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Background: The inability to predict treatment response of colorectal cancer patients results in unnecessary toxicity, decreased efficacy and survival. Response testing on patient-derived organoids (PDOs) is a promising biomarker for treatment efficacy. The aim of this study is to optimize PDO drug screening methods for correlation with patient response and explore the potential to predict responses to standard chemotherapies. Methods: We optimized drug screen methods on 5–11 PDOs per condition of the complete set of 23 PDOs from patients treated for metastatic colorectal cancer (mCRC). PDOs were exposed to 5-fluorouracil (5-FU), irinotecan- and oxaliplatin-based chemotherapy. We compared medium with and without N-acetylcysteine (NAC), different readouts and different combination treatment set-ups to capture the strongest association with patient response. We expanded the screens using the optimized methods for all PDOs. Organoid sensitivity was correlated to the patient's response, determined by % change in the size of target lesions. We assessed organoid sensitivity in relation to prior exposure to chemotherapy, mutational status and sidedness. Results: Drug screen optimization involved excluding N-acetylcysteine from the medium and biphasic curve fitting for 5-FU & oxaliplatin combination screens. CellTiter-Glo measurements were comparable with CyQUANT and did not affect the correlation with patient response. Furthermore, the correlation improved with application of growth rate metrics, when 5-FU & oxaliplatin was screened in a ratio, and 5-FU & SN-38 using a fixed dose of SN-38. Area under the curve was the most robust drug response curve metric. After optimization, organoid and patient response showed a correlation coefficient of 0.58 for 5-FU (n = 6, 95% CI -0.44,0.95), 0.61 for irinotecan- (n = 10, 95% CI -0.03,0.90) and 0.60 for oxaliplatin-based chemotherapy (n = 11, 95% CI -0.01,0.88). Median progression-free survival of patients with resistant PDOs to oxaliplatin-based chemotherapy was significantly shorter than sensitive PDOs (3.3 vs 10.9 months, p = 0.007). Increased resistance to 5-FU in patients with prior exposure to 5-FU/capecitabine was adequately reflected in PDOs (p = 0.003). Conclusions: Our study emphasizes the critical impact of the screening methods for determining correlation between PDO drug screens and mCRC patient outcomes. Our 5-step optimization strategy provides a basis for future research on the clinical utility of PDO screens. [ABSTRACT FROM AUTHOR]

Background: In metastatic breast cancer (MBC), [18F]fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) can be used for staging. We evaluated the correlation between BC histopathological characteristics and [18F]FDG uptake in corresponding metastases. Patients and Methods: Patients with non-rapidly progressive MBC of all subtypes prospectively underwent a baseline histological metastasis biopsy and [18F]FDG-PET. Biopsies were assessed for estrogen, progesterone, and human epidermal growth factor receptor 2 (ER, PR, HER2); Ki-67; and histological subtype. [18F]FDG uptake was expressed as maximum standardized uptake value (SUVmax) and results were expressed as geometric means. Results: Of 200 patients, 188 had evaluable metastasis biopsies, and 182 of these contained tumor. HER2 positivity and Ki-67 ≥ 20% were correlated with higher [18F]FDG uptake (estimated geometric mean SUVmax 10.0 and 8.8, respectively; p = 0.0064 and p = 0.014). [18F]FDG uptake was lowest in ER-positive/HER2-negative BC and highest in HER2-positive BC (geometric mean SUVmax 6.8 and 10.0, respectively; p = 0.0058). Although [18F]FDG uptake was lower in invasive lobular carcinoma (n = 31) than invasive carcinoma NST (n = 146) (estimated geometric mean SUVmax 5.8 versus 7.8; p = 0.014), the metastasis detection rate was similar. Conclusions: [18F]FDG-PET is a powerful tool to detect metastases, including invasive lobular carcinoma. Although BC histopathological characteristics are related to [18F]FDG uptake, [18F]FDG-PET and biopsy remain complementary in MBC staging (NCT01957332). [ABSTRACT FROM AUTHOR]

