Discovering dominant tumor immune archetypes in a pan-cancer census.

Cancers display significant heterogeneity with respect to tissue of origin, driver mutations, and other features of the surrounding tissue. It is likely that individual tumors engage common patterns of the immune system-here "archetypes"-creating prototypical non-destructive tumor immune microenvironments (TMEs) and modulating tumor-targeting. To discover the dominant immune system archetypes, the University of California, San Francisco (UCSF) Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub-compartments uncovered dominant patterns of immune composition across cancers. These archetypes were profound insofar as they also differentiated tumors based upon unique immune and tumor gene-expression patterns. They also partitioned well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune organization and provides a rational path forward to learn how to modulate these to improve therapy.

Synchronous or metachronous breast and colorectal cancers in younger-than-average-age patients: a case series.

BACKGROUND: The incidence of breast and colorectal cancer (CRC) in younger-than-average-age patients is rising and poorly understood. This is the largest study on patients with both cancers who are less than 60 years old and aims to characterize demographic, clinicopathologic, and genetic features and describe therapeutic dilemmas and management strategies. MATERIALS AND METHODS: This is a retrospective medical records review of patients at the University of California San Francisco with both primary breast and CRC before age 60. RESULTS: Fifty-one patients were identified; 41 had detailed medical records. Median age of diagnosis with breast cancer was 43 (range 27-59) and CRC was 50 (28-59). Most were Caucasian (38, 74.5%) and never smokers (23, 56.1%); about half were current alcohol consumers (20, 48.8%) and about one-third had sedentary jobs (14, 34.1%). Average BMI was 25.8 (range: 14-49), and 30% were overweight or obese. Breast was the first cancer diagnosed in 36 patients (70.6%) and 44 (86.3%) had a metachronous CRC diagnosis. Breast cancer was early stage (0-2) in 32 (78.0%) patients whereas CRC was split between early stage (1-2) in 14 (34.1%) and later stage (3-4) in 19 (46.2%). Ten patients (24.3%) had a known germline mutation, although 23 (56.1%) had a family history of cancer in a first-degree relative. CONCLUSION: Younger patients with both breast and CRC are a unique cohort, often without known risk factors. Alcohol consumption and sedentary jobs were the most common risk factors, and about one-quarter had a known genetic predisposition. Comanagement of both cancers requires individualized, multidisciplinary care.

Association between gastrointestinal symptoms and specialty care utilization among colon cancer survivors: a cohort study.

PURPOSE: Persistent gastrointestinal (GI) symptoms are frequently experienced by colon cancer survivors and may help identify patients with higher utilization of healthcare services. To assess the relationship between GI symptoms and specialty care utilization among colon cancer survivors. METHODS: A prospective longitudinal cohort study at an academic medical center of 126 adults surgically treated for stage I-IV colon cancer between February 2017 and June 2022. Participants reported GI symptoms through the EORTC QLQ-C30 and QLQ-CR29 at enrollment and as frequently as every 6 months for 5 years. Main outcome measures were visits, telephone encounters, and secure messages with a medical provider within specialty oncology clinics within 6 months after each survey completion. Generalized linear mixed regression model for repeated measurements with random trajectory for each participant was performed to estimate the associations between symptoms and healthcare use. Models were adjusted for demographics, clinical and surgical factors, and timing in relation to onset of the COVID-19 pandemic. RESULTS: In the 6 months after each survey time point, patients averaged 1.2 visits, 0.5 telephone encounters, and 3.2 patient-initiated messages. In adjusted models, those with any abdominal pain (RR 1.45; p = 0.002), buttock pain (RR 1.30; p = 0.050), or increased stool frequency (RR 1.26; p = 0.046) had more clinic visits in the following 6 months than those without these symptoms. Including these three symptoms in one model revealed that only abdominal pain was statistically significantly associated with increased clinic visits (RR 1.36; p = 0.016). Patients with any blood or mucus in stool (RR 2.46; p = 0.009) had significantly more telephone encounters, and those with any abdominal pain (RR 1.65; p = 0.002) had significantly more patient-initiated messages than those without these symptoms. CONCLUSIONS: Our findings identify GI symptoms associated with increased use of oncologic specialty care among colon cancer survivors, with abdominal pain as an important predictor of utilization. IMPLICATIONS FOR CANCER SURVIVORS: Early identification and anticipatory management of colon cancer survivors experiencing abdominal pain may decrease healthcare utilization.

