Publications by authors named "Timothy Price"

212 Publications

Vigilance for carcinoid heart disease is still required in the era of somatostatin analogues: Lessons from a case series.

Asia Pac J Clin Oncol 2021 Apr 14. Epub 2021 Apr 14.

Department of Endocrine Oncology, University Hospital, Uppsala, Sweden.

Aim: Carcinoid heart disease (CHD) is a well-documented complication of neuroendocrine tumors (NETs) due to secreted hormones causing fibrosis. Somatostatin analogues (SSAs) can decrease hormonal secretion and inhibit tumor growth. The reported incidence of CHD has decreased as SSA use has increased. We describe a series of patients who have developed CHD even though they were treated with SSA therapy.

Methods: Nine patients were seen in four centers in Australia and New Zealand. The average duration of follow-up from diagnosis was 39 months.

Results: Three patients had Grade 1 and six Grade 2 disease by World Health Organization 2010 criteria. All patients had no CHD symptoms at baseline and started SSA therapy soon after diagnosis, yet developed significant, symptomatic cardiac dysfunction in their disease course. The median time from NET diagnosis to SSA initiation was 1 month, and median time from NET diagnosis to CHD diagnosis was 23 months (range 4-52). All patients who were tested had persistently increased hormonal levels (chromogranin A, urinary 5-hydroxyindolacetic acid).

Conclusions: The good symptomatic control afforded by SSAs should not lead to reduced vigilance in screening for CHD, especially in patients with persistently elevated hormonal assays. Clinicians should consider regular echocardiographic screening in patients with a secretory syndrome.
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http://dx.doi.org/10.1111/ajco.13577DOI Listing
April 2021

Real-world management and patient perspectives on QOL with neuroendocrine tumors: An ANZ perspective.

Asia Pac J Clin Oncol 2021 Apr;17 Suppl 2:3-10

NeuroEndocrine Cancer Australia, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/ajco.13587DOI Listing
April 2021

Female breast cancer treatment and survival in South Australia: Results from linked health data.

Eur J Cancer Care (Engl) 2021 Mar 28:e13451. Epub 2021 Mar 28.

Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia.

Objective: We investigated treatment and survival by clinical and sociodemographic characteristics for service evaluation using linked data.

Method: Data on invasive female breast cancers (n = 13,494) from the South Australian Cancer Registry (2000-2014 diagnoses) were linked to hospital inpatient, radiotherapy and universal health insurance data. Treatments ≤12 months from diagnosis and survival were analysed, using adjusted odds ratios (aORs) from logistic regression, and adjusted sub-hazard ratios (aSHRs) from competing risk regression.

Results And Conclusion: Five-year disease-specific survival increased to 91% for 2010-2014. Most women had breast surgery (90%), systemic therapy (72%) and radiotherapy (60%). Less treatment applied for ages 80+ vs <50 years (aOR 0.10, 95% CI 0.05-0.20) and TNM stage IV vs stage I (aOR 0.13, 95% CI 0.08-0.22). Surgical treatment increased during the study period and strongly predicted higher survival. Compared with no surgery, aSHRs were 0.31 (95% CI 0.26-0.36) for women having breast-conserving surgery, 0.49 (95% CI 0.41-0.57) for mastectomy and 0.42 (95% CI 0.33-0.52) when both surgery types were received. Patients aged 80+ years had lower survival and less treatment. More trial evidence is needed to optimise trade-offs between benefits and harms in these older women. Survival differences were not found by residential remoteness and were marginal by socioeconomic status.
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http://dx.doi.org/10.1111/ecc.13451DOI Listing
March 2021

Pharmacogenomics and functional imaging to predict irinotecan pharmacokinetics and pharmacodynamics: the predict IR study.

Cancer Chemother Pharmacol 2021 Mar 23. Epub 2021 Mar 23.

Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, Australia.

Purpose: Irinotecan (IR) displays significant PK/PD variability. This study evaluated functional hepatic imaging (HNI) and extensive pharmacogenomics (PGs) to explore associations with IR PK and PD (toxicity and response).

Methods: Eligible patients (pts) suitable for Irinotecan-based therapy. At baseline: (i) PGs: blood analyzed by the Affymetrix-DMET™-Plus-Array (1936 variants: 1931 single nucleotide polymorphisms [SNPs] and 5 copy number variants in 225 genes, including 47 phase I, 80 phase II enzymes, and membrane transporters) and Sanger sequencing (variants in HNF1A, Topo-1, XRCC1, PARP1, TDP, CDC45L, NKFB1, and MTHFR), (ii) HNI: pts given IV 250 MBq-Tc-IDA, data derived for hepatic extraction/excretion parameters (CL, T, 1hRET, HEF, T). In cycle 1, blood was taken for IR analysis and PK parameters were derived by non-compartmental methods. Associations were evaluated between HNI and PGs, with IR PK, toxicity, objective response rate (ORR) and progression-free survival (PFS).

Results: N = 31 pts. The two most significant associations between PK and PD with gene variants or HNI parameters (P < 0.05) included: (1) PK: SN38-Metabolic Ratio with CL, 1hRET, (2) Grade 3+ diarrhea with SLC22A2 (rs 316019), GSTM5 (rs 1296954), (3) Grade 3+ neutropenia with CL, 1hRET, SLC22A2 (rs 316019), CYP4F2 (rs2074900) (4) ORR with ALDH2 (rs 886205), MTHFR (rs 1801133). (5) PFS with T, XDH (rs 207440), and ABCB11 (rs 4148777).

Conclusions: Exploratory associations were observed between Irinotecan PK/PD with hepatic functional imaging and extensive pharmacogenomics. Further work is required to confirm and validate these findings in a larger cohort of patients.

Australian New Zealand Clinical Trials Registry (anzctr) Number: ACTRN12610000897066, Date registered: 21/10/2010.
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http://dx.doi.org/10.1007/s00280-021-04264-8DOI Listing
March 2021

Exploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia.

Sci Rep 2021 Mar 18;11(1):6353. Epub 2021 Mar 18.

Department of Clinical Neurology and Research, University of Bari, "Pia Fondazione Cardinale G. Panico", Tricase, Lecce, Italy.

