Publications by authors named "Jeanne Tie"

76 Publications

Detection of low-frequency DNA variants by targeted sequencing of the Watson and Crick strands.

Nat Biotechnol 2021 May 3. Epub 2021 May 3.

Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Identification and quantification of low-frequency mutations remain challenging despite improvements in the baseline error rate of next-generation sequencing technologies. Here, we describe a method, termed SaferSeqS, that addresses these challenges by (1) efficiently introducing identical molecular barcodes in the Watson and Crick strands of template molecules and (2) enriching target sequences with strand-specific PCR. The method achieves high sensitivity and specificity and detects variants at frequencies below 1 in 100,000 DNA template molecules with a background mutation rate of <5 × 10 mutants per base pair (bp). We demonstrate that it can evaluate mutations in a single amplicon or simultaneously in multiple amplicons, assess limited quantities of cell-free DNA with high recovery of both strands and reduce the error rate of existing PCR-based molecular barcoding approaches by >100-fold.
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http://dx.doi.org/10.1038/s41587-021-00900-zDOI Listing
May 2021

Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: A prospective cohort study.

PLoS Med 2021 May 3;18(5):e1003620. Epub 2021 May 3.

The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.

Background: In patients with resectable colorectal liver metastases (CRLM), the role of pre- and postoperative systemic therapy continues to be debated. Previous studies have shown that circulating tumor DNA (ctDNA) analysis, as a marker of minimal residual disease, is a powerful prognostic factor in patients with nonmetastatic colorectal cancer (CRC). Serial analysis of ctDNA in patients with resectable CRLM could inform the optimal use of perioperative chemotherapy. Here, we performed a validation study to confirm the prognostic impact of postoperative ctDNA in resectable CRLM observed in a previous discovery study.

Methods And Findings: We prospectively collected plasma samples from patients with resectable CRLM, including presurgical and postsurgical samples, serial samples during any pre- or postoperative chemotherapy, and serial samples in follow-up. Via targeted sequencing of 15 genes commonly mutated in CRC, we identified at least 1 somatic mutation in each patient's tumor. We then designed a personalized assay to assess 1 mutation in plasma samples using the Safe-SeqS assay. A total of 380 plasma samples from 54 patients recruited from July 2011 to Dec 2014 were included in our analysis. Twenty-three (43%) patients received neoadjuvant chemotherapy, and 42 patients (78%) received adjuvant chemotherapy after surgery. Median follow-up was 51 months (interquartile range, 31 to 60 months). At least 1 somatic mutation was identified in all patients' tumor tissue. ctDNA was detectable in 46/54 (85%) patients prior to any treatment and 12/49 (24%) patients after surgery. There was a median 40.93-fold (19.10 to 87.73, P < 0.001) decrease in ctDNA mutant allele fraction with neoadjuvant chemotherapy, but ctDNA clearance during neoadjuvant chemotherapy was not associated with a better recurrence-free survival (RFS). Patients with detectable postoperative ctDNA experienced a significantly lower RFS (HR 6.3; 95% CI 2.58 to 15.2; P < 0.001) and overall survival (HR 4.2; 95% CI 1.5 to 11.8; P < 0.001) compared to patients with undetectable ctDNA. For the 11 patients with detectable postoperative ctDNA who had serial ctDNA sampling during adjuvant chemotherapy, ctDNA clearance was observed in 3 patients, 2 of whom remained disease-free. All 8 patients with persistently detectable ctDNA after adjuvant chemotherapy have recurred. End-of-treatment (surgery +/- adjuvant chemotherapy) ctDNA detection was associated with a 5-year RFS of 0% compared to 75.6% for patients with an undetectable end-of-treatment ctDNA (HR 14.9; 95% CI 4.94 to 44.7; P < 0.001). Key limitations of the study include the small sample size and the potential for false-positive findings with multiple hypothesis testing.

Conclusions: We confirmed the prognostic impact of postsurgery and posttreatment ctDNA in patients with resected CRLM. The potential utility of serial ctDNA analysis during adjuvant chemotherapy as an early marker of treatment efficacy was also demonstrated. Further studies are required to define how to optimally integrate ctDNA analyses into decision-making regarding the use and timing of adjuvant therapy for resectable CRLM.

Trial Registration: ACTRN12612000345886.
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http://dx.doi.org/10.1371/journal.pmed.1003620DOI Listing
May 2021

Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer: A Systematic Review and Metaanalysis of Oncological and Operative Outcomes.

Ann Surg Oncol 2021 Apr 23. Epub 2021 Apr 23.

Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Background: Total neoadjuvant therapy in rectal cancer refers to the administration of chemoradiotherapy plus chemotherapy before surgery. Recent studies have shown improved pathological complete response and disease-free survival with this approach. However, survival benefits remain unproven. Our objective is to present a metaanalysis of oncological outcomes of total neoadjuvant therapy in locally advanced rectal cancer.

Patients And Methods: A comprehensive search was performed on PubMed, Medline, and Google Scholars. Studies comparing total neoadjuvant therapy with standard neoadjuvant chemoradiotherapy were included. Data extracted from the individual studies were pooled and a metaanalysis performed. The outcomes of interest are the rate of complete pathological response, nodal response, resection margin, anal preservation, anastomotic leak, local recurrence, distant recurrence, disease-free survival, and overall survival.

Results: There were 15 comparative studies with 2437 patients in the neoadjuvant chemoradiotherapy group and 2284 in the total neoadjuvant therapy group. The pooled complete pathological response was 22.3% in the total neoadjuvant therapy group, compared with 14.2% in the standard neoadjuvant chemoradiotherapy group (p < 0.001). Even though there was no difference in local recurrence rate, there was a significantly lower rate of distant recurrence (OR 0.81, p = 0.02), and better 3-year disease-free survival (70.6% vs. 65.3%, respectively, p < 0.001) and overall survival (84.9% vs. 82.3%, respectively, p = 0.006), favoring the total neoadjuvant therapy group. Due to significant heterogeneity in the study protocols, there remains uncertainty on the ideal chemotherapy/radiotherapy sequence.

Conclusions: This study provides supporting evidence on the favorable immediate and intermediate oncological outcomes with the use of total neoadjuvant therapy for locally advanced rectal cancer.
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http://dx.doi.org/10.1245/s10434-021-09837-8DOI Listing
April 2021

Immunohistochemical evaluation of the prognostic and predictive power of epidermal growth factor receptor ligand levels in patients with metastatic colorectal cancer.

Growth Factors 2021 Mar 27:1-10. Epub 2021 Mar 27.

Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

For patients with metastatic colorectal cancer (mCRC), epidermal growth factor receptor (EGFR) inhibitors are limited to patients with wild-type tumours. Not all patients will benefit from treatment and better predictive biomarkers are needed. Here we investigated the prognostic and predictive impact of the EGFR ligands amphiregulin (AREG) and epiregulin (EREG). Expression levels were assessed by immunohistochemistry on 99 wild-type tumours. AREG and EREG positivity was seen in 49% and 50% of cases, respectively. No difference in expression was observed by primary tumour side. There was no significant difference in OS by AREG or EREG expression. In the subset of patients who received an EGFR inhibitor, EREG positivity was associated with longer OS (median 34.0 vs. 27.0 months,  = 0.033), driven by a difference in patients with a left-sided primary (HR 0.37,  = 0.015). Our study supports further investigation into EREG as a predictive biomarker in mCRC.
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http://dx.doi.org/10.1080/08977194.2021.1878166DOI Listing
March 2021

BRAFV600E Mutations Arising from a Left-Side Primary in Metastatic Colorectal Cancer: Are They a Distinct Subset?

Target Oncol 2021 03 18;16(2):227-236. Epub 2021 Feb 18.

The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

Background: B-Raf proto-oncogene (BRAF)-V600E mutations (BRAFmt) in colorectal cancer (CRC) predominantly occur in right-side (RS) primaries. In metastatic CRC (mCRC), there is substantial overlap between the reported features of BRAFmt and of an RS primary.

Objectives: To explore the significance of BRAFmt in a left-side (LS) primary, we analysed data from a multi-site mCRC registry. Tumours distal to the splenic flexure were considered LS.

Results: Of 3380 patients enrolled from June 2009 to June 2020, 214 (13%) of 1657 with known status were BRAFmt: 127 (24%) of 524 RS and 87 (8%) of 1133 LS. LS versus RS BRAFmt were younger (mean 59.5 vs. 65.1 years; p = 0.01), whereas sex (48 vs. 59% female; p = 0.13), mismatch repair-deficiency (dMMR) (16 vs. 21%; p = 0.47), and overall survival (OS) (median 15.1 vs. 17.7 months; p = 0.98) were similar. LS BRAFmt versus LS BRAF wildtype (wt) were of similar age (59.5 vs. 61.3 years; p = 0.28) with more females (48 vs. 37%; p = 0.04), more dMMR (16 vs. 1%; p < 0.0001), and inferior OS (median 15.1 vs. 36.6 months; p < 0.0001). Initial treatment with chemotherapy plus an epidermal growth factor receptor inhibitor produced median progression-free survival (PFS) of 4.3 versus 12.3 months (p = 0.20) for LS BRAFmt (n = 9) versus LS BRAFwt (n = 104). Initial chemotherapy and bevacizumab produced a median PFS of 7.6 versus 11.6 months (p = 0.02) for LS BRAFmt (n = 36) versus LS BRAFwt (n = 438), respectively.

Conclusion: LS BRAFmt cancers share many features with RS BRAFmt cancers, including poor survival outcomes. Mature data on the activity of BRAF-targeted therapies in the first-line setting are eagerly awaited.
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http://dx.doi.org/10.1007/s11523-021-00793-7DOI Listing
March 2021

ctDNA and Adjuvant Therapy for Colorectal Cancer: Time to Re-Invent Our Treatment Paradigm.

Cancers (Basel) 2021 Jan 19;13(2). Epub 2021 Jan 19.

Peter MacCallum Cancer Centre, Department of Medical Oncology, Melbourne, VIC 3000, Australia.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. While there have been significant developments in the treatments for patients with metastatic CRC in recent years, improving outcomes in the adjuvant setting has been more challenging. Recent technological advances in circulating tumour DNA (ctDNA) assay with the ability to detect minimal residual disease (MRD) after curative intent surgery will fundamentally change how we assess recurrence risk and conduct adjuvant trials. Studies in non-metastatic CRC have now demonstrated the prognostic impact of ctDNA analysis after curative intent surgery over and above current standard of care clinicopathological criteria. This ability of ctDNA analysis to stratify patients into low- and very-high-risk groups provides a window of opportunity to personalise adjuvant treatment where escalation/de-escalation of adjuvant systemic therapy could potentially increase cure rates and also reduce treatment-related physical and financial toxicity. Emerging data suggest that conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy may reflect treatment efficacy. This real-time assessment of treatment benefit could be used as a surrogate endpoint for adjuvant novel drug development. Several ctDNA-based randomized adjuvant trials are ongoing internationally to confirm the clinical utility of ctDNA in colorectal cancer.
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http://dx.doi.org/10.3390/cancers13020346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832902PMC
January 2021

Towards Routine Implementation of Liquid Biopsies in Cancer Management: It Is Always Too Early, until Suddenly It Is Too Late.

Diagnostics (Basel) 2021 Jan 11;11(1). Epub 2021 Jan 11.

Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne Centre for Cancer Research, Parkville, VIC 3000, Australia.

Blood-based liquid biopsies are considered a new and promising diagnostic and monitoring tool for cancer. As liquid biopsies only require a blood draw, they are non-invasive, potentially more rapid and assumed to be a less costly alternative to genomic analysis of tissue biopsies. A multi-disciplinary workshop ( = 98 registrations) was organized to discuss routine implementation of liquid biopsies in cancer management. Real-time polls were used to engage with experts' about the current evidence of clinical utility and the barriers to implementation of liquid biopsies. Clinical, laboratory and health economics presentations were given to illustrate the opportunities and current levels of evidence, followed by three moderated break-out sessions to discuss applications. The workshop concluded that tumor-informed assays using next-generation sequencing (NGS) or PCR-based genotyping assays will most likely provide better clinical utility than tumor-agnostic assays, yet at a higher cost. For routine application, it will be essential to determine clinical utility, to define the minimum quality standards and performance of testing platforms and to ensure their use is integrated into current clinical workflows including how they complement tissue biopsies and imaging. Early health economic models may help identifying the most viable application of liquid biopsies. Alternative funding models for the translation of complex molecular diagnostics, such as liquid biopsies, may also be explored if clinical utility has been demonstrated and when their use is recommended in multi-disciplinary consensus guidelines.
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http://dx.doi.org/10.3390/diagnostics11010103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826562PMC
January 2021

Characteristics and outcomes of participants in colorectal cancer biomarker trials versus a real-world cohort.