Sexual function remains persistently low in women after treatment for colorectal cancer and anal squamous cell carcinoma.

BACKGROUND: Women diagnosed with colorectal cancer (CRC) or anal squamous cell carcinoma (ASCC) are at high risk of sexual dysfunction after treatment, yet little is known about recovery and risk factors for chronic dysfunction. AIM: We aimed to describe sexual function and sexual activity among women who underwent definitive treatment for CRC or ASCC, examine relationships between time since treatment completion and sexual function, and explore factors associated with desire and changes in sexual desire over time. METHODS: As part of a prospective cohort study of patients with gastrointestinal cancer at the University of California San Francisco, female-identifying participants who finished definitive treatment for CRC or ASCC completed the Female Sexual Function Index (FSFI) at 6- to 12-month intervals. We used multivariable linear mixed models to explore factors associated with the FSFI desire subscale. OUTCOMES: Outcomes were rates of sexual activity, proportion at risk for sexual dysfunction (FSFI score <26.55), total FSFI score, and FSFI desire subscale. RESULTS: Among the 97 cancer survivors who completed at least 1 FSFI, the median age was 59 years, the median time since treatment end was 14 months, and 87% were menopausal. Fifty-five women (57%) had a history of colon cancer; 21 (22%), rectal cancer; and 21 (22%), ASCC. An additional 13 (13%) had a current ostomy. Approximately half the women were sexually active (n = 48, 49%). Among these 48 sexually active women, 34 (71%) had FSFI scores indicating risk for sexual dysfunction. Among the 10 sexually active women who completed a FSFI ≥2 years since end of treatment, the median total score was 22.6 (IQR, 15.6-27.3). None of the evaluated characteristics were associated with desire (age, tumor site, treatment, menopause status, or ostomy status). CLINICAL IMPLICATIONS: Consistent with prior studies, we found low desire scores after treatment for CRC or ASCC, with little recovery over time, suggesting that patients should not expect an eventual rebound of sexual function. STRENGTHS AND LIMITATIONS: Strengths of our study include longitudinal data and use of the validated FSFI. Women with ASCC composed 22% of our cohort, allowing for insight into this rare disease group. Limitations of this study include the small sample size, particularly for longitudinal analyses, and the enrollment of patients at variable times since treatment end. CONCLUSION: We observed a high prevalence of sexual health concerns, including low desire, after the treatment of CRC and ASCC that persisted for years after treatment was completed.

Quality of life among colorectal cancer survivors participating in a pilot randomized controlled trial of a web-based dietary intervention with text messages.

PURPOSE: We aimed to estimate the effect of a 12-week web-based dietary intervention with text messages on quality of life (QoL) among colorectal cancer (CRC) survivors. METHODS: Between 2017 and 2018, 50 CRC survivors were randomized (1:1) to receive a 12-week web-based dietary intervention with daily text messages or wait-list control. Health-related QoL was assessed using the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) and colorectal quality of life module (QLQ-CR29) at baseline, 12, and 24 weeks. Within- and between-group mean changes in health-related QoL with 95% confidence intervals (CI) were calculated for both arms. RESULTS: Compared to the controls, participants receiving the intervention had an improvement in emotional functioning (mean change: 14.3; 95% CI: 3.0, 25.6) at 12 weeks and social functioning (mean change: 13.8; 95% CI: 2.1, 25.5) at 24 weeks. A decrease of fatigue from baseline was also observed in the intervention arm (mean change: - 9.1; 95% CI: - 17.1, - 1.1) at 24 weeks. No other changes in QoL scores were associated with the intervention. CONCLUSION: CRC survivors randomized to receive a web-based dietary intervention with text messages experienced higher emotional and social functioning. Further study with a larger population may be warranted. TRIAL REGISTRATION: clinicaltrials.gov, NCT02965521. Registered 16 November 2016, https://clinicaltrials.gov/ct2/keydates/NCT02965521.