Frontotemporal dementia (FTD) refers to a complex spectrum of clinically and genetically heterogeneous disorders. Although fully penetrant mutations in several genes have been identified and can explain the pathogenic mechanisms underlying a great portion of the Mendelian forms of the disease, still a significant number of families and sporadic cases remains genetically unsolved. We performed whole exome sequencing in 100 patients with a late-onset and heterogeneous FTD-like clinical phenotype from Apulia and screened mendelian dementia and neuronal ceroid lipofuscinosis genes. We identified a nonsense mutation in SORL1 VPS domain (p.R744X), in 2 siblings displaying AD with severe language problems and primary progressive aphasia and a near splice-site mutation in CLCN6 (p.S116P) segregating with an heterogeneous phenotype, ranging from behavioural FTD to FTD with memory onset and to the logopenic variant of primary progressive aphasia in one family. Moreover 2 sporadic cases with behavioural FTD carried heterozygous mutations in the CSF1R Tyrosin kinase flanking regions (p.E573K and p.R549H). By contrast, only a minority of patients carried pathogenic C9orf72 repeat expansions (1%) and likely moderately pathogenic variants in GRN (p.C105Y, p.C389fs and p.C139R) (3%). In concert with recent studies, our findings support a common pathogenic mechanisms between FTD and neuronal ceroid lipofuscinosis and suggests that neuronal ceroid lipofuscinosis genes should be investigated also in dementia patients with predominant frontal symptoms and language impairments.
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http://dx.doi.org/10.1038/s41598-021-85494-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973810PMC
March 2021

Immunohistochemistry features and molecular pathology of appendiceal neoplasms.

Crit Rev Clin Lab Sci 2021 Feb 11:1-36. Epub 2021 Feb 11.

Department of Haematology and Oncology, The Queen Elizabeth Hospital, Adelaide, Australia.

Primary appendiceal neoplasms (ANs) comprise a heterogeneous group of tumors. The pathology and classification of ANs have been controversial, and thus, a new classification of these neoplasms was published in the World Health Organization (WHO) classification of tumors (5th edition, 2019). However, immunohistochemistry (IHC) features of epithelial ANs are not explained in this edition and the limited data on the molecular pathology of these tumors shows inconsistent findings in various studies. It would be useful to identify biomarkers appropriate for each subtype to better aid in treatment selection. Therefore, we reviewed the literature to investigate what is known of the molecular pathology and IHC features of the most frequently diagnosed pathological subtypes of epithelial ANs based on the recent classification. The inconsistencies in research findings regarding the IHC features and molecular pathology of ANs could be due to differences in the number of samples and their collection and preparation as well as to the lack of a universally accepted classification system for these neoplasms. However, the literature shows that epithelial ANs typically stain positive for MUC2, CK20, and CDX2 and that the expression of SATB2 protein could be used as a biomarker for appendix tumor origin. Low-grade appendiceal mucinous neoplasms tend to have mutations in and but are usually wild-type for , , and . Conversely, appendiceal adenocarcinomas are frequently found with mutations in , , , , and , and have significant nuclear expression of β-catenin, loss of nuclear or nuclear and cytoplasmic expression of SMAD4, and loss of cytoplasmic membranous expression of E-cadherin. Goblet cell carcinomas (GCCs) typically stain positive for keratin and mucin markers and are frequently mutated in and chromatin-modifier genes, but they tend to be wild-type for , , , and The expression of CK7 and SATB2 proteins is usually negative in appendiceal neuroendocrine neoplasms and they lack the mutations in common cancer-associated genes including , , , and The available data suggest that GCCs have distinct molecular and immunohistochemical features and that they have characteristics more in common with adenocarcinoma than classical neuroendocrine tumors. In addition, MSI does not seem to have a role in the pathogenesis of epithelial ANs because they are rarely detected in these tumors. Finally, hereditary predisposition may have a role in the development of ANs because heterozygous , and germline mutations have recently been identified in low and high grades ANs.
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http://dx.doi.org/10.1080/10408363.2021.1881756DOI Listing
February 2021

Dual Antiangiogenesis Agents Bevacizumab Plus Trebananib, without Chemotherapy, in First-line Treatment of Metastatic Colorectal Cancer: Results of a Phase II Study.

Clin Cancer Res 2021 Apr 29;27(8):2159-2167. Epub 2021 Jan 29.

Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.

Purpose: To assess the efficacy and safety of dual antiangiogenesis agents, bevacizumab plus trebananib, without chemotherapy, in first-line treatment of metastatic colorectal cancer (mCRC).

Patients And Methods: This open-label phase II study enrolled patients with unresectable mCRC with no prior systemic treatment. All patients received bevacizumab 7.5 mg/kg 3-weekly and trebananib 15 mg/kg weekly. The primary endpoint was disease control [stable disease, partial response (PR), or complete response (CR)] at 6 months (DC6m). Secondary endpoints included toxicity, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarkers in plasma angiogenesis-related proteins, tumor gene expression, and plasma antibodies to tumor antigens were examined.

Results: Forty-five patients were enrolled from four Australian sites. DC6m was 63% [95% confidence interval (CI), 47-77]. ORR was 17% (95% CI, 7-32), comprising of seven PRs. Median duration of response was 20 months (range, 10-48 months). Median PFS was 8.4 months and median OS 31.4 months. Grade 1-2 peripheral edema and joint-related symptoms were common. Overall incidence of grade 3-4 adverse events (AE) of any type was 33% ( = 15). Expected AEs of bevacizumab treatment did not appear to be increased by the addition of trebananib.

Conclusions: In a first-line mCRC population, the dual antiangiogenic combination, bevacizumab plus trebananib, without chemotherapy, was efficacious with durable responses. The toxicity profile of the combination was manageable and did not exceed that expected with bevacizumab +/- chemotherapy. Exploratory biomarker results raise the hypothesis that the antiangiogenic combination may enable the antitumor immune response in immunotolerant colorectal cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2714DOI Listing
April 2021

Metastatic myxopapillary ependymoma treated with immunotherapy achieving durable response.

BMJ Case Rep 2020 Dec 17;13(12). Epub 2020 Dec 17.

Medical Oncology, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia.

Myxopapillary ependymoma (MPE) is a rare glial tumour mainly located in the areas of the conus medullaris, cauda equina and filum terminale of the spinal cord. Ectopic MPE tends to behave more aggressively and distant metastases are often seen. Unfortunately, no standard treatment options are established as only small series of treated patients and a few reported cases are available in the literature. We report the case of a 25-year-old woman who was initially diagnosed with a metastatic MPE, with multiple bilateral lung metastases. She was treated with an investigational monoclonal antibody antiprogrammed cell death protein 1, called tislelizumab (BGB-A317), following surgical resection of the perisacral primary mass. The response was long-lasting and side effects nil. Immunotherapy is a treatment modality to be considered in patients with rare tumours.
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http://dx.doi.org/10.1136/bcr-2020-236242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747573PMC
December 2020

Salvage systemic therapy for advanced gastric and oesophago-gastric junction adenocarcinoma.

Cochrane Database Syst Rev 2020 11 19;11:CD012078. Epub 2020 Nov 19.