Acta Oncol 2021 Apr 30;60(4):482-490. Epub 2020 Dec 30.

Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.

Background: The restrictive eligibility criteria of therapy-focused cancer clinical trials can limit the external validity of the results. The characteristics and survival outcomes of patients enrolled in stand-alone biomarker studies have yet to be explored. We examined the characteristics of patients enrolled in a series of biomarker studies in stage II and III colorectal cancer (CRC) and of the broader patient population from which the study cohorts were recruited.

Material And Methods: We examined three distinct trial scenarios: a retrospective cohort study (RCS) where archival tissue samples were analyzed, a prospective observational study (POS) where blood samples were collected but patients received standard treatment and a randomized clinical trial (RCT) where biomarker analysis could inform clinical care. Clinical data for each study time period were extracted from a prospective registry.

Results: For all CRC patients ( = 4033) in this study, the median age was 70 years and 54% were ECOG 0. For patients in the RCS ( = 450), POS ( = 284) and RCT ( = 230), the median age was 72, 65 and 64 years, with 45%, 74% and 79% being ECOG 0. For the POS and RCT, 33% and 36% of all patients with the relevant disease stage were enrolled over the study recruitment period. Survival outcomes were similar for patients in the RCS and POS. RCT outcome data are not available.

Conclusion: As for therapy-based trials, enrollment in prospective biomarker studies may be selective, despite relatively broad eligibility criteria. Characteristics and recruitment were similar for POS and RCT patients, indicating study complexity may not necessarily limit patient recruitment. For the prospective biomarker study cohorts examined, the selective recruitment did not significantly impact survival outcomes, suggesting potential for high external validity.
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http://dx.doi.org/10.1080/0284186X.2020.1862907DOI Listing
April 2021

Circulating Tumour DNA to Guide Treatment of Gastrointestinal Malignancies.

Visc Med 2020 Oct 18;36(5):388-396. Epub 2020 Sep 18.

Division of Systems Biology and Personalised Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

Background: Gastrointestinal cancers are among the most common cancers worldwide and account for a high proportion of cancer-related mortality. Advancements to improve outcomes are constrained by the lack of biomarkers that can offer early diagnostic and prognostic information as traditional serological tumour markers and conventional imaging approaches are not able to provide early information regarding disease recurrence and treatment outcomes. Recent advances in technology have allowed the detection of circulating tumour DNA (ctDNA) in plasma, nucleic acid fragments released into the circulation from primary or metastatic lesions undergoing apoptosis and necrosis. A growing body of evidence has emerged supporting the use of ctDNA in many aspects of cancer care.

Summary: This review focuses on the potential role of ctDNA in the management of patients with gastrointestinal cancers including colorectal, pancreatic, and upper gastrointestinal cancers. In this review, we discuss its possible utility in screening, detection of minimal residual disease and prognostication, longitudinal surveillance, and identification of therapeutic targets and resistance incorporating recent literature and ongoing randomised clinical trials.

Key Messages: ctDNA has substantial potential as a clinically useful marker in the management of gastrointestinal cancers from cancer screening through to treatment of advanced disease.
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http://dx.doi.org/10.1159/000509657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590785PMC
October 2020

Safety and efficacy of AMG 820, an anti-colony-stimulating factor 1 receptor antibody, in combination with pembrolizumab in adults with advanced solid tumors.

J Immunother Cancer 2020 10;8(2)

Clinical Research, South Texas Accelerated Research Therapeutics (START), San Antonio, Texas, USA

Background: To determine the safety and efficacy of the anti-colony-stimulating factor 1 receptor (anti-CSF1R) monoclonal antibody AMG 820 in combination with pembrolizumab in patients with select solid tumors.

Patients And Methods: Patients had advanced, refractory mismatch repair-proficient colorectal cancer, pancreatic cancer, or non-small cell lung cancer (NSCLC) with low (<50%) programmed cell death-ligand 1 (PD-L1) expression and were naïve to anti-programmed cell death-1 (PD-1)/PD-L1 or had relapsed/refractory NSCLC after anti-PD-1/PD-L1 treatment with low or high (≥50%) PD-L1 expression; all were anti-CSF1/CSF1R naïve. Patients received 1100 mg or 1400 mg AMG 820 plus 200 mg pembrolizumab intravenously every 3 weeks. The primary endpoints were incidence of dose-limiting toxicities (DLTs) and adverse events (AEs) and objective response rate per immune-related Response Evaluation Criteria in Solid Tumours at the recommended combination dose.

Results: Overall, 116 patients received ≥1 dose of AMG 820 plus pembrolizumab (18 at 1400 mg AMG 820; 98 at 1100 mg AMG 820). Most patients (64%) were male; the median age was 64 (range 30-86) years. Seven patients had DLTs (1 at 1400 mg AMG 820; 6 at 1100 mg AMG 820). Almost all patients (99.1%) had AEs, 87.9% with grade ≥3 AEs. The most common AEs were increased aspartate aminotransferase (59.5%), fatigue (48.3%), periorbital/face edema (48.3%), and rash/maculopapular rash (37.1%). The best response was immune-related partial response in 3 patients (3%; duration of response 9.2, 10.0, 12.5 months) and immune-related stable disease in 39 patients (34%). None of the completed phase II cohorts met the predefined threshold for efficacy. Post-treatment there was accumulation of serum colony-stimulating factor 1 (CSF1) and interleukin-34, reduction in CSF1-dependent CD16-expressing monocytes, and increased PD-L1 expression and CD4 and CD8 cell numbers in tumor biopsies.

Conclusions: The recommended combination dose of 1100 mg AMG 820 plus 200 mg pembrolizumab had an acceptable safety profile. Although pharmacodynamic effects were observed, antitumor activity was insufficient for further evaluation of this combination in selected patient populations.

Trial Registration Number: NCT02713529.
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http://dx.doi.org/10.1136/jitc-2020-001006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552843PMC
October 2020

Prognostic significance of postsurgery circulating tumor DNA in nonmetastatic colorectal cancer: Individual patient pooled analysis of three cohort studies.

Int J Cancer 2021 Feb 6;148(4):1014-1026. Epub 2020 Oct 6.

Division of Personalised Oncology, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.