We studied the prognostic value of primary tumor sidedness in metastatic colorectal cancer over time and across treatment lines. Population data on synchronous metastatic colorectal cancer patients were extracted from the Netherlands Cancer Registry and SEER database. Pubmed, EMBASE and Cochrane library were searched for prospective studies on metastatic colorectal cancer to conduct a meta‐analysis. Inclusion criteria consisted of metastatic disease, systemic treatment with palliative intent and specification of primary tumor location. Data were pooled using a random‐effects model. For the population‐based data, multivariable Cox models were constructed. The Grambsch‐Therneau test was conducted to evaluate the potential time‐varying nature of sidedness. Meta‐regression incorporating treatment‐line as variable was conducted to test the pre‐specified hypothesis that the prognostic value of sidedness varies over time. Analysis of 12 885 and 16 160 synchronous metastatic colorectal cancer patients registered in the Netherlands Cancer Registry and SEER database, respectively, indicated a time‐varying prognostic value of sidedness (P <.01). Thirty‐one studies were selected for the meta‐analysis (9558 patients for overall survival analysis). Pooled univariable hazard ratioleft‐sided/right‐sided for overall survival was 0.71 (95% CI: 0.65‐0.76) in 1st‐line, 0.76 (0.54‐1.06) in 2nd‐line and 1.01 (0.86‐1.19) in 3rd‐line studies. Hazard ratios were significantly influenced by treatment line (P =.035). The prognostic value of sidedness of the primary tumor in metastatic colorectal cancer patients treated with palliative systemic therapy decreases over time since diagnosis, suggesting that sidedness may not be a useful stratification factor in late‐line trials. This decrease in prognostic value should be taken into account when providing prognostic information to patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with colorectal liver metastases (CRLM) are able to achieve long-term survival when they receive local treatment of CRLM (resection or tumor ablation). Existing clinical risk scores (CRSs) predicting prognosis of patients after resection of colorectal liver metastases were developed in highly specialized centers and thus may not function in the general population. We validated the Fong and GAME CRSs in a large population-based cohort, including two important subgroups: young/elderly and with/without perioperative chemotherapy. Both CRSs showed predictive ability. However, they were not able to discriminate preoperative risk sufficiently for clinical decision-making and, thus, require improvement. Optimized surgical techniques and systemic therapy have increased the number of patients with colorectal liver metastases (CRLM) eligible for local treatment. To increase postoperative survival, we need to stratify patients to customize therapy. Most clinical risk scores (CRSs) which predict prognosis after CRLM resection were based on the outcome of studies in specialized centers, and this may hamper the generalizability of these CRSs in unselected populations and underrepresented subgroups. We aimed to externally validate two CRSs in a population-based cohort of patients with CRLM. A total of 1105 patients with local treatment of CRLM, diagnosed in 2015/2016, were included from a nationwide population-based database. Survival outcomes were analyzed. The Fong and more recently developed GAME CRS were externally validated, including in pre-specified subgroups (≤70/>70 years and with/without perioperative systemic therapy). The three-year DFS was 22.8%, and the median OS in the GAME risk groups (high/moderate/low) was 32.4, 46.7, and 68.1 months, respectively (p < 0.005). The median OS for patients with versus without perioperative therapy was 47.6 (95%CI [39.8, 56.2]) and 54.9 months (95%CI [48.8, 63.7]), respectively (p = 0.152), and for below/above 70 years, it was 54.9 (95%CI [49.3–64.1]) and 44.2 months (95%CI [37.1–54.3]), respectively (p < 0.005). The discriminative ability for OS of Fong CRS was 0.577 (95%CI [0.554, 0.601]), and for GAME, it was 0.596 (95%CI [0.572, 0.621]), and was comparable in the subgroups. In conclusion, both CRSs showed predictive ability in a population-based cohort and in predefined subgroups. However, the limited discriminative ability of these CRSs results in insufficient preoperative risk stratification for clinical decision-making. [ABSTRACT FROM AUTHOR]

Introduction: Uncertainty exists about a possible survival benefit of primary tumor resection (PTR) in synchronous metastatic colon cancer (mCC). Since sidedness of the primary tumor is regarded as an important prognostic factor, our objective was to study the interaction between PTR and sidedness in synchronous mCC. Methods: In this retrospective study, we used data from 2 first-line phase 3 randomized controlled trials (RCTs). A mixed Cox regression model was used to study the multiplicative interaction between PTR and sidedness. We adjusted for age, treatment arm, WHO performance status, number of affected organs by metastases, serum lactate dehydrogenase, and year of enrollment. Results: We found that PTR is associated with better survival in both right-sided (hazard ratio [HR] 0.59 [95% confidence interval 0.42–0.8 2]) and left-sided mCC (HR 0.70 [95% confidence interval 0.52–0.93]). The interaction between PTR and sidedness was not significant (p = 0.45). Conclusion: Our data suggest that the prognostic value of PTR is independent of sidedness. Validation of these results will be performed in ongoing RCTs. [ABSTRACT FROM AUTHOR]