Medical Oncology, The Queen Elizabeth Hospital and University of Adelaide, Woodville, Adelaide, Australia.

Background: Salvage systemic therapy has become the new standard of care in patients with advanced gastric and oesophago-gastric junction (OGJ) adenocarcinoma, following disease progression on first-line fluoropyrimidine and platinum-containing chemotherapy. Pharmacological agents proven to be effective in this setting include both chemotherapy and biological therapy, however, the consensus on the best salvage systemic therapy has not been reached.

Objectives: To assess the effects of systemic chemotherapy and biological therapy, either alone or in combination, on overall survival (OS) and progression-free survival (PFS) in patients with advanced gastric and OGJ adenocarcinoma, whose disease has progressed on, or relapsed after first-line fluoropyrimidine and platinum-containing chemotherapy. Adverse events (AEs), tumour response rate (TRR) and quality of life (QoL) associated with systemic chemotherapy and/or biological therapy were additionally assessed.

Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, trial registries and proceedings of the major oncology conferences up to October 2020. We additionally handsearched the reference lists of studies. No language restriction was applied.

Selection Criteria: We included randomised controlled trials (RCTs) comparing salvage systemic therapy (chemotherapy and/or biological therapy) and either another type of salvage systemic therapy, placebo, best supportive care (BSC) or no treatment in patients with gastric and OGJ adenocarcinoma refractory to first-line fluoropyrimidine and platinum-containing chemotherapy.

Data Collection And Analysis: Two review authors independently performed selection of eligible studies and the primary author extracted study characteristics and outcome data from included studies. We assessed the quality and risk of bias of eligible studies according to the Cochrane Handbook for Systematic Reviews of Interventions. We expressed pooled estimates of effect using hazard ratio (HR) calculated using an inverse variance random-effects model for time-to-event data, and risk ratio (RR) calculated using Mantel-Haenszel random-effects model for binary data. The certainty of evidence was graded using GRADEpro.

Main Results: We identified 17 RCTs with 5110 participants for inclusion in this review. Tweenty-nine studies are ongoing and twenty studies are awaiting classification. No studies examined the following comparisons: chemotherapy combined with biological therapy versus placebo, BSC or no treatment, chemotherapy combined with biological therapy versus biological therapy, biological therapy versus biological therapy and chemotherapy combined with biological therapy versus chemotherapy combined with biological therapy. Chemotherapy versus placebo, best supportive care or no treatment Chemotherapy probably improves OS (HR = 0.66, 95% CI 0.52 to 0.83, moderate-certainty evidence) based on two studies involving 547 participants and improves PFS (HR = 0.57, 95% CI 0.47 to 0.69, high-certainty evidence) based on one study involving 507 participants over placebo and BSC. Chemotherapy probably increases serious AEs (SAEs) (RR = 1.38, 95% CI 1.20 to 1.59, moderate-certainty evidence) based on one study involving 503 participants. Biological therapy versus placebo, best supportive care or no treatment Biological therapy improves OS (HR = 0.55, 95% CI 0.41 to 0.73, high-certainty evidence) and probably improves PFS (HR = 0.33, 95% CI 0.19 to 0.57, moderate-certainty evidence) over placebo based on three studies involving 781 participants. There is currently insufficient evidence for increased SAEs from biological therapy (RR = 1.14, 95% CI 0.95 to 1.37, low-certainty evidence) based on two studies involving 638 participants. Chemotherapy versus biological therapy This comparison only considered immunotherapy. There is probably no evidence of a difference for OS (HR = 0.82, 95% CI 0.66 to 1.02, moderate-certainty evidence) between chemotherapy and immunotherapy, and immunotherapy probably reduces PFS (HR = 1.27, 95% CI 1.03 to 1.57, moderate-certainty evidence) based on one study involving 395 participants. SAEs may be less frequent with immunotherapy compared to chemotherapy (RR = 0.41, 95% CI 0.30 to 0.57, low-certainty evidence). Chemotherapy combined with biological therapy versus chemotherapy Addition of biological therapy to chemotherapy probably does not improve OS (HR = 0.93, 95% CI 0.83 to 1.04, moderate-certainty evidence) and we are uncertain whether it improves PFS (HR = 0.87, 95% CI 0.74 to 1.02, very low-certainty evidence) based on seven studies involving 2743 participants. We are similarly uncertain whether combined chemotherapy and biological therapy increases SAEs (RR = 1.17, 95% CI 0.95 to 1.44, very low-certainty evidence) based on four studies involving 1618 participants. Chemotherapy versus chemotherapy There is no evidence of a difference for OS and PFS between irinotecan and paclitaxel (HR = 1.13, 95% CI 0.86 to 1.48, low-certainty evidence for OS; HR = 1.14, 95% CI 0.88 to 1.48, low-certainty evidence for PFS) based on one study involving 219 participants. Similarly, there is no evidence to indicate improved OS and PFS from addition of another chemotherapy to docetaxel (HR = 1.05, 95% CI 0.72 to 1.54, low-certainty evidence for OS; HR = 0.75, 95% CI 0.52 to 1.09, low-certainty evidence for PFS) based on two studies involving 121 participants. Grade ≥ 3 neutropenia occurred commonly with both mono- and poly-chemotherapy except for docetaxel-S1 and EOX chemotherapy.

Authors' Conclusions: Survival outcome of patients with advanced gastric and OGJ adenocarcinoma whose disease progressed on first-line fluoropyrimidine and platinum-containing chemotherapy can be improved by chemotherapy and biological therapy. Biological therapy, in particular, achieves this without clear increase in SAEs or QoL impairment. Whether biological therapy is preferred over chemotherapy is still unclear and there is no evidence of a difference for OS outcome, although immunotherapy may be associated with less SAEs. Addition of biological therapy to chemotherapy and poly-chemotherapy are associated with frequent treatment-related toxicity without clear survival benefit.
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http://dx.doi.org/10.1002/14651858.CD012078.pub2DOI Listing
November 2020

Curative therapy for rectal cancer.

Expert Rev Anticancer Ther 2021 Feb 8;21(2):193-203. Epub 2021 Jan 8.

Department of Medical Oncology, The Queen Elizabeth Hospital and University of Adelaide, Adelaide, Australia.