Phase I prospective trial of TAS-102 (trifluridine and tipiracil) and radioembolization with 90Y resin microspheres for chemo-refractory colorectal liver metastases.

BACKGROUND: Extrahepatic disease progression limits clinical efficacy of Yttrium-90 (90Y) radioembolization (TARE) for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). Trifluridine and tipiracil (TAS-102) has overall survival benefit for patients with refractory mCRC and may be a radiosensitizer. METHODS: Sequential lobar TARE using 90Y resin microspheres in combination with TAS-102 in 28-day cycles were used to treat adult patients with bilobar liver-dominant chemo-refractory mCRC according to 3 + 3 dose escalation design with a 12-patient dose expansion cohort. Study objectives were to establish safety and determine maximum tolerated dose (MTD) of TAS-102 in combination with TARE. RESULTS: A total of 21 patients (14 women, 7 men) with median age of 60 years were enrolled. No dose limiting toxicities were observed. Treatment related severe adverse events included cytopenias (10 patients, 48%) and radioembolization-induced liver disease (2 patients, 10%). Disease control rate in the liver lobes treated with TARE was 100%. Best observed radiographic responses were partial response for 4 patients (19%) and stable disease for 12 patients (57%). CONCLUSIONS: The combination of TAS-102 and TARE for patients with liver-dominant mCRC is safe and consistently achieves disease control within the liver. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02602327 (first posted 11/11/2015).

Quality of life of colorectal cancer survivors participating in a pilot randomized controlled trial of physical activity trackers and daily text messages.

PURPOSE: There are over 1.3 million colorectal cancer (CRC) survivors in the USA, many of whom report lower health-related quality of life (HRQoL) years after treatment. This study aimed to explore the effect of digital health tools on HRQoL in CRC survivors. METHODS: We conducted a two-arm, randomized controlled trial of 42 subjects who had completed treatment for CRC. Participants in the intervention arm received a Fitbit Flex™ and daily text messages for 12 weeks. HRQoL was assessed as a secondary endpoint in both arms at enrollment and 12 weeks using the Medical Outcomes Study Short Form Survey (SF-36) and the Functional Assessment of Cancer Therapy-Colorectal (FACT-C). Survey score changes from enrollment to 12 weeks were compared between the two arms using independent t tests, and scores at enrollment and 12 weeks were compared using paired t tests. RESULTS: An increase in the FACT-C functional well-being subscale was observed in individuals in the intervention arm pre- to post-intervention (median difference, 2; interquartile range (IQR), 1, 4; P = .02). Although the between-group comparison was not statistically significant, no change in the functional well-being subscale was observed in the control arm (median difference, 0; IQR, 1, 1; P = .71). No other measures of HRQoL appeared to differ within arm across time points or between arms. CONCLUSION: A 12-week digital physical activity intervention may improve functional well-being among CRC survivors. Larger randomized studies are needed to determine if digital health tools improve functional well-being among CRC survivors and if this improvement can be sustained over time. TRIAL REGISTRATION: NCT02966054; registration date, November 17, 2016.

Clinicopathologic Characteristics and Impact of Oophorectomy for Ovarian Metastases from Colorectal Cancer.