Background: Translating results from randomized trials to individual patients is challenging, since treatment effects may vary due to heterogeneous prognostic characteristics. We aimed to demonstrate model development for individualized treatment effect predictions in cancer patients. We used data from two randomized trials that investigated sequential versus combination chemotherapy in unresectable metastatic colorectal cancer (mCRC) patients. Material and methods: We used data from 803 patients included in CAIRO for prediction model development and internal validation, and data from 1423 patients included in FOCUS for external validation. A Weibull model with pre-specified patient and tumour characteristics was developed for a prediction of gain in median overall survival (OS) by upfront combination versus sequential chemotherapy. Decision curve analysis with net benefit was used. A nomogram was built using logistic regression for estimating the probability of receiving second-line treatment after the first-line monochemotherapy. Results: Median-predicted gain in OS for the combination versus sequential chemotherapy was 2.3 months (IQR: −1.1 to 3.7 months). A predicted gain in favour of sequential chemotherapy was found in 231 patients (29%) and a predicted gain of >3 months for combination chemotherapy in 294 patients (37%). Patients with benefit from sequential chemotherapy had metachronous metastatic disease and a left-sided primary tumour. Decision curve analyses showed improvement in a net benefit for treating all patients according to prediction-based treatment compared to treating all patients with combination chemotherapy. Multiple characteristics were identified as prognostic variables which identify patients at risk of never receiving second-line treatment if treated with initial monochemotherapy. External validation showed good calibration with moderate discrimination in both models (C-index 0.66 and 0.65, respectively). Conclusions: We successfully developed individualized prediction models including prognostic characteristics derived from randomized trials to estimate treatment effects in mCRC patients. In times where the heterogeneity of CRC becomes increasingly evident, such tools are an important step towards personalized treatment. [ABSTRACT FROM AUTHOR]

Background: In patients with stage II colorectal cancer (CRC) the number of surgically retrieved lymph nodes (LNs) is associated with prognosis, resulting in a minimum of 10-12 retrieved LNs being recommended for this stage. Current guidelines do not provide a recommendation regarding LN yield in T1 CRC. Studies evaluating LN yield in T1 CRC suggest that such high LN yields are not feasible in this early stage, and a lower LN yield might be appropriate. We aimed to validate the cut-off of 10 retrieved LNs on risk for recurrent cancer and detection of LN metastasis (LNM) in T1 CRC, and explored whether this number is feasible in clinical practice.Methods: Patients diagnosed with T1 CRC and treated with surgical resection between 2000 and 2014 in thirteen participating hospitals were selected from the Netherlands Cancer Registry. Medical records were reviewed to collect additional information. The association between LN yield and recurrence and LNM respectively were analyzed using 10 LNs as cut-off. Propensity score analysis using inverse probability weighting (IPW) was performed to adjust for clinical and histological confounding factors (i.e., age, sex, tumor location, size and morphology, presence of LNM, lymphovascular invasion, depth of submucosal invasion, and grade of differentiation).Results: In total, 1017 patients with a median follow-up time of 49.0 months (IQR 19.6-81.5) were included. Four-hundred five patients (39.8%) had a LN yield ≥ 10. Forty-one patients (4.0%) developed recurrence. LN yield ≥ 10 was independently associated with a decreased risk for recurrence (IPW-adjusted HR 0.20; 95% CI 0.06-0.67; P = 0.009). LNM were detected in 84 patients (8.3%). LN yield ≥ 10 was independently associated with increased detection of LNM (IPW-adjusted OR 2.27; 95% CI 1.39-3.69; P = 0.001).Conclusions: In this retrospective observational study, retrieving < 10 LNs was associated with an increased risk of CRC recurrence, advocating the importance to perform an appropriate oncologic resection of the draining LNs and diligent LN search when patients with T1 CRC at high-risk for LNM are referred for surgical resection. Given that both gastroenterologists, surgeons and pathologists will encounter T1 CRCs with increasing frequency due to the introduction of national screening programs, awareness on the consequences of an inadequate LN retrieval is of utmost importance. [ABSTRACT FROM AUTHOR]