: A comprehensive trimodality approach has become the standard of care for patients with locally advanced rectal cancer. However, the sequencing and duration of chemotherapy and chemoradiotherapy around surgery varies between clinical studies and geographical regions. Growing evidence is also mounting for strategies such as total neoadjuvant therapy and non-operative management for carefully selected patients.: We provide a perspective review of the current evidence and controversies in the treatment of locally advanced rectal cancer including the recent updates from the 2020 ASCO annual conference.: With ongoing advances in the management of locally advanced rectal cancer, a multidisciplinary team approach is necessary as treatments could involve multiple approaches. Chemoradiotherapy whether short or long course followed by at least 3 months of systemic chemotherapy may be the preferred option to balance local and distant disease control. Albeit the choice of doublet or triplet chemotherapy is still controversial. As total neoadjuvant treatment becomes part of the standard of care in rectal cancer, modification of the surveillance schedule is needed to detect early recurrences which may be limited by resources and availability of services.
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http://dx.doi.org/10.1080/14737140.2021.1845145DOI Listing
February 2021

Anti-Angiogenic Properties of Ginsenoside Rg3.

Molecules 2020 Oct 23;25(21). Epub 2020 Oct 23.

Molecular Oncology, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Woodville South, SA 5011, Australia.

Ginsenoside Rg3 (Rg3) is a member of the ginsenoside family of chemicals extracted from . Like other ginsenosides, Rg3 has two epimers: 20(S)-ginsenoside Rg3 (SRg3) and 20(R)-ginsenoside Rg3 (RRg3). Rg3 is an intriguing molecule due to its anti-cancer properties. One facet of the anti-cancer properties of Rg3 is the anti-angiogenic action. This review describes the controversies on the effects and effective dose range of Rg3, summarizes the evidence on the efficacy of Rg3 on angiogenesis, and raises the possibility that Rg3 is a prodrug.
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http://dx.doi.org/10.3390/molecules25214905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660320PMC
October 2020

Expanded Low Allele Frequency and V600E Testing in Metastatic Colorectal Cancer as Predictive Biomarkers for Cetuximab in the Randomized CO.17 Trial.

Clin Cancer Res 2021 Jan 21;27(1):52-59. Epub 2020 Oct 21.

University of Texas, MD Anderson Cancer Center, Houston, Texas.

Purpose: Expanded mutations have not been assessed as predictive for single-agent cetuximab in metastatic colorectal cancer (mCRC), and low mutant allele frequency (MAF) mutations are of unclear significance. We aimed to establish cetuximab efficacy in optimally selected patients using highly sensitive beads, emulsion, amplification, and magnetics (BEAMing) analysis, capable of detecting alterations below standard clinical assays.

Patients And Methods: CO.17 trial compared cetuximab versus best supportive care (BSC) in -unselected mCRC. We performed analysis on microdissected tissue of 242 patients in CO.17 trial using BEAMing for (codons 12/13/59/61/117/146) and V600E. Patients without BEAMing but with previous Sanger sequencing-detected mutations were included.

Results: , and mutations were present in 53%, 4%, and 3% of tumors, respectively. Cetuximab improved overall survival [OS; HR, 0.51; 95% confidence interval (CI), 0.32-0.81; = 0.004] and progression-free survival (PFS; HR, 0.25; 95% CI, 0.15-0.41; < 0.0001) compared with BSC in wild-type patients. Cetuximab did not improve OS/PFS for , or mutated tumors, and tests of interaction confirmed expanded ( = 0.0002) and ( = 0.006) as predictive, while mutations were not ( = 0.089). BEAMing identified 14% more tumors as mutant than Sanger sequencing, and cetuximab lacked activity in these patients. Mutations at MAF < 5% were noted in 6 of 242 patients (2%). One patient with a A59T mutation (MAF = 2%) responded to cetuximab. More than mutations were low MAF (OR, 20.50; 95% CI, 3.88-96.85; = 0.0038).

Conclusions: We establish single-agent cetuximab efficacy in optimally selected patients and show that subclonal alterations are uncommon and remain of indeterminate significance.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785657PMC
January 2021

Rechallenge with Anti-EGFR Therapy in Metastatic Colorectal Cancer (mCRC): Results from South Australia mCRC Registry.

Target Oncol 2020 12;15(6):751-757

Department of Medical Oncology, The Queen Elizabeth Hospital, Adelaide, SA, Australia.

Background: Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) are today increasingly used in the first- or second-line setting for RAS wild-type metastatic colorectal cancer (CRC) patients. Following progression beyond third- or fourth-line therapy, some patients are unsuitable for further chemotherapy because of poor performance status or patient choice. However, a significant number of patients are still candidates for further therapy despite limited standard options being available. The role of rechallenge with anti-EGFR therapy, particularly in patients who had previously responded, is often considered, but there is limited evidence in the literature to support such a strategy.

Objective: This retrospective study aims to review the outcome of metastatic CRC patients who had anti-EGFR rechallenge.

Patients And Methods: Patients who had been rechallenged with anti-EGFR therapy were identified from the South Australian metastatic CRC database. Patient characteristics were recorded and tumor response was retrospectively assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Kaplan-Meier analysis was used to assess progression free survival (PFS) for each rechallenge and overall survival (OS).

Results: Twenty-two patients were eligible for inclusion in this analysis. Disease control rate (stable disease and partial response) was 45.4% (ten patients) for patients who received rechallenge anti-EGFR. Seven patients received a second rechallenge and disease control rate was 28.6% (two patients). The median interval time between initial anti-EGFR therapy and rechallenge was 13.5 months. The median PFS after rechallenge 1 was 4.1 months and after rechallenge 2 was 3.5 months. The median OS was 7.7 months from date of rechallenge.

Conclusions: Anti-EGFR rechallenge provides clinical benefit in patients with RAS wild-type metastatic CRC.
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http://dx.doi.org/10.1007/s11523-020-00760-8DOI Listing
December 2020

Frequency of S492R mutations in the epidermal growth factor receptor: analysis of plasma DNA from patients with metastatic colorectal cancer treated with panitumumab or cetuximab monotherapy.

Cancer Biol Ther 2020 10 7;21(10):891-898. Epub 2020 Oct 7.

Department of Oncology, Antwerp University Hospital , Edegem, Belgium.

Background: Antibodies against epidermal growth factor receptor (EGFR), panitumumab, a fully human monoclonal antibody, and cetuximab, a human/mouse chimeric monoclonal antibody, have shown clinical efficacy in metastatic colorectal cancer (mCRC). In the phase 3 noninferiority ASPECCT (ClinicalTrials.gov, NCT01001377) study, panitumumab was demonstrated to be noninferior to cetuximab and provided a similar overall survival benefit for patients with chemotherapy-refractory wild-type exon 2 mCRC. However, some patients eventually develop resistance to anti-EGFR therapy. EGFR p.S492R mutation was previously identified as conferring resistance to cetuximab, but not to panitumumab.

Methods: This biomarker study analyzed plasma samples from ASPECCT collected at both baseline and posttreatment.