BACKGROUND: As survival with metastatic colorectal cancer (CRC) and imaging modalities improve, detection of ovarian metastases may be increasing. The ovary may serve as a sanctuary site for malignant cells; however, there is a paucity of data regarding the role for oophorectomy. METHODS: This is a single-institution retrospective study of patients with CRC with ovarian metastases from 2009 to 2017. We evaluated patient, disease, and treatment related factors associated with overall survival (OS) from initial diagnosis of metastatic CRC. RESULTS: Of 108 patients assessed, the median age was 50, 19% had localized disease at initial presentation, 64% had ovarian metastases at initial CRC diagnosis, and 77% underwent oophorectomy. Median OS was 29.6 months across all patients, and it was 36.7 months in patients who underwent oophorectomy versus 25.0 months in patients who did not (hazard ratio [HR] 0.54). In multivariate analysis, the effect of oophorectomy on OS suggested protection but was not statistically significant (HR 0.57). Resection of primary tumor was performed in 71% of patients, which was independently associated with improved OS (HR 0.21). Twelve patients (11%) remained alive at 5 years after diagnosis of metastatic disease. CONCLUSION: Although it has been previously reported that patients with CRC with ovarian metastases have poor prognosis, the median OS for this cohort was comparable to existing OS data for patients with metastatic CRC. In patients treated with chemotherapy, we did not find the ovarian metastasis to frequently serve as a sanctuary site of disease. However, we found that in carefully selected patients, oophorectomy may confer a survival benefit. IMPLICATIONS FOR PRACTICE: In colorectal cancer (CRC) ovarian metastasis is not necessarily associated with worse prognosis than metastasis to other sites. In carefully selected patients with ovarian metastases from CRC, oophorectomy may confer a survival benefit. Specifically, development of ovarian metastasis early in the disease course, resection of the primary tumor, and limited extraovarian metastatic disease are clinical features that are potentially associated with benefit from oophorectomy. A subset of patients with ovarian metastasis from CRC have potential to become long-term survivors (>5 years).

Factors Impacting Differential Outcomes in the Definitive Radiation Treatment of Anal Cancer Between HIV-Positive and HIV-Negative Patients.

BACKGROUND: Anal squamous cell carcinoma (ASCC) is uncommon, yet seen more frequently in the setting of the human immunodeficiency virus (HIV). Chemoradiotherapy is the definitive modality of treatment for patients with ASCC; this study examines factors impacting clinical outcomes in a large cohort of HIV-positive and HIV-negative patients. METHODS: A retrospective review was conducted of patients treated for nonmetastatic ASCC at a single institution between 2005 and 2018. Freedom from local recurrence (FFLR), freedom from distant metastasis, and overall survival (OS) were calculated using the Kaplan-Meier method, and univariate and multivariate analysis were performed using the Cox proportional hazards model. RESULTS: During the study period, 111 patients initiated definitive treatment for ASCC. Median age of the entire cohort was 56.7 years (interquartile range, 51.5-63.5), with 52 patients (46.8%) being HIV-positive. At median follow-up of 28.0 months, the 2- and 5-year FFLR were 78.2% (95% confidence interval [CI], 70.4-87.0) and 74.6% (95% CI, 65.8-84.5), respectively. Multivariate analysis revealed time from diagnosis to treatment initiation (median, 8 weeks; hazard ratio, 1.06; 95% CI, 1.03-1.10) to be significantly associated with worse FFLR and OS. HIV-positive patients had a trend toward worse FFLR (log-ranked p = .06). For HIV-positive patients with post-treatment CD4 less than 150 cells per mm3 , there was significantly worse OS (log-ranked p = .015). CONCLUSION: A trend toward worse FFLR was seen in HIV-positive patients, despite similar baseline disease characteristics as HIV-negative patients. Worse FFLR and OS was significantly associated with increased time from diagnosis to treatment initiation. Poorer OS was seen in HIV-positive patients with a post-treatment CD4 count less than 150 cells per mm3 . IMPLICATIONS FOR PRACTICE: Human immunodeficiency virus (HIV)-positive patients with anal squamous cell carcinoma can represent a difficult clinical scenario. Definitive radiation with concurrent chemotherapy is highly effective but can result in significant toxicity and a decrease in CD4 count that could predispose to HIV-related complications. As HIV-positive patients have largely been excluded from prospective clinical trials, this study seeks to provide greater understanding of their outcomes with radiation therapy, potential predictors of worse local control and overall survival, and those most at risk after completion of treatment.

Sampling strategies to capture single-cell heterogeneity.

Advances in single-cell technologies have highlighted the prevalence and biological significance of cellular heterogeneity. A critical question researchers face is how to design experiments that faithfully capture the true range of heterogeneity from samples of cellular populations. Here we develop a data-driven approach, illustrated in the context of image data, that estimates the sampling depth required for prospective investigations of single-cell heterogeneity from an existing collection of samples.

Molecular Insights in Transmission of Cancer From an Organ Donor to Four Transplant Recipients.

