents. We now have 2 more agents in the arsenal against metastatic colorectal cancer and the future is looking brighter for patients, although we still have a long way to go.

A paradigm shift from one-size-fits-all to tailor-made therapy for metastatic colorectal cancer.

Colorectal cancer is the second leading cause of cancer death in the United States. At least 50% of patients develop metastases, and most of these patients have unresectable tumors. Treatment options for metastatic colorectal cancer (mCRC) include several lines of chemotherapy, salvage surgery, maintenance therapy, and local therapy. For decades, 5-fluorouracil (5-FU) was the only chemotherapy option for patients with mCRC. This changed markedly over the last decade with the approval of irinotecan, oxaliplatin, capecitabine, humanized monoclonal antibodies that target either vascular endothelial growth factor (bevacizumab, aflibercept, and ramucirumab) or the epidermal growth factor receptor (cetuximab and panitumumab), and, most recently, regorafenib and trifluridine/tipiracil. In this review, we focus on first-line treatments for mCRC. We discuss how results from multiple clinical trials over the last 10 to 20 years confirmed the benefit of adding oxaliplatin and irinotecan to the established 5-FU chemotherapy backbone, and then further defined benefit in certain patient subgroups with the addition of mAbs. Ongoing investigations attempt to illustrate the role of newer molecular and immune therapies in the fight against mCRC. We acknowledge the tremendous advances made in first-line mCRC treatment, admit that we still have a long way to go, and highlight exciting lines of research for patients with mCRC in the burgeoning fields of precision medicine and immunotherapy.

Current Standards and Novel Treatment Options for Metastatic Pancreatic Adenocarcinoma.

Pancreatic cancer is one of the most lethal solid tumors. The prognosis of metastatic pancreatic adenocarcinoma remains dismal, with a median survival of less than 1 year, due in large part to the fact that pancreatic adenocarcinoma is notoriously refractory to chemotherapy. However, there recently have been significant improvements in outcomes for patients with pancreatic adenocarcinoma: ongoing trials have shown promise, and these may lead to still further progress. Here we review the current treatment paradigms for metastatic disease, focusing on ways to ameliorate symptoms and lengthen survival. We then summarize recent advances in our understanding of the molecular and cellular aspects of pancreatic cancer. Finally, we outline new approaches currently under development for the treatment of metastatic disease, arising from our improved understanding of the genetic and nongenetic alterations within pancreatic cancer cells-and of interactions between cancer cells, the tumor microenvironment, and the immune system.

Comparative molecular profiling of pancreatic ductal adenocarcinoma of the head versus body and tail.

Pancreatic ductal adenocarcinoma (PDAC) of the head (H) and body/tail (B/T) differ in embryonic origin, cell composition, blood supply, lymphatic and venous drainage, and innervation. We aimed to compare the molecular and tumor immune microenvironment (TIME) profiles of PDAC of the H vs. B/T. A total of 3499 PDAC samples were analyzed via next-generation sequencing (NGS) of RNA (whole transcriptome, NovaSeq), DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing), and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Significance was determined as p values adjusted for multiple corrections (q) of <0.05. Anatomic subsites of PDAC tumors were grouped by primary tumor sites into H (N = 2058) or B/T (N = 1384). There were significantly more metastatic tumors profiled from B/T vs. H (57% vs. 44%, p < 0.001). KRAS mutations (93.8% vs. 90.2%), genomic loss of heterozygosity (12.7% vs. 9.1%), and several copy number alterations (FGF3, FGF4, FGF19, CCND1, ZNF703, FLT4, MUTYH, TNFRS14) trended higher in B/T when compared to H (p < 0.05 but q > 0.05). Expression analysis of immuno-oncology (IO)-related genes showed significantly higher expression of CTLA4 and PDCD1 in H (q < 0.05, fold change 1.2 and 1.3) and IDO1 and PDCD1LG2 expression trended higher in B/T (p < 0.05, fold change 0.95). To our knowledge, this is one of the largest cohorts of PDAC tumors subjected to broad molecular profiling. Differences in IO-related gene expression and TIME cell distribution suggest that response to IO therapies may differ in PDAC arising from H vs. B/T. Subtle differences in the genomic profiles of H vs. B/T tumors were observed.

Evolving Standards of Care in the Management of Localized Colorectal Cancer.

The treatment of patients with localized rectal cancer is complex and requires input from a multidisciplinary team. Baseline local staging and mismatch repair protein testing are vital to develop individualized treatment plans. There are multiple options in terms of treatment modalities and sequencing, including transanal excision, short-course radiation, long-course chemoradiation, chemotherapy doublet or triplet, nonoperative management, and immune checkpoint blockade for patients with mismatch repair deficient tumors. While localized colon cancer is typically treated with surgical resection and consideration of adjuvant chemotherapy, emerging data suggest that neoadjuvant chemotherapy may be beneficial in patients with higher-risk disease. Quality-of-life considerations are imperative to prevent potential chronic effects on psychosocial health, neuropathy, fertility, and bowel, bladder, and sexual function. The omission of radiation or surgery can mitigate these toxicities without diminishing oncologic outcomes. The optimal treatment plan and sequence is not a one-size-fits-all approach but rather should be personalized to the patient's disease burden, tumor location, comorbidities, and preferences.

Phase 1 Study of Hypofractionated Proton Beam Radiation Therapy in Adjuvant Pancreatic Cancer (PROTON-PANC).

PURPOSE: Despite improvement in systemic therapy, patients with pancreatic ductal adenocarcinoma (PDAC) frequently experience local recurrence. We sought to determine the safety of hypofractionated proton beam radiation therapy (PBT) during adjuvant chemotherapy. METHODS AND MATERIALS: Nine patients were enrolled in a single-institution phase 1 trial (NCT03885284) between 2019 and 2022. Patients had PDAC of the pancreatic head and underwent R0 or R1 resection and adjuvant modified FOLFIRINOX (mFFX) chemotherapy. The primary endpoint was to determine the dosing schedule of adjuvant PBT (5 Gy × 5 fractions) using limited treatment volumes given between cycles 6 and 7 of mFFX. Patients received PBT on days 15 to 19 in a 28-day cycle before starting cycle 7 (dose level 1, DL1) or on days 8 to 12 in a 21-day cycle before starting cycle 7 (DL2). RESULTS: The median patient age was 66 years (range, 52-78), and the follow-up time from mFFX initiation was 12.5 months (range, 6.2-37.4 months). No patients received preoperative therapy. Four had R1 resections and 5 had node-positive disease. Three patients were enrolled on DL1 and 6 patients on DL2. One dose-limiting toxicity (DLT) occurred at DL2 (prolonged grade 3 neutropenia resulting in discontinuation of mFFX after cycle 7). No other DLTs were observed. Four patients completed 12 cycles of mFFX (range, 7-12; median, 11). No patients have had local recurrence. Five of 9 patients had recurrence: 3 in the liver, 1 in the peritoneum, and 1 in the bone. Six patients are still alive, 4 of whom are recurrence-free. The median time to recurrence was 12 months (95% CI, 4 to not reached [NR]), and median overall survival was NR (95% CI, 6 to NR; 2-year survival rate, 57%). CONCLUSIONS: PBT integrated within adjuvant mFFX was well tolerated, and no local recurrence was observed. These findings warrant further exploration in a phase 2 trial.