Results: No EGFR p.S492R mutations were identified at baseline; however, after treatment the EGFR p.S492R mutation was detected in 1% of patients treated with panitumumab versus 16% of those treated with cetuximab, supporting that, in a large population, this mutation is more likely to be induced by cetuximab than by panitumumab. There were, however, no significant differences in progression-free survival or overall survival between patients who were wild-type compared with those with the S492R mutation within the cetuximab arm or the overall population.

Conclusions: These results may support targeting treatment to small patient subgroups based on the presence of emerging EGFR mutations and provide a molecular rationale for rechallenging with a different anti-EGFR agent in patients who develop resistance. Prospective studies are needed to evaluate the efficacy of panitumumab in the EGFR p.S492R mutant population.
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http://dx.doi.org/10.1080/15384047.2020.1798695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583702PMC
October 2020

Appendiceal neoplasm incidence and mortality rates are on the rise in Australia.

Expert Rev Gastroenterol Hepatol 2021 Feb 4;15(2):203-210. Epub 2020 Nov 4.

Department of Haematology and Oncology, The Queen Elizabeth Hospital , Woodville South, Australia.

Objectives: The study aimed to examine the incidence and mortality rates of appendiceal neoplasms (ANs) in Australia.

Methods: A retrospective analysis was performed on national data obtained from the Australian Institute of Health and Welfare (AIHW) from 1982 to 2013. Changes to the incidence, and the cancer-specific mortality following the diagnosis of ANs were analyzed over this time period, with stratification performed for histological subtype, gender, and age groups (<50y and ≥50y).

Results: Incidence and mortality rates of ANs increased significantly across both genders and age groups. Incidence rates increased by 415%, from 0.40/100 000 population in 1982 to 2.06/100 000 in 2013. Overall mortality rates increased by 130%, from 0.057/100 000 during 1982-1985 to 0.131/100 000 during 2010-2013. Controlling for age group and gender, the incidence rates increased by 20% every four years (Incidence rate ratio (IRR) = 1.20, 95% confidence interval (CI): 1.17, 1.23, global P value<0.0001), and controlling for age, the mortality rates increased by 8% every four years (IRR = 1.08, 95% CI: 1.00, 1.17, global P-value = 0.0401).

Conclusion: The increasing use of CT scanning, improvements in pathological assessment of the appendix, and the growing aging population may have contributed in part to the apparent rise in the incidence of ANs.
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http://dx.doi.org/10.1080/17474124.2021.1832467DOI Listing
February 2021

Intratumoral Transcriptome Heterogeneity Is Associated With Patient Prognosis and Sidedness in Patients With Colorectal Cancer Treated With Anti-EGFR Therapy From the CO.20 Trial.

JCO Precis Oncol 2020 29;4. Epub 2020 Sep 29.

Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom.

Purpose: Metastatic colorectal cancers (mCRCs) assigned to the transit-amplifying (TA) CRCAssigner subtype are more sensitive to anti-epidermal growth factor receptor (EGFR) therapy. We evaluated the association between the intratumoral presence of TA signature (TA-high/TA-low, dubbed as TA-ness classification) and outcomes in CRCs treated with anti-EGFR therapy.

Patients And Methods: The TA-ness classes were defined in a discovery cohort (n = 84) and independently validated in a clinical trial (CO.20; cetuximab monotherapy arm; n = 121) and other samples using an established NanoString-based gene expression assay. Progression-free survival (PFS), overall survival (OS), and disease control rate (DCR) according to TA-ness classification were assessed by univariate and multivariate analyses.

Results: The TA-ness was measured in 772 samples from 712 patients. Patients (treated with anti-EGFR therapy) with TA-high tumors had significantly longer PFS (discovery hazard ratio [HR], 0.40; 95% CI, 0.25 to 0.64; < .001; validation HR, 0.65; 95% CI, 0.45 to 0.93; = .018), longer OS (discovery HR, 0.48; 95% CI, 0.29 to 0.78; = .003; validation HR, 0.67; 95% CI, 0.46 to 0.98; = .04), and higher DCR (discovery odds ratio [OR]; 14.8; 95% CI, 4.30 to 59.54; < .001; validation OR, 4.35; 95% CI, 2.00 to 9.09; < .001). TA-ness classification and its association with anti-EGFR therapy outcomes were further confirmed using publicly available data (n = 80) from metastatic samples (PFS < .001) and patient-derived xenografts ( = .042). In an exploratory analysis of 55 patients with wild-type and left-sided tumors, TA-high class was significantly associated with longer PFS and trend toward higher response rate (PFS HR, 0.53; 95% CI, 0.28 to 1.00; = .049; OR, 5.88; 95% CI, 0.71 to 4.55; = .09; response rate 33% in TA-high and 7.7% in TA-low).

Conclusion: TA-ness classification is associated with prognosis in patients with mCRC treated with anti-EGFR therapy and may further help understanding the value of sidedness in patients with wild-type tumors.
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http://dx.doi.org/10.1200/PO.20.00050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529528PMC
September 2020

Pre- and Postoperative Capecitabine Without or With Oxaliplatin in Locally Advanced Rectal Cancer: PETACC 6 Trial by EORTC GITCG and ROG, AIO, AGITG, BGDO, and FFCD.

J Clin Oncol 2021 Jan 1;39(1):17-29. Epub 2020 Oct 1.

University Hospitals and KU Leuven, Leuven, Belgium.

Purpose: The PETACC 6 trial investigates whether the addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative capecitabine improves disease-free survival (DFS) in locally advanced rectal cancer.

Methods: Between November 2008 and September 2011, patients with rectal adenocarcinoma within 12 cm from the anal verge, T3/4 and/or node positive, were randomly assigned to 5 weeks preoperative capecitabine-based chemoradiation (45-50.4 Gy) followed by six cycles of adjuvant capecitabine, both without (control arm, 1) or with (experimental arm, 2) oxaliplatin. The primary end point was improvement of 3-year DFS by oxaliplatin from 65% to 72% (hazard ratio [HR], 0.763).

Results: A total of 1,094 patients were randomly assigned (intention to treat), and 1,068 eligible patients started their allocated treatment (arm 1, 543; arm 2, 525), with completion of protocol treatment in 68% (arm 1) 54% (arm 2). A higher rate of grade 3/4 adverse events was reported in the experimental arm (14.4% 37.3% and 23.4% 46.6% for neoadjuvant and adjuvant treatment, respectively). At a median follow-up of 68 months (interquartile range, 58-74 months), 157 and 156 DFS events were observed in arms 1 and 2, respectively (adjusted HR, 1.02; 95% CI, 0.82 to 1.28; = .835). Three-year DFS rate was not different, with 76.5% (95% CI, 72.7% to 79.9%) in arm 1, which is higher than anticipated, and 75.8% (95% CI, 71.9% to 79.3%) in arm 2. The 7-year DFS and overall survival (OS) rates were not different as well, with DFS of 66.1% 65.5% (HR, 1.02) and OS of 73.5% 73.7% (HR, 1.19) in arms 1 and 2, respectively. Subgroup analyses revealed heterogeneity in treatment effect according to German versus non-German site location, without detectable confounding factors in multivariable analysis.