Organ donors are systematically screened for infection, whereas screening for malignancy is less rigorous. The true incidence of donor-transmitted malignancies is unknown due to a lack of universal tumor testing in the posttransplant setting. Donor-transmitted malignancy may occur even when not suspected based on donor or recipient factors, including age and time to cancer diagnosis. We describe the detection of a gastrointestinal adenocarcinoma transmitted from a young donor to 4 transplant recipients. Multidimensional histopathologic and genomic profiling showed a CDH1 mutation and MET amplification, consistent with gastric origin. At the time of writing, one patient in this series remains alive and without evidence of cancer after prompt organ explant after cancer was reported in other recipients. Because identification of a donor-derived malignancy changes management, our recommendation is to routinely perform short tandem repeat testing (or a comparable assay) immediately upon diagnosis of cancer in any organ transplant recipient. Routine testing for a donor-origin cancer and centralized reporting of outcomes are necessary to establish a robust evidence base for the future development of clinical practice guidelines.

Embedded palliative care for patients with metastatic colorectal cancer: a mixed-methods pilot study.

PURPOSE: Palliative care is recommended for patients with metastatic cancer, but there has been limited research about embedded palliative care for specific patient populations. We describe the impact of a pilot program that provided routine, early, integrated palliative care to patients with metastatic colorectal cancer. METHODS: Mixed methods pre-post intervention cohort study at an academic cancer center. Thirty control then 30 intervention patients with metastatic colorectal cancer were surveyed at baseline and 1, 3, 6, 9, and 12 months thereafter about symptoms, quality-of-life, and likelihood of cure. We compared survey responses, trends over time, rates of advance care planning, and healthcare utilization between groups. Patients, family caregivers, and clinicians were interviewed. RESULTS: Patients in the intervention group were followed for an average of 6.5 months and had an average of 3.5 palliative care visits. At baseline, symptoms were mild (average 1.85/10) and 78.2% of patients reported good/excellent quality-of-life. Half (50.9%) believed they were likely to be cured of cancer. Over time, symptoms and quality-of-life metrics remained similar between groups, however intervention patients were more realistic about their likelihood of cure (p = 0.008). Intervention patients were more likely to have a surrogate documented (83.3% vs. 26.7%, p < 0.0001), an advance directive completed (63.3% vs. 13.3%, p < 0.0001), and non-full code status (43.3% vs. 16.7%, p < 0.03). All patients and family caregivers would recommend the program to others with cancer. CONCLUSIONS: We describe the impact of an embedded palliative care program for patients with metastatic colorectal cancer, which improved prognostic awareness and rates of advance care planning.

Self-monitoring and reminder text messages to increase physical activity in colorectal cancer survivors (Smart Pace): a pilot randomized controlled trial.

BACKGROUND: Over 1.3 million people live with colorectal cancer in the United States. Physical activity is associated with lower risk of colorectal cancer recurrence and mortality. Interventions are needed to increase physical activity in colorectal cancer survivors. METHODS: We conducted a 2-arm non-blinded pilot randomized controlled trial at the University of California, San Francisco among 42 individuals who had completed curative-intent treatment for colorectal cancer to determine the feasibility and acceptability of a 12-week (84 days) physical activity intervention using a Fitbit Flex™ and daily text messages. Participants were randomized 1:1 to receive the intervention with print educational materials or print educational materials alone. We explored the impact of the intervention versus usual care on physical activity using ActiGraph GT3X+ accelerometers pre-/post-intervention. RESULTS: We screened 406 individuals and randomized 42 to intervention (n = 21) or control (n = 21) groups. During the 12-week study, the intervention arm wore their Fitbits a median of 74 days [88% of days in study period, interquartile range: 23-83 days] and responded to a median of 34 (out of 46) text messages that asked for a reply (interquartile range: 13-38 text messages). Among the 16 intervention participants who completed the feedback survey, the majority (88%) reported that the intervention motivated them to exercise and that they were satisfied with their experience. No statistically significant difference in change in moderate-to-vigorous physical activity was found from baseline to 12 weeks between arms. CONCLUSION: A 12-week physical activity intervention with a Fitbit and text messages was feasible and acceptable among colorectal cancer patients after curative treatment. Larger studies are needed to determine whether the intervention increases physical activity. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT02966054 . Registered 17 November 2016, retrospectively registered.