Checkpoint inhibition has radically improved the perspective for patients with metastatic cancer, but predicting who will not respond with high certainty remains difficult. Imaging-derived biomarkers may be able to provide additional insights into the heterogeneity in tumour response between patients. In this systematic review, we aimed to summarise and qualitatively assess the current evidence on imaging biomarkers that predict response and survival in patients treated with checkpoint inhibitors in all cancer types. PubMed and Embase were searched from database inception to 29th November 2021. Articles eligible for inclusion described baseline imaging predictive factors, radiomics and/or imaging machine learning models for predicting response and survival in patients with any kind of malignancy treated with checkpoint inhibitors. Risk of bias was assessed using the QUIPS and PROBAST tools and data was extracted. In total, 119 studies including 15,580 patients were selected. Of these studies, 73 investigated simple imaging factors. 45 studies investigated radiomic features or deep learning models. Predictors of worse survival were (i) higher tumour burden, (ii) presence of liver metastases, (iii) less subcutaneous adipose tissue, (iv) less dense muscle and (v) presence of symptomatic brain metastases. Hazard rate ratios did not exceed 2.00 for any predictor in the larger and higher quality studies. The added value of baseline fluorodeoxyglucose positron emission tomography parameters in predicting response to treatment was limited. Pilot studies of radioactive drug tracer imaging showed promising results. Reports on radiomics were almost unanimously positive, but numerous methodological concerns exist. There is well-supported evidence for several imaging biomarkers that can be used in clinical decision making. Further research, however, is needed into biomarkers that can more accurately identify which patients who will not benefit from checkpoint inhibition. Radiomics and radioactive drug labelling appear to be promising approaches for this purpose. [Display omitted] • Higher tumour burden and the presence of liver metastasis indicate worse survival. • presence of symptomatic brain metastases predicts worse survival in patients with melanoma. • More subcutaneous fat and skeletal muscle may be predictive of better survival. • Radioactive drug labelling techniques show promising results in pilot studies. • Radiomics appear promising in published literature but require further validation. [ABSTRACT FROM AUTHOR]

Background: Radioembolization is an established treatment modality in colorectal cancer patients with liver-dominant disease in a salvage setting. Selection of patients who will benefit most is of vital importance. The aim of this study was to assess response (and mode of progression) at 3 months after radioembolization and the impact of baseline characteristics. Methods: Three months after radioembolization with either yttrium-90 resin/glass or holmium-166, anatomic response, according to RECIST 1.1, was evaluated in 90 patients. Correlations between baseline characteristics and efficacy were evaluated. For more detailed analysis of progressive disease as a dismal clinical entity, distinction was made between intra- and extrahepatic progression, and between progression of existing metastases and new metastases. Results: Forty-two patients (47%) had extrahepatic disease (up to five ≥ 1 cm lung nodules, and ≤ 2 cm lymph nodes) at baseline. No patients showed complete response, 5 (5.5%) patients had partial response, 16 (17.8%) had stable disease, and 69 (76.7%) had progressive disease. Most progressive patients (67/69; 97%) had new metastases (intra-hepatic N = 11, extrahepatic N = 32; or both N = 24). Significantly fewer patients had progressive disease in the group of patients presenting without extrahepatic metastases at baseline (63% versus 93%; p = 0.0016). Median overall survival in patients with extrahepatic disease was 6.5 months, versus 10 months in patients without extrahepatic disease at baseline (hazard ratio 1.79, 95%CI 1.24–2.57). Conclusions: Response at 3-month follow-up and survival were heavily influenced by new metastases. Patients with extrahepatic disease at baseline had a worse outcome compared to patients without. [ABSTRACT FROM AUTHOR]