Conclusion: The addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative adjuvant chemotherapy impairs tolerability and feasibility and does not improve efficacy.
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http://dx.doi.org/10.1200/JCO.20.01740DOI Listing
January 2021

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

KRAS Inhibition with Sotorasib in Advanced Solid Tumors.

N Engl J Med 2020 09 20;383(13):1207-1217. Epub 2020 Sep 20.

From the Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, University of Texas M.D. Anderson Cancer Center, Houston (D.S.H., F.M.-B.); the Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte (M.G.F.), the University of California, San Francisco, San Francisco (P.N.M.), and Amgen, Thousand Oaks (H.H., J.N., G.N., J.K., B.E.H., J.C., J.R.L., G.F.) - all in California; Duke University Medical Center, Durham, NC (J.H.S.); Royal Melbourne Hospital/Peter MacCallum Cancer Centre, Melbourne, VIC (J.D.), Queen Elizabeth Hospital and University of Adelaide, Woodville South, SA (T.J.P.), and Scientia Clinical Research, Randwick, NSW (J.C. Kuo) - all in Australia; the Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis (G.A.D.); Dana-Farber Cancer Institute, Harvard Medical School, Boston (G.I.S.); the Sarah Cannon Research Institute at HealthONE, Denver (G.S.F.); Princess Margaret Cancer Centre, University Health Network, Toronto (A.S.); Fox Chase Cancer Center, Philadelphia (C.S.D.); the University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh, Pittsburgh (T.F.B.); Seoul National University College of Medicine (Y.-J.B.), Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.), and the Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine (T.W.K.) - all in Seoul, South Korea; Roswell Park Cancer Institute, Buffalo (G.K.D.), and Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York (P.L., B.T.L.) - all in New York; the University of Michigan, Ann Arbor (J.C. Krauss); the Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan (Y.K.); the Department of Medicine, Division of Oncology, University of Washington, Seattle (A.L.C.); Aix Marseille University, Centre National de la Recherche Scientifique, INSERM, Centre de Recherche en Cancérologie de Marseille, Assistance Publique-Hôpitaux de Marseille, Marseille, France (F.B.); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, St. Louis (R.G.).

Background: No therapies for targeting mutations in cancer have been approved. The p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRAS.

Methods: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.

Results: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.

Conclusions: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
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http://dx.doi.org/10.1056/NEJMoa1917239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571518PMC
September 2020

Young-onset colorectal cancer is associated with a personal history of type 2 diabetes.

Asia Pac J Clin Oncol 2021 Feb 3;17(1):131-138. Epub 2020 Sep 3.

Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia.

Background: Colorectal cancer (CRC) is rising in incidence in young adults, and this observation is currently unexplained. We investigated whether having a personal history of type 2 diabetes mellitus (T2D) was a potential risk factor for young-onset colorectal cancer (YOCRC).

Methods: The South Australian Young Onset (SAYO) CRC study is a series of young adults with CRC below age 55. Ninety unrelated YOCRC cases were recruited to the study. Personal history and detailed family history of T2D were obtained at face-to-face interview and confirmed from medical records. Whole exome sequencing was conducted on germline DNA from each CRC case. Controls for personal history studies of T2D were 240 patients with proven clear colonoscopies and no known CRC predispositions.

Results: The median age of YOCRC cases was 44 years (18-54) and of controls was 45 years (18-54), and 53% of both cases and controls were females (P = 0.99). Left-sided (distal) CRC was seen in 67/89 (75%) of cases. A personal history of T2D was confirmed in 17/90 (19%) YOCRC patients compared with controls (12/240, 5%; P < 0.001; odds ratio = 4.4; 95% confidence interval, 2.0-9.7). YOCRC patients frequently reported at least one first-degree relative with T2D (32/85, 38%). Ten of 87 (12%) of YOCRC cases had CRC-related pathogenic germline variants, however, no pathogenic variants in familial diabetes-associated genes were seen.

Conclusions: Though the mechanism remains unclear, our observations suggest that there is enrichment for personal history of T2D in YOCRC patients.

Impact: A diagnosis of T2D could therefore potentially identify a subset of young adults at increased risk for CRC and in whom early screening might be appropriate.
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http://dx.doi.org/10.1111/ajco.13428DOI Listing
February 2021

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

Discordance in 21-gene recurrence scores between paired breast cancer samples is inversely associated with patient age.

Breast Cancer Res 2020 08 18;22(1):90. Epub 2020 Aug 18.

Discipline of Surgery, Adelaide Medical School, University of Adelaide, The Queen Elizabeth Hospital DX465702, 28 Woodville Rd, Woodville, Adelaide, 5011, Australia.

Background: The Oncotype DX 21-gene Recurrence Score is a genomic-based algorithm that guides adjuvant chemotherapy treatment decisions for women with early-stage, oestrogen receptor (ER)-positive breast cancer. However, there are age-related differences in chemotherapy benefit for women with intermediate Oncotype DX Recurrence Scores that are not well understood. Menstrual cycling in younger women is associated with hormonal fluctuations that might affect the expression of genomic predictive biomarkers and alter Recurrence Scores. Here, we use paired human breast cancer samples to demonstrate that the clinically employed Oncotype DX algorithm is critically affected by patient age.

Methods: RNA was extracted from 25 pairs of formalin-fixed paraffin-embedded, invasive ER-positive breast cancer samples that had been collected approximately 2 weeks apart. A 21-gene signature analogous to the Oncotype DX platform was assessed through quantitative real-time PCR, and experimental recurrence scores were calculated using the Oncotype DX algorithm.

Results: There was a significant inverse association between patient age and discordance in the recurrence score. For every 1-year decrease in age, discordance in recurrence scores between paired samples increased by 0.08 units (95% CI - 0.14, - 0.01; p = 0.017). Discordance in recurrence scores for women under the age of 50 was driven primarily by proliferation- and HER2-associated genes.

Conclusion: The Oncotype DX 21-gene Recurrence Score algorithm is critically affected by patient age. These findings emphasise the need for the consideration of patient age, particularly for women younger than 50, in the development and application of genomic-based algorithms for breast cancer care.
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http://dx.doi.org/10.1186/s13058-020-01327-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437067PMC
August 2020

Timing of breast cancer surgery during the menstrual cycle-is there an optimal time of the month?