Prolonged Response to HER2-Directed Therapy in a Patient With HER2-Amplified, Rapidly Progressive Metastatic Colorectal Cancer.

HER2 gene amplifications and activating mutations in the HER2 receptor tyrosine kinase are present in 4% of metastatic colorectal cancers (mCRCs). HER2-targeted therapy is not standard of care, although preclinical and clinical data suggest that patients with HER2 amplifications and/or HER2-activating mutations may benefit from HER2-directed therapy. HER2 amplifications and activating mutations have also been implicated in resistance to anti-epidermal growth factor receptor-based therapy. This report describes a patient with KRAS, NRAS, and BRAF wild-type mCRC who experienced disease progression on first-line treatment with FOLFIRI and cetuximab after only 5 months, and subsequently experienced progression on second-line treatment with capecitabine and oxaliplatin plus bevacizumab after 2 months with significant functional decline. Next-generation sequencing of the primary tumor identified HER2 amplification, and we were able to obtain trastuzumab-DM1 for off-label use. The patient had symptomatic clinical benefit from trastuzumab-DM1 and had radiographic disease control for 7 months. On progression, therapy was changed to trastuzumab and pertuzumab, but the patient's disease progressed 3 months later. Treatment with the trastuzumab-DM1 resulted in a sustained response that was longer than his prior responses in the first and second lines of treatment, with a dramatic improvement in the patient's functional status. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-amplifed CRC with trastuzumab-DM1. Clinical trials targeting patients with HER2-mutated and -amplified metastatic colon cancer are currently underway. Molecular insights from investigating HER2 activation and the impact of HER2-directed therapies in a wide variety of solid tumors will create the needed evidence base to more broadly inform patient care.

Differential Radiographic Appearance of BRAF V600E-Mutant Metastatic Colorectal Cancer in Patients Matched by Primary Tumor Location.

BACKGROUND: BRAF-mutant metastatic colorectal cancers (mCRCs) share many clinicopathologic features with right-sided colon tumors, including frequent peritoneal involvement. Because of the poorer outcomes associated with BRAF mutations, early enrollment in clinical trials has been encouraged. However, the use of standard eligibility and assessment criteria, such as measurable disease, has anecdotally impeded patient accrual and restricted appraisal of treatment response. We investigated whether the presence of a BRAF V600E mutation is differentially associated with sites and appearance of metastatic disease in patients matched by primary tumor location. METHODS: A total of 40 patients with BRAF-mutant mCRC were matched to 80 patients with BRAF wild-type mCRC by location of primary tumor (right or left colon; rectum), sex, and age. Associations between BRAF mutation status and clinicopathologic characteristics and metastatic sites were analyzed using proportion tests. Survival was summarized with Kaplan-Meier and Cox regression methods. RESULTS: The distribution of primary tumor locations was: 60% right colon, 30% left colon, and 10% rectum. Compared with BRAF wild-type tumors, BRAF-mutant tumors more commonly associated with peritoneal metastases (50% vs 31%; P=.045) and ascites (50% vs 24%; P=.0038). In patients with left colon primaries, BRAF mutations were associated with more frequent ascites (58% vs 12%; P=.0038) and less frequent liver metastases (42% vs 79%; P=.024). Among patients with right colon primaries, no significant difference in sites of disease by BRAF mutation status was observed. Disease was not measurable by RECIST 1.1 in 24% of patients with right-sided primary tumors, irrespective of BRAF mutation status. In the BRAF-mutated cohort, ascites correlated unfavorably with survival (hazard ratio, 2.35; 95% CI, 1.14, 4.83; P=.02). CONCLUSIONS: Greater frequency of ascites and peritoneal metastases, which pose challenges for RECIST 1.1 interpretation of therapeutic outcomes, are seen with BRAF-mutant mCRC, even when patients are matched for primary tumor location.

Potent antitumor activity of cabozantinib, a c-MET and VEGFR2 inhibitor, in a colorectal cancer patient-derived tumor explant model.