Studies in multiple solid tumor types have demonstrated the prognostic significance of ctDNA analysis after curative intent surgery. A combined analysis of data across completed studies could further our understanding of circulating tumor DNA (ctDNA) as a prognostic marker and inform future trial design. We combined individual patient data from three independent cohort studies of nonmetastatic colorectal cancer (CRC). Plasma samples were collected 4 to 10 weeks after surgery. Mutations in ctDNA were assayed using a massively parallel sequencing technique called SafeSeqS. We analyzed 485 CRC patients (230 Stage II colon, 96 Stage III colon, and 159 locally advanced rectum). ctDNA was detected after surgery in 59 (12%) patients overall (11.0%, 12.5% and 13.8% for samples taken at 4-6, 6-8 and 8-10 weeks; P = .740). ctDNA detection was associated with poorer 5-year recurrence-free (38.6% vs 85.5%; P < .001) and overall survival (64.6% vs 89.4%; P < .001). The predictive accuracy of postsurgery ctDNA for recurrence was higher than that of individual clinicopathologic risk features. Recurrence risk increased exponentially with increasing ctDNA mutant allele frequency (MAF) (hazard ratio, 1.2, 2.5 and 5.8 for MAF of 0.1%, 0.5% and 1%). Postsurgery ctDNA was detected in 3 of 20 (15%) patients with locoregional and 27 of 60 (45%) with distant recurrence (P = .018). This analysis demonstrates a consistent long-term impact of ctDNA as a prognostic marker across nonmetastatic CRC, where ctDNA outperforms other clinicopathologic risk factors and MAF further stratifies recurrence risk. ctDNA is a better predictor of distant vs locoregional recurrence.
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http://dx.doi.org/10.1002/ijc.33312DOI Listing
February 2021

CD8 tumor-infiltrating lymphocytes within the primary tumor of patients with synchronous metastatic colorectal carcinoma do not track with survival.

Clin Transl Immunology 2020 17;9(7):e1155. Epub 2020 Jul 17.

Peter MacCallum Cancer Centre Melbourne VIC Australia.

Objectives: Tumor-infiltrating lymphocytes (TIL), particularly CD8 TILs in patients with colorectal cancer (CRC), are highly prognostic in the early-disease stages (I-II). In metastatic disease (stage IV; mCRC), their influence is less well defined. It has presumably failed to contain tumor cells to the primary site; however, is this evident? We explored the prognostic impact of TILs at the primary site in patients who presented with mCRC.

Methods: Treatment-naïve patients (109) with mCRC were assessed for CD8 TILs and PD-L1 expression. Microsatellite instability (MSI) was evaluated by IHC for PMS2 and MSH6 proteins and/or by PCR using the Bethesda panel.

Results: Microsatellite instability-high tumors had significantly more CD8 TILs, with no significant survival advantage observed between MSI-H and microsatellite stable (MSS) tumors (12 vs 19 months,  = 0.304). TIL density for all cases had no impact on OS (low: 20 vs high: 13 months,  = 0.426), while PD-L1 of 1% or higher was associated with reduced mean survival (9.6 vs 18.9 months;  = 0.038). MSI-H tumors and associated immune cells had higher PD-L1 expression than in MSS cases. A positive correlation between PD-L1 on immune cells and CD8+ve TILs was found. A subset of MSS tumors had relatively high TILs approximating that of MSI-H tumors.

Conclusion: In contrast to early-stage CRC, the immune response in primary tumors of patients with mCRC does not appear to influence survival. A subgroup of MSS tumors was identified with increased TILs/PD-L1 comparable to MSI-H tumors, traditionally not be considered for immune checkpoint blockade and perhaps should be.
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http://dx.doi.org/10.1002/cti2.1155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484874PMC
July 2020

Real-World Treatment and Outcomes of Metastatic Colorectal Cancer Patients With a Poor or Very Poor Performance Status.

Clin Colorectal Cancer 2021 Mar 12;20(1):e21-e34. Epub 2020 Aug 12.

Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Western Health, Footscray, Australia.

Background: The management of metastatic colorectal cancer patients with a poor performance status (PS) continues to be a clinical dilemma, with the potential activity and safety of treating this population remaining poorly understood. Few of these patients are enrolled onto clinical trials, and poor PS is often multifactorial.

Patients And Methods: We analyzed the Treatment of Recurrent and Advanced Colorectal Cancer registry to describe treatment practices and outcomes in poor (Eastern Cooperative Oncology Group [ECOG] PS 2) and very poor PS (ECOG PS > 2) patients to explore the relationship between age, tumor burden, comorbidities, and PS, and to evaluate the benefit of systemic therapy. Standard descriptive statistical methods, Kaplan-Meier analysis, and a multivariate Cox regression model were used.

Results: Of 2769 registry patients (diagnosed January 2009 to June 2018), 329 (12%) and 182 (7%) patients had a poor and very poor PS, respectively. Good PS patients were more likely to receive systemic therapy than poor and very poor PS patients (85%, 55%, and 21.5%, P < .0001), but clinician assessed response was observed in all subsets (53%, 41%, and 29%, P = .0003). Treatment with chemotherapy was associated with longer median overall survival across PS groups. Exploratory analysis based on comorbidity score and tumor burden subgroups demonstrated a consistently positive overall survival association with treatment. Benefit was observed where poor overall survival was attributable to medical comorbidities and to tumor burden.

Conclusion: In routine clinical care, a substantial proportion of poor and very poor PS patients receive active treatment, which is often associated with meaningful clinical benefit.
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http://dx.doi.org/10.1016/j.clcc.2020.08.002DOI Listing
March 2021

Real world outcomes for neoadjuvant capecitabine versus infusional 5-fluorouracil in the treatment of locally advanced rectal cancer.

Intern Med J 2020 Sep 8. Epub 2020 Sep 8.

Division of Personalised Oncology, Walter and Eliza Hall, Parkville, Victoria, Australia.

Background: Neoadjuvant chemoradiation therapy (CRT) is standard of care treatment for locally advanced rectal cancer (LARC). A pathologic complete response (pCR) following CRT is an early indicator of treatment benefit and associated with excellent survival outcomes. As capecitabine replaces infusional 5-fluorouracil (5-FU) as the fluoropyrimidine of choice in routine care of LARC, on the back of clinical trial data demonstrating equivalence, it is important to confirm that efficacy is maintained in the real-world setting.

Methods: We analysed data from a prospectively maintained colorectal cancer database at 3 Australian hospitals including patients diagnosed January 2009 to December 2018. Pathological response was determined as either complete or incomplete and compared for patients receiving 5FU or capecitabine.