Oncol Lett 2020 Sep 24;20(3):2045-2057. Epub 2020 Jun 24.

Discipline of Surgery, Adelaide Medical School, The Queen Elizabeth Hospital, University of Adelaide, Woodville, South Australia 5011, Australia.

An intriguing relationship between menstrual cycle phase at the time of breast cancer surgery and clinical outcomes was first proposed in the late 1980s. Despite a number of clinical studies conducted to address this, as well as meta-analyses and systematic reviews, there remains significant controversy surrounding the effect of menstrual cycle phase at time of surgery on the prognosis of premenopausal breast cancer. While some studies have suggested that surgery performed during the luteal phase results in the most favourable outcome, other studies report the follicular phase is more favourable, and others show no association. Given the conflicting results, there remains insufficient evidence to determine whether there is an optimal time of the month to perform surgery. This issue has dogged breast cancer surgery for decades; knowledge of an optimal time of the month to conduct surgery would be a simple approach to improving patient outcomes. This review explores the potential biological mechanisms through which the hormonal milieu might contribute to differences in prognosis, and why clinical findings are so variable. It is concluded that a significant problem with current clinical research is the lack of insight from mechanistic studies. While there are a number of plausible biological mechanisms that could lead to altered survival, supporting evidence is limited. There are also variable approaches to defining the menstrual cycle phase and hormone receptor status of the tumour and few studies controlled for prognostic factors such as tumour size and stage, or addressed the impact of adjuvant treatments. Elucidation of the specific confounding factors, as well as biological mechanistic pathways that could explain the potential relationship between timing of surgery and survival, will greatly assist in designing robust well-controlled prospective clinical studies to evaluate this paradigm.
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http://dx.doi.org/10.3892/ol.2020.11771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400969PMC
September 2020

Efficacy of Panitumumab and Cetuximab in Patients with Colorectal Cancer Previously Treated with Bevacizumab; a Combined Analysis of Individual Patient Data from ASPECCT and WJOG6510G.

Cancers (Basel) 2020 Jun 28;12(7). Epub 2020 Jun 28.

Department of Medical Oncology, Queen Elizabeth Hospital and University of Adelaide, 5011 Woodville, Australia.

Background: Phase-III ASPECCT and randomised phase-II WJOG6510G trials demonstrated the noninferiority of panitumumab, when compared with cetuximab, for overall survival in patients with chemotherapy-refractory wild-type exon 2 metastatic colorectal cancer.

Methods: The subgroup that received bevacizumab either prior to panitumumab or cetuximab monotherapy (ASPECCT) or in combination with irinotecan (WJOG6510G) was included. Multivariate Cox models were created, including the treatment arms as covariates together with patient, disease and treatment characteristics.

Results: We included 185 and 189 patients in the panitumumab and cetuximab arms, respectively. The median overall survival was 12.8 and 10.1 months [ = 0.0031; log-rank test, stratified by trial; hazard ratio (HR), 0.72; 95% confidence interval (CI), 0.58-0.90], and the median progression-free survival was 4.7 and 4.1 months, in the panitumumab and cetuximab arms, respectively ( = 0.0207; HR, 0.79; 95% CI, 0.64-0.97). The treatment regimen was an independent prognostic factor of overall survival (adjusted HR, 0.69; 95% CI, 0.54-0.87; = 0.0013).

Conclusions: Panitumumab significantly prolonged the overall survival and progression-free survival, when compared with cetuximab in the cohort that previously received bevacizumab in the included studies. Clinical Trial Registration ASPECCT trial registered with ClinicalTrials.gov (NCT01001377) and WJOG6510G trial registered with UMIN-CTR (UMIN000006643).
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http://dx.doi.org/10.3390/cancers12071715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407286PMC
June 2020

Monitoring TNM stage of female breast cancer and survival across the South Australian population, with national and international TNM benchmarking: A population-based cohort study.

BMJ Open 2020 06 28;10(6):e037069. Epub 2020 Jun 28.

Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia.

Objective: Using linked cancer registry and administrative data to monitor, tumour, node and metastases (TNM) stage and survival from female breast cancer in Australia.

Method: Analysis of 2000-2014 diagnoses with linked population-based data to investigate: (1) sociodemographic predictors of advanced stage (stages III and IV), using unadjusted and adjusted logistic regression; and (2) sociodemographic factors and stage as predictors of breast cancer survival using competing risk regression.

Design: Population-based registry cohort.

Setting And Participants: 14 759 South Australian women diagnosed in 2000-2014.

Primary And Secondary Outcome Measures: Stage and survival.

Results: At diagnosis, 46% of women were classified as stage I, 39% as stage II, 12% as stage III and 4% as stage IV. After adjusting for sociodemographic factors, advanced stage was more common: (1) for ages <50 years; and although not statistically significant, for ages 80+ years; and (2) in women from socioeconomically disadvantaged areas. Compared with 2000-2004 diagnoses, stage and sociodemographic adjusted risks (sub-HRs (SHRs)) of breast cancer death were lower in 2005-2009 (SHR 0.75, 95% CI 0.67 to 0.83) and 2010-2015 (SHR 0.57, 95% CI 0.48 to 0.67). Compared with stage I, the SHR was 3.87 (95% CI 3.32 to 4.53) for stage II, 10.87 (95% CI 9.22 to 12.81) for stage III, and 41.97 (95% CI 34.78 to 50.65) for stage IV. Women aged 70+ years at diagnosis and those living in the most socioeconomically disadvantaged areas were at elevated risk of breast cancer death, independent of stage and sociodemographic factors.

Conclusions: Stage varied by age, diagnostic period and socioeconomic status, and was a stronger predictor of survival than other statistically significant sociodemographic predictors. Achieving earlier diagnosis outside the original BreastScreen target of 50-69 years (as applying <2014) and in residents of socioeconomically disadvantaged areas likely would increase cancer survival at a population level.
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http://dx.doi.org/10.1136/bmjopen-2020-037069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322288PMC
June 2020

Safety, efficacy and patient-reported outcomes with trifluridine/tipiracil in pretreated metastatic colorectal cancer: results of the PRECONNECT study.

ESMO Open 2020 06;5(3):e000698

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Toscana, Italy.

Background: In RECOURSE (, trifluridine/tipiracil significantly improved overall survival and progression-free survival (PFS) versus placebo in patients with pretreated metastatic colorectal cancer (mCRC). PRECONNECT was designed to further characterise safety and clinical use of trifluridine/tipiracil.