In patients who have undergone surgery for colorectal cancer (CRC), 3% have recurrence of (metachronous) CRC. We investigated whether tumor seeding during colonoscopy (iatrogenic implantation of tumor cells in damaged mucosa) increases risk for metachronous CRC. In a proof of principle study, we collected data from the Dutch National Pathology Registry for patients with a diagnosis of CRC from 2013 through 2015, with a second diagnosis of CRC within 6 months to 3.5 years after surgery. We reviewed pathology reports to identify likely metachronous CRC (histologically proven adenocarcinoma located elsewhere in the colon or rectum from the surgical anastomosis). For 22 patients fulfilling the inclusion criteria, we ascribed the most likely etiology to tumor seeding when endoscopic manipulations, such as biopsies or polypectomy, occurred at the location where the metachronous tumor was subsequently detected, after endoscopic manipulation of the primary tumor. We collected clinical data from patients and compared molecular profiles of the primary and metachronous colorectal tumors using next-generation sequencing. We then examined the source of seeded tumor. We tested whether tumor cells stay behind in the working channel of the endoscope after biopsies of colorectal tumors, and whether these cells maintain viability in organoid cultures. In total, tumor seeding was suspected as the most likely etiology of metachronous CRC in 5 patients. Tumor tissues were available from 3 patients. An identical molecular signature was observed in the primary and metachronous colorectal tumors from all 3 patients. In 5 control cases with a different etiology of metachronous CRC, the molecular signature of the primary and metachronous tumor were completely different. Based on review of 2147 patient records, we estimated the risk of tumor seeding during colonoscopy to be 0.3%–0.6%. We demonstrated that the working channel of the colonoscope becomes contaminated with viable tumor cells during biopsy collection. Subsequent instruments introduced through this working channel also became contaminated. These cells were shown to maintain their proliferative potential. In an analysis of primary and secondary tumors from patients with metachronous CRC, we found that primary tumor cells might be seeded in a new location after biopsy of the primary tumor. Although our study does not eliminate other possibilities of transmission, our findings and experiments support the hypothesis that tumor seeding can occur during colonoscopy via the working channel of the endoscope. The possibility of iatrogenic seeding seems low. However, our findings compel awareness on this potentially preventable cause of metachronous CRC. [ABSTRACT FROM AUTHOR]

Adding cyclin-dependent kinase (CDK) inhibitor to endocrine treatment improves outcome in œstrogen receptor (ER) positive metastatic breast cancer, but identifying the subset of patients who benefit is challenging. Response is potentially associated with ER expression heterogeneity. This is because, unlike the primary tumour in the breast that is localized to the organ, the metastatic breast cancer has spread and continues to spread to distant locations in the body such as bones, lungs, liver, axial skeleton, even to the central nervous system like the brain, wherefrom obtaining biopsies are not easy, and also, the metastasised tissues are heterogeneous. Positron emission tomography (PET) with 16α-[18F]fluoro-17β-œstradiol (FES), briefly referred to as FES-PET, allows whole-body ER assessment. We explored whether FES-PET heterogeneity and FES uptake were related to letrozole and palbociclib outcome, in patients with ER positive, metastatic breast cancer. Patients underwent a baseline FES-PET and 18F-fluorodeoxyglucose (FDG) PET, the FDG-PET served to help identify active sites of breast cancer with contrast-enhanced computed tomography (CT). FES-PET heterogeneity score (% FES positive lesions divided by all lesions on FDG-PET and/or CT) and FES uptake were related to outcome and 8-week FDG-PET response. Circulating tumour DNA (CtDNA) samples for ESR1 mutation analysis were collected at baseline. In 30 patients with 864 metastatic lesions, baseline FES-PET heterogeneity was assessed. In 27 patients with 688 lesions, response was evaluated. Median time to progression (TTP) was 73 weeks (95% confidence interval [CI] 21 to ∞) in 7 patients with 100% FES positive disease, 27 weeks (14–49) in heterogeneous FES positive disease (20 patients), and 15 weeks (9 to ∞) without FES positivity (three patients; log-rank P = 0.30). Geometric mean FES uptake was 2.3 for metabolic progressive patients, 2.5 (P vs progression = 0.82) for metabolic stable disease, and 3.3 (P vs progression = 0.40) for metabolic response (P trend = 0.21). ESR1 mutations, found in 13/23 patients, were unrelated to FES uptake. This exploratory study suggests that FES-PET heterogeneity may potentially identify the subset of ER positive, metastatic breast cancer patients who benefit from letrozole combined with CDK inhibition. NCT02806050. • Endocrine treatment with CDK-i does not benefit breast cancer patients equally. • Oestrogen receptor (ER) heterogeneity can be assessed with FES- and FDG-PET. • With ER positive homogeneity, combined treatment response is longer than with heterogeneity. • FES- and FDG-PET may identify patients with most combined treatment benefit. [ABSTRACT FROM AUTHOR]