Results: 657 patients were analysed, 498 receiving infusional 5-FU and 159 capecitabine. Capecitabine use has markedly increased from approval in 2014 in Australia, now being used in more than 80% of patients. Patient characteristics were similar by treatment, including age, tumour location and pre-treatment stage. pCR was reported in 22/159 (13.8%) of capecitabine treated patients and 118/380 (23.7%) that received 5-FU (p = <0.01). More capecitabine-treated patients received post-operative oxaliplatin (44.2% vs 6.3%, p < 0.01). Two-year progression free survival was similar (84.9% vs 88.0%, p = 0.34).

Conclusion: Capecitabine is now the dominantly used neoadjuvant chemotherapy in LARC. Capecitabine use was associated with a lower rate of pCR versus infusional 5-FU, a difference not explained by examined patient or tumour characteristics. Poor treatment compliance with oral therapy in the real-world setting is one possible explanation. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.15045DOI Listing
September 2020

Metastasectomy and BRAF mutation; an analysis of survival outcome in metastatic colorectal cancer.

Curr Probl Cancer 2021 Feb 14;45(1):100637. Epub 2020 Aug 14.

Department of Medical Oncology, The Canberra Hospital, Garran, ACT, Australia; ANU Medical School, Australian National University, Australia.

Background: Resection of oligometastases improves survival in metastatic colorectal cancer (mCRC). It is unclear whether the benefit is consistent for BRAF V600E mutant (MT) and wild type (WT) mCRC. This retrospective analysis explores the influence of BRAF MT on survival after metastasectomy.

Methods: Overall survival (OS) and recurrence-free survival (RFS) for BRAF MT and WT mCRC were evaluated. Survival was also analyzed in the cohort of BRAF MT with or without metastasectomy.

Results: Five hundred and thirteen patients who had undergone metastasectomy were identified, 6% were BRAF-MT. Median age 63. Median OS in BRAF MT vs WT: 25.7 vs 48.5 months (hazard ratio [HR] 1.95; 1.18-3.22). However, difference was not significant in a multivariate model. Right primary tumor, intact primary, >1 metastatic site, non-R0 resection, peritoneal metastasis, and synchronous metastasis were independent predictors of worse OS. Among 364 patients with RFS data there was no difference between BRAF MT and WT (16 vs 19 months, p=0.09). In another cohort of 158 BRAF-MT patients, OS was significantly better after metastasectomy compared to "no metastasectomy" (HR 0.34; 0.18-0.65, P= 0.001). Proficient mismatch repair status showed a trend toward worse survival after metastasectomy in BRAF MT (HR 1.71, P = 0.08).

Conclusion: OS did not differ after metastasectomy between BRAF MT and WT in a multivariate model. Median OS was >2 years in this study after metastasectomy among BRAFV600E MT patients suggesting a survival benefit of metastasectomy in this group where systemic therapeutic options are limited. Metastasectomy may be considered in carefully selected BRAF-MT patients.
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http://dx.doi.org/10.1016/j.currproblcancer.2020.100637DOI Listing
February 2021

Simulating Progression-Free and Overall Survival for First-Line Doublet Chemotherapy With or Without Bevacizumab in Metastatic Colorectal Cancer Patients Based on Real-World Registry Data.

Pharmacoeconomics 2020 11;38(11):1263-1275

Health Technology and Services Research Department, Faculty of Behavioural, Management and Social Sciences, Technical Medical Centre, University of Twente, Enschede, The Netherlands.

Background: Simulation models utilizing real-world data have potential to optimize treatment sequencing strategies for specific patient subpopulations, including when conducting clinical trials is not feasible. We aimed to develop a simulation model to estimate progression-free survival (PFS) and overall survival for first-line doublet chemotherapy with or without bevacizumab for specific subgroups of metastatic colorectal cancer (mCRC) patients based on registry data.

Methods: Data from 867 patients were used to develop two survival models and one logistic regression model that populated a discrete event simulation (DES). Discrimination and calibration were used for internal validation of these models separately and predicted and observed medians and Kaplan-Meier plots were compared for the integrated DES. Bootstrapping was performed to correct for optimism in the internal validation and to generate correlated sets of model parameters for use in a probabilistic analysis to reflect parameter uncertainty.

Results: The survival models showed good calibration based on the regression slopes and modified Hosmer-Lemeshow statistics at 1 and 2 years, but not for short-term predictions at 0.5 years. Modified C-statistics indicated acceptable discrimination. The simulation estimated that median first-line PFS (95% confidence interval) of 219 (25%) patients could be improved from 175 days (156-199) to 269 days (246-294) if treatment would be targeted based on the highest expected PFS.

Conclusions: Extensive internal validation showed that DES accurately estimated the outcomes of treatment combination strategies for specific subpopulations, with outcomes suggesting treatment could be optimized. Although results based on real-world data are informative, they cannot replace randomized trials.
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http://dx.doi.org/10.1007/s40273-020-00951-1DOI Listing
November 2020

Effect of Aspirin on Cancer Incidence and Mortality in Older Adults.

J Natl Cancer Inst 2021 Mar;113(3):258-265

Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Background: ASPirin in Reducing Events in the Elderly, a randomized, double-blind, placebo-controlled trial of daily low-dose aspirin (100 mg) in older adults, showed an increase in all-cause mortality, primarily due to cancer. In contrast, prior randomized controlled trials, mainly involving younger individuals, demonstrated a delayed cancer benefit with aspirin. We now report a detailed analysis of cancer incidence and mortality.

Methods: 19 114 Australian and US community-dwelling participants aged 70 years and older (US minorities 65 years and older) without cardiovascular disease, dementia, or physical disability were randomly assigned and followed for a median of 4.7 years. Fatal and nonfatal cancer events, a prespecified secondary endpoint, were adjudicated based on clinical records.

Results: 981 cancer events occurred in the aspirin and 952 in the placebo groups. There was no statistically significant difference between groups for all incident cancers (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 0.95 to 1.14), hematological cancer (HR = 0.98, 95% CI = 0.73 to 1.30), or all solid cancers (HR = 1.05, 95% CI = 0.95 to 1.15), including by specific tumor type. However, aspirin was associated with an increased risk of incident cancer that had metastasized (HR = 1.19, 95% CI = 1.00 to 1.43) or was stage 4 at diagnosis (HR = 1.22, 95% CI = 1.02 to 1.45), and with higher risk of death for cancers that presented at stages 3 (HR = 2.11, 95% CI = 1.03 to 4.33) or 4 (HR = 1.31, 95% CI = 1.04 to 1.64).