Methods: In this ongoing, international, multicentre, open-label trial, patients with pretreated mCRC received oral trifluridine/tipiracil 35 mg/m twice daily on days 1-5 and 8-12 of each 28-day cycle. The primary endpoint was safety; secondary endpoints included PFS and quality of life (QoL).

Results: 793 patients (median age 62 years) from 13 countries received trifluridine/tipiracil for a median of 2.84 months (IQR 2.64). Adverse events (AEs) were experienced by 96.7%; the most common (≥20% of patients) were neutropaenia, asthenia/fatigue, nausea, anaemia and diarrhoea. Grade ≥3 AEs occurred in 73.9% of patients, with the most common being neutropaenia (39.1% of patients), anaemia (9.8%) and asthenia/fatigue (5.0%). Median PFS was 2.8 months (95% CI 2.7 to 2.9). Median time to Eastern Cooperative Oncology Group performance status deterioration (≥2) was 8.9 months (range 0.03-14.72). There was no clinically relevant change from baseline in QoL.

Conclusions: PRECONNECT showed consistent results with the previously demonstrated safety and efficacy profile of trifluridine/tipiracil, with no new safety concerns identified. QoL was maintained during treatment.

Trial Registration Number: NCT03306394.
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http://dx.doi.org/10.1136/esmoopen-2020-000698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264999PMC
June 2020

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

Trifluridine/tipiracil: A practical guide to its use in the management of refractory metastatic colorectal cancer in Australia.

Asia Pac J Clin Oncol 2020 Apr;16 Suppl 1:3-12

NHMRC Clinical Trials Centre, University of Sydney, NSW, Australia.

Trifluridine/tipiracil is available on the Australian Pharmaceutical Benefits Scheme for the treatment of patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-vascular endothelial growth factor agents and anti-epidermal growth factor receptor agents. This article reviews trifluridine/tipiracil clinical data and presents practical information on its use in the management of refractory mCRC in Australia. Whereas the primary mechanism of action of fluoropyrimidines such as fluorouracil (5-FU) and capecitabine is enzyme inhibition of nucleotide synthesis, trifluridine/tipiracil primarily acts by incorporation into DNA, resulting in DNA dysfunction. Trifluridine/tipiracil has activity in patients with 5-FU-resistant tumors and can be considered in patients with prior intolerance or toxicity to 5-FU. In the pivotal phase III RECOURSE trial evaluating trifluridine/tipiracil in chemotherapy-refractory mCRC, efficacy benefits were observed across all a priori prognostic subgroups including those defined by age (≥65 and ≥75 years), geographical origin, primary tumor site or KRAS status. Trifluridine/tipiracil therapy benefits appropriately selected patients who have an ECOG performance status of 0 or 1, with no more than mild hepatic impairment or mild-to-moderate renal impairment, and who are capable of adhering to oral therapy safely. Appropriate dosing, monitoring for adverse events and effective management of side effects are essential.
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http://dx.doi.org/10.1111/ajco.13336DOI Listing
April 2020

Update on optimal treatment for metastatic colorectal cancer from the AGITG expert meeting: ESMO congress 2019.

Expert Rev Anticancer Ther 2020 04 6;20(4):251-270. Epub 2020 Apr 6.

Medical Oncology, The Queen Elizabeth Hospital, Woodville, Australia.

: Outcomes in metastatic colorectal cancer are improving, due to the tailoring of therapy enabled by better understanding of clinical behavior according to molecular subtype.: A review of the literature and recent conference presentations was undertaken on the topic of systemic treatment of metastatic colorectal cancer. This review summarizes expert discussion of the current evidence for therapies in metastatic colorectal cancer (mCRC) based on molecular subgrouping.: EGFR-targeted and VEGF-targeted antibodies are now routinely incorporated into treatment strategies for mCRC. EGFR-targeted antibodies are restricted to patients with extended wild-type profiles, with evidence that they should be further restricted to patients with left-sided tumors. Clinically distinct treatment pathways based on tumor and MMR status, are now clinically applicable. Evidence suggests therapy for additional subgroups will soon be defined; the most advanced being for patients with G12 C mutation and gene fusion defects.
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http://dx.doi.org/10.1080/14737140.2020.1744439DOI Listing
April 2020

Antecedent cancer in Takotsubo syndrome predicts both cardiovascular and long-term mortality.

Cardiooncology 2019 22;5:20. Epub 2019 Nov 22.

1Cardiology Unit, Department of Cardiology, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville South, SA 5011 Australia.

Background: Takotsubo syndrome (TTS), primarily an acute myocardial inflammatory condition engendered by catecholamine exposure, is associated with similar long-term mortality rates to those of patients with acute myocardial infarction. However, there is increasing evidence of a nexus between TTS and underlying malignancies:- many patients have antecedent cancer (A/Ca), while incremental risk of late cancer-related death has also been reported.

Purpose: To evaluate potential interactions between A/Ca among TTS patients and both early and late clinical course.

Methods: Three hundred forty-six consecutive TTS patients [aged 69 ± 13 (SD) years, males: 8.2%] were prospectively followed up for a median duration of 4.1 (IQR 2.2-6.4) years. Associations between A/Ca and severity of acute attacks, in-hospital complications and long-term death rates were sought utilising univariate analyses followed by multiple logistic regression analysis.

Results: A/Ca (present in 16.8% of patients) was associated with (i) greater elevation of hs-CRP and NT-proBNP concentrations ( = 0.01 and 0.04, respectively), (ii) more complicated in-hospital clinical course, with major adverse cardiac events (MACE) in 30.9% of patients, compared to 18.2% in non-A/Ca patients ( = 0.04). Long-term all-cause mortality rate was also greater [hazard ratio (HR) = 2.4,  = 0.0001] in A/Ca patients, with an excess cardiovascular (CVS) fatality rate (HR = 3.1,  = 0.001). On multivariate analysis, male gender, peak plasma concentrations of normetanephrine and hs-CRP, early arrhythmias and development of shock, but not A/Ca per se were all independently associated with increased long-term mortality rate. Furthermore, patients discharged on β-adrenoceptor antagonists (βBl) or angiotensin converting enzyme inhibitors/ angiotensin receptor blockers (ACEi/ARB) had lower long-term mortality rates (β = - 0.2,  = 0.01; β = - 0.14,  = 0.05, respectively).

Conclusions: (1) A/Ca is associated with greater clinical severity of initial TTS attacks and substantially greater long-term CVS-related as well as all-cause mortality.(2) Post-discharge therapy with either βBl or ACEi/ARB is associated with reductions in long-term mortality rates.Overall, the current data suggest operation of substantial interactions between neoplasia and TTS, both at the level of pathogenesis and of outcomes.
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http://dx.doi.org/10.1186/s40959-019-0053-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048128PMC
November 2019