Antiangiogenic therapy is commonly used for the treatment of colorectal cancer (CRC). Although patients derive some clinical benefit, treatment resistance inevitably occurs. The MET signaling pathway has been proposed to be a major contributor of resistance to antiangiogenic therapy. MET is upregulated in response to vascular endothelial growth factor pathway inhibition and plays an essential role in tumorigenesis and progression of tumors. In this study, we set out to determine the efficacy of cabozantinib in a preclinical CRC patient-derived tumor xenograft model. We demonstrate potent inhibitory effects on tumor growth in 80% of tumors treated. The greatest antitumor effects were observed in tumors that possess a mutation in the PIK3CA gene. The underlying antitumor mechanisms of cabozantinib consisted of inhibition of angiogenesis and Akt activation and significantly decreased expression of genes involved in the PI3K pathway. These findings support further evaluation of cabozantinib in patients with CRC. PIK3CA mutation as a predictive biomarker of sensitivity is intriguing and warrants further elucidation. A clinical trial of cabozantinib in refractory metastatic CRC is being activated.

Mindfulness-Based Group Medical Visits: Strategies to Improve Equitable Access and Inclusion for Diverse Patients in Cancer Treatment.

Background: Mindfulness-based interventions (MBIs) are supported by clinical practice guidelines as effective non-pharmacologic interventions for common symptoms experienced by cancer patients, including anxiety, depression, and fatigue. However, the evidence predominately derives from White breast cancer survivors. Racial and ethnic minority patients have less access to integrative oncology care and worse cancer outcomes. To address these gaps, we designed and piloted a series of mindfulness-based group medical visits (MB-GMVs), embedded into comprehensive cancer care, for racially and ethnically diverse patients in cancer treatment. Methods: As a quality improvement project, we launched a telehealth MB-GMV series for patients undergoing cancer treatment, delivered as four weekly 2-hour visits billable to insurance. Content was concordant with evidence-based guidelines and established MBIs and adapted to improve cultural relevance and fit (eg, access-centered, trauma-informed, with inclusive communication practices). Program structure was adapted to address barriers to participation, with ≥50% slots per series reserved for racial and ethnic minority patients. Intake surveys incorporated a demographic questionnaire and symptom assessments. Evaluations were sent following the visits. Results: In our first ten cohorts (n = 78), 80% of referred patients enrolled. Participants were: 22% Asian, 14% Black, 17% Latino, 45% non-Latino White; 65% female; with a median age of 54 years (range 27-79); and 80% had metastatic cancer. Common baseline symptoms included lack of energy, difficulty sleeping, and worrying. Most patients (90%) attended ≥3 visits. On final evaluations, 87% patients rated the series as "excellent"; 81% "strongly agreed" that they liked the GMV format; and 92% would "definitely" recommend the series to others. Qualitative themes included empowerment and connectedness. Conclusion: Telehealth GMVs are a feasible, acceptable, and financially sustainable model for increasing access to MBIs. Diverse patients in active cancer treatment were able to participate and reported high levels of satisfaction with this series that was tailored to center health equity and inclusion.

Expansion of a bacterial operon during cancer treatment ameliorates drug toxicity.

Dose-limiting toxicities remain a major barrier to drug development and therapy, revealing the limited predictive power of human genetics. Herein, we demonstrate the utility of a more comprehensive approach to studying drug toxicity through longitudinal study of the human gut microbiome during colorectal cancer (CRC) treatment (NCT04054908) coupled to cell culture and mouse experiments. 16S rRNA gene and metagenomic sequencing revealed significant shifts in gut microbial community structure during treatment with oral fluoropyrimidines, which was validated in an independent cohort. Gene abundance was also markedly changed by oral fluoropyrimidines, including an enrichment for the preTA operon, which is sufficient for the inactivation of active metabolite 5-fluorouracil (5-FU). Higher levels of preTA led to increased 5-FU depletion by the gut microbiota grown ex vivo. Germ-free and antibiotic-treated mice had increased fluoropyrimidine toxicity, which was rescued by colonization with the mouse gut microbiota, preTA+ E. coli, or CRC patient stool with high preTA levels. preTA abundance was negatively associated with patient toxicities. Together, these data support a causal, clinically relevant interaction between a human gut bacterial operon and the dose-limiting side effects of cancer treatment. Our approach is generalizable to other drugs, including cancer immunotherapies, and provides valuable insights into host-microbiome interactions in the context of disease.