Conclusions: In older adults, aspirin treatment had an adverse effect on later stages of cancer evolution. These findings suggest that in older persons, aspirin may accelerate the progression of cancer and, thus, suggest caution with its use in this age group.
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http://dx.doi.org/10.1093/jnci/djaa114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936068PMC
March 2021

Medium-throughput Drug Screening of Patient-derived Organoids from Colorectal Peritoneal Metastases to Direct Personalized Therapy.

Clin Cancer Res 2020 07 6;26(14):3662-3670. Epub 2020 May 6.

Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

Purpose: Patients with colorectal cancer with peritoneal metastases (CRPMs) have limited treatment options and the lowest colorectal cancer survival rates. We aimed to determine whether organoid testing could help guide precision treatment for patients with CRPMs, as the clinical utility of prospective, functional drug screening including nonstandard agents is unknown.

Experimental Design: CRPM organoids (peritonoids) isolated from patients underwent parallel next-generation sequencing and medium-throughput drug panel testing to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing.

Results: Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for two patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications.

Conclusions: Our approach is feasible, reproducible, and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0073DOI Listing
July 2020

Circulating Tumor DNA as a Prognostic Marker in Stage III Colon Cancer-Reply.

JAMA Oncol 2020 06;6(6):932-933

Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1001/jamaoncol.2020.0289DOI Listing
June 2020

Redefining Colorectal Cancer by Tumor Biology.

Am Soc Clin Oncol Educ Book 2020 Mar;40:1-13

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Colorectal cancer treatment has undergone a paradigm shift. We no longer see this disease as a singular, anatomic tumor type but rather a set of disease subgroups. Largely because of a better understanding of cancer biology and the introduction and integration of molecular biomarkers-the premise of precision therapy-we are beginning to direct treatments toward the right tumor target(s) in the right patients. The field of molecular profiling is continually evolving, and new biomarkers are constantly being discovered that have investigational, therapeutic, and/or prognostic implications-negative or positive. To date, only a few biomarkers have sufficient actionable, clinical implication to earn international guideline-recommended routine testing. Hence, it is vital that the treating oncologist should know which biomarkers to assess, when in the treatment course to test for them, and how the test is to be done. Correct interpretation of profiling results is imperative. Herein, we focus on international guideline-recommended mutation testing for patients prior to their colorectal cancer treatment initiation. The clinical applications of circulating tumor DNA (ctDNA) in patients with metastatic disease, based on our current knowledge and capabilities, are also addressed.
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http://dx.doi.org/10.1200/EDBK_279867DOI Listing
March 2020

Assessing aneuploidy with repetitive element sequencing.

Proc Natl Acad Sci U S A 2020 03 19;117(9):4858-4863. Epub 2020 Feb 19.

Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287;

We report a sensitive PCR-based assay called Repetitive Element AneupLoidy Sequencing System (RealSeqS) that can detect aneuploidy in samples containing as little as 3 pg of DNA. Using a single primer pair, we amplified ∼350,000 amplicons distributed throughout the genome. Aneuploidy was detected in 49% of liquid biopsies from a total of 883 nonmetastatic, clinically detected cancers of the colorectum, esophagus, liver, lung, ovary, pancreas, breast, or stomach. Combining aneuploidy with somatic mutation detection and eight standard protein biomarkers yielded a median sensitivity of 80% in these eight cancer types, while only 1% of 812 healthy controls scored positive.
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http://dx.doi.org/10.1073/pnas.1910041117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060727PMC
March 2020

Circulating tumour DNA in early stage colorectal cancer: can blood tell all?

Ann Transl Med 2019 Dec;7(Suppl 8):S358

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.21037/atm.2019.09.55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976399PMC
December 2019

Epidermal growth factor receptor ligands: targets for optimizing treatment of metastatic colorectal cancer.

Growth Factors 2019 12 26;37(5-6):209-225. Epub 2019 Dec 26.

Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.

The discovery of epidermal growth factor (EGF) and its receptor (EGFR) revealed the connection between EGF-like ligands, signaling from the EGFR family members and cancer. Over the next fifty years, analysis of EGFR expression and mutation led to the use of monoclonal antibodies to target EGFR in the treatment of metastatic colorectal cancer (mCRC) and this treatment has improved outcomes for patients. The use of the oncogene mutational status has helped to refine patient selection for EGFR antibody therapy, but an effective molecular predictor of likely responders is lacking. This review analyzes the potential utility of measuring the expression, levels and activation of EGF-like ligands and associated processes as prognostic or predictive markers for the identification of patient risk and more effective mCRC therapies.
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http://dx.doi.org/10.1080/08977194.2019.1703702DOI Listing
December 2019

Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer.

JAMA Oncol 2019 Dec;5(12):1710-1717

Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.

Importance: Adjuvant chemotherapy in patients with stage III colon cancer prevents recurrence by eradicating minimal residual disease. However, which patients remain at high risk of recurrence after completing standard adjuvant treatment cannot currently be determined. Postsurgical circulating tumor DNA (ctDNA) analysis can detect minimal residual disease and is associated with recurrence in colorectal cancers.

Objective: To determine whether serial postsurgical and postchemotherapy ctDNA analysis could provide a real-time indication of adjuvant therapy efficacy in stage III colon cancer.

Design, Setting, And Participants: This multicenter, Australian, population-based cohort biomarker study recruited 100 consecutive patients with newly diagnosed stage III colon cancer planned for 24 weeks of adjuvant chemotherapy from November 1, 2014, through May 31, 2017. Patients with another malignant neoplasm diagnosed within the last 3 years were excluded. Median duration of follow-up was 28.9 months (range, 11.6-46.4 months). Physicians were blinded to ctDNA results. Data were analyzed from December 10, 2018, through June 23, 2019.

Exposures: Serial plasma samples were collected after surgery and after chemotherapy. Somatic mutations in individual patients' tumors were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. Personalized assays were designed to quantify ctDNA.

Main Outcomes And Measures: Detection of ctDNA and recurrence-free interval (RFI).

Results: After 4 exclusions, 96 eligible patients were eligible; median patient age was 64 years (range, 26-82 years); 49 (51%) were men. At least 1 somatic mutation was identified in the tumor tissue of all 96 evaluable patients. Circulating tumor DNA was detectable in 20 of 96 (21%) postsurgical samples and was associated with inferior recurrence-free survival (hazard ratio [HR], 3.8; 95% CI, 2.4-21.0; P < .001). Circulating tumor DNA was detectable in 15 of 88 (17%) postchemotherapy samples. The estimated 3-year RFI was 30% when ctDNA was detectable after chemotherapy and 77% when ctDNA was undetectable (HR, 6.8; 95% CI, 11.0-157.0; P < .001). Postsurgical ctDNA status remained independently associated with RFI after adjusting for known clinicopathologic risk factors (HR, 7.5; 95% CI, 3.5-16.1; P < .001).

Conclusions And Relevance: Results suggest that ctDNA analysis after surgery is a promising prognostic marker in stage III colon cancer. Postchemotherapy ctDNA analysis may define a patient subset that remains at high risk of recurrence despite completing standard adjuvant treatment. This high-risk population presents a unique opportunity to explore additional therapeutic approaches.
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http://dx.doi.org/10.1001/jamaoncol.2019.3616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802034PMC
December 2019

Evolution of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases: 8-Year Single-Institutional Experience.

Dis Colon Rectum 2019 10;62(10):1195-1203

Peter MacCallum Cancer Centre, Department of Surgical Oncology, Melbourne, Victoria, Australia.

Background: Colorectal cancer is the second leading cause of cancer-related mortality worldwide. Peritoneal metastases carry the worst prognosis among all sites of colorectal cancer metastases. In recent years, the advent and acceptance of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have greatly improved survival for selected patients with low-volume peritoneal metastases.

Objective: Here, we report the evolution of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases at a statewide tertiary referral center over an 8-year period.

Design: This is a retrospective study from 2009 to 2017.

Setting: The study was conducted at a single center over 8 years.

Patients: Patients with colorectal peritoneal metastases undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy were included.

Main Outcomes: Main outcomes included evaluation of grade III/IV morbidity rate, mortality rate, overall and relapse-free survival, and prognostic factors influencing survival on a Cox multivariate analysis model.

Results: One hundred one cytoreductive surgeries were undertaken on 96 patients during this time for colorectal peritoneal metastases. The median patient age was 60 years with 55.2% being female. The median Peritoneal Carcinomatosis Index was 9, with complete cytoreduction achieved in 76 (75.2%) cases. Grade III or IV complications occurred in 26 cases (25.7%) with 2 (2%) perioperative mortalities. Median overall survival for the entire cohort was 32 months, with a 3-year survival of 38%. For patients who achieved a complete cytoreduction, median overall survival was 37 months, with a relapse-free survival of 13 months and a 3-year survival of 54%. Complete cytoreduction and nonmucinous histology were key factors independently associated with improved overall survival.

Limitations: The main limitation this study is its retrospective nature.

Conclusion: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for isolated low-volume colorectal peritoneal metastases is safe and effective, with low morbidity. It offers selected patients a highly favorable overall and relapse-free survival. See Video Abstract at http://links.lww.com/DCR/B2. EVOLUCIÓN DE LA CIRUGÍA CITORREDUCTIVA Y QUIMIOTERAPIA INTRAPERITONEAL HIPERTÉRMICA (HIPEC) PARA METÁSTASIS PERITONEALES COLORRECTALES: EXPERIENCIA INSTITUCIONAL DE 8 AÑOS: El cáncer colorrectal es la segunda causa de mortalidad relacionada con el cáncer en todo el mundo. Las metástasis peritoneales tienen el peor pronóstico entre todos los sitios de metástasis del cáncer colorrectal. En los últimos años, el advenimiento y la aceptación de la cirugía citorreductiva y la quimioterapia intraperitoneal hipertérmica ha mejorado enormemente la supervivencia de pacientes seleccionados con metástasis peritoneales de bajo volumen.

Objetivo: Aquí, informamos sobre la evolución de la cirugía citorreductiva y la quimioterapia intraperitoneal hipertérmica para las metástasis peritoneales colorrectales en un centro de referencia terciario para todo el estado durante un período de ocho años. DISEÑO:: Estudio retrospectivo del 2009 a 2017. CONFIGURACIÓN:: Centro único a lo largo de ocho años.

Pacientes: Pacientes con metástasis peritoneales colorrectales sometidos a cirugía citorreductiva y quimioterapia intraperitoneal hipertérmica.

Resultados Principales: Los resultados principales incluyeron la evaluación de la tasa de morbilidad de grado III / IV, la tasa de mortalidad, la supervivencia general y libre de recaída y los factores pronósticos que influyen en la supervivencia en el modelo de análisis multivariado Cox.

Resultados: Se realizaron el ciento uno cirugías citorreductivas en noventa y seis pacientes durante este tiempo por metástasis peritoneales colorrectales. La edad media de los pacientes fue de 60 años, con un 55.2% de mujeres. El Índice de Carcinomatosis Peritoneal mediano fue de 9, con una citorreducción completa lograda en 76 (75.2%) casos. Las complicaciones de grado III o IV ocurrieron en 26 casos (25.7%) con dos (2%) de mortalidad perioperatoria. La supervivencia mediana general para toda la cohorte fue de 32 meses, con una supervivencia de 3 años del 38%. Para los pacientes que lograron una citorreducción completa, la supervivencia global media fue de 37 meses, con una supervivencia sin recaída de 13 meses y una supervivencia de 3 años del 54%. La citorreducción completa y la histología no mucinosa fueron factores clave asociados de forma independiente con una mejor supervivencia general.

Limitaciones: La principal limitación es la naturaleza retrospectiva del estudio. CONCLUSIÓN:: La cirugía citorreductiva y la quimioterapia intraperitoneal hipertérmica para las metástasis peritoneales colorrectales aisladas de bajo volumen son seguras y eficaces, con baja morbilidad. Ofrece a los pacientes seleccionados una supervivencia global altamente favorable y libre de recaída. Vea el Resumen del video en http://links.lww.com/DCR/B2.
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http://dx.doi.org/10.1097/DCR.0000000000001456DOI Listing
October 2019

Emerging strategies in the initial management of locally advanced rectal cancer.

Future Oncol 2019 Sep 19;15(25):2955-2965. Epub 2019 Aug 19.

Personalised Oncology Division, The Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

The initial management of locally advanced rectal cancer continues to evolve and formulating the ideal treatment plan remains challenging, with a multitude of emerging treatment strategies and either limited or inconsistent data to support these. The main objective of neoadjuvant treatment is to maximize disease control and minimize toxicity and impact on quality of life. Ultimately, the optimal approach needs to be personalized to the individual. In this Review, we discuss the various strategies currently used and being further investigated in the initial treatment of patients presenting with locally advanced rectal cancer. We describe the evidence behind the current standard of care recommendations and emerging new options, as well as potential biomarkers that may assist with further refining treatment selection.
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http://dx.doi.org/10.2217/fon-2018-0941DOI Listing
September 2019

Evaluation of cytoreductive surgery and HIPEC for peritoneal surface malignancies: analysis of 384 consecutive cases.