Minimal Residual Disease using a Plasma-Only Circulating Tumor DNA Assay to Predict Recurrence of Metastatic Colorectal Cancer Following Curative Intent Treatment.

PURPOSE: Minimal residual disease (MRD) detection can identify the recurrence in patients with colorectal cancer (CRC) following definitive treatment. We evaluated a plasma-only MRD assay to predict recurrence and survival in patients with metastatic CRC who underwent curative intent procedures (surgery and/or radiotherapy), with or without (neo)adjuvant chemotherapy. The primary objective of this study was to assess the correlation of postprocedure tumor cell-free DNA detection status with radiographic disease recurrence. EXPERIMENTAL DESIGN: Preprocedure and postprocedure longitudinal samples were collected from 53 patients and analyzed with a multiomic MRD assay detecting circulating tumor DNA (ctDNA) from genomic and epigenomic signals. Preprocedure and postprocedure ctDNA detection correlated with recurrence-free and overall survival (OS). RESULTS: From 52 patients, 230/233 samples were successfully analyzed. At the time of data cutoff, 36 (69.2%) patients recurred with median follow-up of 31 months. Detectable ctDNA was observed in 19/42 patients (45.2%) with ctDNA analyzed 3 weeks postprocedure. ctDNA detection 3 weeks postprocedure was associated with shorter median recurrence-free survival (RFS; HR, 5.27; 95% CI, 2.31-12.0; P < 0.0001) and OS (HR, 12.83; 95% CI, 3.6-45.9; P < 0.0001). Preprocedure ctDNA detection status was not associated with RFS but was associated with improved OS (HR, 4.65; 95% CI, 1.4-15.2; P = 0.0111). Undetectable ctDNA preprocedure had notable long-term OS, >90% 3 years postprocedure. CONCLUSIONS: In this cohort of oligometastatic CRC, detection of ctDNA preprocedure or postprocedure was associated with inferior outcomes even after accounting for known prognostic clinicopathologic variables. This suggests ctDNA may enhance current risk stratification methods helping the evaluation of novel treatments and surveillance strategies toward improving patient outcomes.

Associations between the Gut Microbiota, Race, and Ethnicity of Patients with Colorectal Cancer: A Pilot and Feasibility Study.

BACKGROUND: Colorectal cancer (CRC) is more prevalent among some racial and ethnic minority and low socioeconomic status populations. Although the gut microbiota is a risk factor for CRC and varies with race and ethnicity, its role in CRC disparities remains poorly understood. METHODS: We examined the feasibility of recruiting sociodemographically diverse CRC patients for a microbiome study involving a home stool collection. We also explored whether race and ethnicity were associated with gut microbiome composition. We recruited Black/African American, Hispanic/Latino, and non-Hispanic White patients who were receiving care for active CRC to complete a comprehensive dietary and lifestyle survey, self-collect a stool sample, and complete an exit interview. Gut microbial diversity and composition were analyzed using 16S rRNA gene sequencing. RESULTS: 30 individuals consented (of 35 who were eligible and contacted) with 5 (17%) Black/African American, 11 (37%) Hispanic/Latino, and 14 (46%) non-Hispanic White. A total of 22 (73%) completed the dietary and lifestyle survey; 18 (63%) returned a stool sample. Even after controlling for socioeconomic, dietary, or treatment-related covariates, microbiome composition was associated with race and ethnicity. Fusobacteriota (a phylum associated with the development and progression of CRC) was significantly higher in the Black/African American group compared to others, and microbial diversity was higher in samples from non-Hispanic White individuals compared to Hispanic/Latino individuals. CONCLUSION: Our study shows that it is feasible to recruit and collect stool samples from diverse individuals with CRC and found significant associations in gut microbial structure with race and ethnicity.