Langenbecks Arch Surg 2019 Aug 3;404(5):527-539. Epub 2019 Aug 3.

Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.

Background: Peritoneal surface malignancy (PSM) was historically associated with a poor survival. The adoption of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) can now offer patients with PSM a favourable overall survival. Here, we report our single-institute outcomes following CRS and HIPEC for PSM and evaluate changes in our practice over time.

Methods: This is a retrospective review from 2009 to 2018 of all patients undergoing CRS and HIPEC for PSM at a statewide peritoneal disease centre. Cases were divided into the first half and second to compare changes in practice over time.

Results: Three hundred and eighty four CRS and HIPEC cases were performed during this time. The median age was 56 years with 59.6% female. The median peritoneal carcinomatosis index (PCI) was 11, with a reduction in PCI in the second cohort (9 v 15, p < 0.01). Complete cytoreduction rates were significantly higher in the second cohort (82.3% v 67.7%, p < 0.01). Overall, grade III/IV complications occurred in 101 cases (26.3%) with three (0.8%) perioperative mortalities. Median overall survival (OS) for the entire cohort was 85 months, with a 5-year survival of 52%. Median OS was 97 months for PMP, 34 months for colorectal peritoneal metastases and 27 months for other histologies. Completeness of cytoreduction, histology type, and PCI were factors independently associated with overall survival.

Conclusion: CRS and HIPEC can offer highly favourable outcomes for PSM with low morbidity. Successful complete cytoreduction rates improved significantly with greater experience and better patient selection.
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http://dx.doi.org/10.1007/s00423-019-01805-xDOI Listing
August 2019

Clinical Applications of Circulating Tumour DNA in Pancreatic Adenocarcinoma.

J Pers Med 2019 Jul 18;9(3). Epub 2019 Jul 18.

Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville 3050, Australia.

Pancreatic adenocarcinoma remains one of the most aggressive cancers with an ongoing dismal survival rate despite some recent advances in treatment options. This is largely due to the typically late presentation and limited effective therapeutic options in advanced disease. There are numerous circulating biomarkers that have potential clinical application as tumour markers, including circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), cell-free RNA (cfRNA), exosomes and circulating tumour proteins. This review will focus on the development of ctDNA as a non-invasive liquid biopsy, with its high sensitivity and specificity having potential clinical applications in pancreatic cancer. These include a role in screening, prognostication via the detection of minimal residual disease, early detection of recurrence, and for patients with advanced disease; tumour genotyping and monitoring treatment response. Prospective randomised adjuvant clinical trials are currently underway, exploring the impact of ctDNA-guided adjuvant therapy decisions. In this review, we provide perspectives on the current literature and considerations of future directions.
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http://dx.doi.org/10.3390/jpm9030037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789869PMC
July 2019

Outcomes Following Cytoreduction and HIPEC for Pseudomyxoma Peritonei: 10-Year Experience.

J Gastrointest Surg 2020 04 14;24(4):899-906. Epub 2019 May 14.

Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.

Background: Pseudomyxoma peritonei (PMP) is a rare clinical presentation, with considerable morbidity and mortality if left untreated. In recent decades, there is growing acceptance for the use of cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC). The aim of this study was to report on our 10-year single-center experience on outcomes following CRS and HIPEC for PMP of appendiceal origin.

Methods: A retrospective analysis of a prospectively maintained database of all patients undergoing CRS and HIPEC for PMP of appendiceal origin over a 10-year period at a statewide referral center was conducted.

Results: One hundred and seventy-five cytoreductive procedures were undertaken in 140 patients. The mean patient age was 57.4 years, with a female preponderance (56%). The median PCI was 16, with 73.1% of cases having a complete cytoreduction. Grade III/IV complications occurred in 36 (20.6%) cases, with no mortalities. The median overall and disease-free survival was 100 months and 40 months, respectively, with a 71% 5-year survival. High-grade histology was the main factor identified as an independent predictor of worse overall survival.

Conclusion: CRS and HIPEC are safe with acceptable rates of morbidity. It can provide very favorable survival in patients with PMP. High-grade histology is a key prognostic factor associated with a worse overall survival.
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http://dx.doi.org/10.1007/s11605-019-04239-4DOI Listing
April 2020

Prognostic Potential of Circulating Tumor DNA Measurement in Postoperative Surveillance of Nonmetastatic Colorectal Cancer.

JAMA Oncol 2019 Aug;5(8):1118-1123

Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Importance: For patients with resected, nonmetastatic colorectal cancer (CRC), the optimal surveillance protocol remains unclear.

Objective: To evaluate whether serial circulating tumor DNA (ctDNA) levels detected disease recurrence earlier, compared with conventional postoperative surveillance, in patients with resected CRC.

Design, Setting, And Participants: This study included patients (n = 58) with stage I, II, or III CRC who underwent radical surgical resection at 4 Swedish hospitals from February 2, 2007, to May 8, 2013. Eighteen patients received adjuvant chemotherapy at the discretion of their clinicians, who were blinded to the ctDNA results. Blood samples were collected at 1 month after the surgical procedure and every 3 to 6 months thereafter for ctDNA analysis. Patients were followed up until metachronous metastases were detected, or for a median of 49 months. Data analysis was performed from March 1, 2009, to June 23, 2018.

Main Outcomes And Measures: Sensitivity and timing of ctDNA positivity were compared with those of conventional surveillance modalities (computed tomographic scans and serum carcinoembryonic antigen tests) for the detection of disease recurrence.

Results: This study included 319 blood samples from 58 patients, with a median (range) age of 69 (47-83) years and 34 males (59%). The recurrence rate among patients with positive ctDNA levels was 77% (10 of 13 patients). Positive ctDNA preceded radiologic and clinical evidence of recurrence by a median of 3 months. Of the 45 patients with negative ctDNA throughout follow-up, none (0%; 95% CI, 0%-7.9%) experienced a relapse, with a median follow-up of 49 months. However, 3 (6%; 95% CI, 1.3%-17%) of the 48 patients without relapse had a positive ctDNA result, which subsequently fell to undetectable levels during follow-up.

Conclusion And Relevance: Although these findings need to be validated in a larger, prospective trial, they suggest that ctDNA analysis could complement conventional surveillance strategies as a triage test to stratify patients with resected CRC on the basis of risk of disease recurrence.
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http://dx.doi.org/10.1001/jamaoncol.2019.0512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512291PMC
August 2019