Hui-Li Wong

Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer

Detection of circulating tumor DNA in patients with resected stage II colon cancer provides evidence of residual disease. Footprints of persistent cancer Stage II colon cancer, which has spread through the wall of the colon but has not metastasized to the lymph nodes, can present a therapeutic dilemma. On one hand, these tumors can usually be completely removed by surgery, and the majority does not recur even without chemotherapy. On the other hand, it is difficult to determine which of these tumors will recur and to identify patients who would benefit from adjuvant chemotherapy after surgery. Tie et al. show that the presence of circulating tumor DNA in a patient’s blood after surgery is a sign of persistent tumor and a greatly increased risk of relapse, suggesting that this group of patients may require chemotherapy to prevent recurrence. Detection of circulating tumor DNA (ctDNA) after resection of stage II colon cancer may identify patients at the highest risk of recurrence and help inform adjuvant treatment decisions. We used massively parallel sequencing–based assays to evaluate the ability of ctDNA to detect minimal residual disease in 1046 plasma samples from a prospective cohort of 230 patients with resected stage II colon cancer. In patients not treated with adjuvant chemotherapy, ctDNA was detected postoperatively in 14 of 178 (7.9%) patients, 11 (79%) of whom had recurred at a median follow-up of 27 months; recurrence occurred in only 16 (9.8 %) of 164 patients with negative ctDNA [hazard ratio (HR), 18; 95% confidence interval (CI), 7.9 to 40; P < 0.001]. In patients treated with chemotherapy, the presence of ctDNA after completion of chemotherapy was also associated with an inferior recurrence-free survival (HR, 11; 95% CI, 1.8 to 68; P = 0.001). ctDNA detection after stage II colon cancer resection provides direct evidence of residual disease and identifies patients at very high risk of recurrence.

Circulating Tumor DNA as an Early Marker of Therapeutic Response in Patients with Metastatic Colorectal Cancer

BACKGROUND Early indicators of treatment response in metastatic colorectal cancer (mCRC) could conceivably be used to optimize treatment. We explored early changes in circulating tumor DNA (ctDNA) levels as a marker of therapeutic efficacy. PATIENTS AND METHODS This prospective study involved 53 mCRC patients receiving standard first-line chemotherapy. Both ctDNA and CEA were assessed in plasma collected before treatment, 3 days after treatment and before cycle 2. Computed tomography (CT) scans were carried out at baseline and 8-10 weeks and were centrally assessed using RECIST v1.1 criteria. Tumors were sequenced using a panel of 15 genes frequently mutated in mCRC to identify candidate mutations for ctDNA analysis. For each patient, one tumor mutation was selected to assess the presence and the level of ctDNA in plasma samples using a digital genomic assay termed Safe-SeqS. RESULTS Candidate mutations for ctDNA analysis were identified in 52 (98.1%) of the tumors. These patient-specific candidate tissue mutations were detectable in the cell-free DNA from the plasma of 48 of these 52 patients (concordance 92.3%). Significant reductions in ctDNA (median 5.7-fold; P < 0.001) levels were observed before cycle 2, which correlated with CT responses at 8-10 weeks (odds ratio = 5.25 with a 10-fold ctDNA reduction; P = 0.016). Major reductions (≥10-fold) versus lesser reductions in ctDNA precycle 2 were associated with a trend for increased progression-free survival (median 14.7 versus 8.1 months; HR = 1.87; P = 0.266). CONCLUSIONS ctDNA is detectable in a high proportion of treatment naïve mCRC patients. Early changes in ctDNA during first-line chemotherapy predict the later radiologic response.

Impact of regular aspirin use on overall and cancer-specific survival in patients with colorectal cancer harboring a PIK3CA mutation

Abstract Background. Recent data have suggested that regular aspirin use improves overall and cancer-specific survival in the subset of colorectal cancer (CRC) patients harboring PIK3CA mutations. However, the number of PIK3CA-mutated CRC patients examined in these studies was modest. Our collaborative study aims to validate the association between regular aspirin use and survival in patients with PIK3CA-mutated CRC. Patients and methods. Patients with PIK3CA-mutated CRC were identified at Moffitt Cancer Center (MCC) in the United States and Royal Melbourne Hospital (RMH) in Australia. Prospective clinicopathological data and survival data were available. At MCC, PIK3CA mutations were identified by targeted exome sequencing using the Illumina GAIIx Next Generation Sequencing platform. At RMH, Sanger sequencing was utilized. Multivariate survival analyses were conducted using Cox logistic regression. Results. From a cohort of 1487 CRC patients, 185 patients harbored a PIK3CA mutation. Median age of patients with PIK3CA-mutated tumors was 72 years (range: 34–92) and median follow up was 54 months. Forty-nine (26%) patients used aspirin regularly. Regular aspirin use was not associated with improved overall survival (multivariate HR 0.96, p = 0.86). There was a trend towards improved cancer-specific survival (multivariate HR 0.60, p = 0.14), but this was not significant. Conclusions. Despite examining a large number of patients, we did not confirm that regular aspirin use was associated with statistically significant improvements in survival in PIK3CA-mutated CRC patients. Prospective evaluation of this relationship is warranted.

Developing a national database for metastatic colorectal cancer management: perspectives and challenges

The changing treatment landscape for metastatic colorectal cancer creates multiple potential treatment strategies. An Australian‐centric database capturing comprehensive information across a range of treatment locations would create a valuable resource enabling multiple important research questions to be addressed.

Analysis of local chronic inflammatory cell infiltrate combined with systemic inflammation improves prognostication in stage II colon cancer independent of standard clinicopathologic criteria

In Stage II colon cancer, multiple independent studies have shown that a dense intratumoural immune infiltrate (local inflammation) is associated with improved outcomes, while systemic inflammation, measured by various markers, has been associated with poorer outcomes. However, previous studies have not considered the interaction between local and systemic inflammation, nor have they assessed the type of inflammatory response compared with standard clinicopathologic criteria. In order to evaluate the potential clinical utility of inflammatory markers in Stage II colon cancer, we examined local and systemic inflammation in a consecutive series of patients with resected Stage II colon cancer between 2000 and 2010 who were identified from a prospective clinical database. Increased intratumoural chronic inflammatory cell (CIC) density, as assessed by pathologist review of hematoxylin and eosin stained slides, was used to represent local inflammation. Neutrophil‐to‐lymphocyte ratio (NLR) >5, as calculated from pre‐operative full blood counts, was used to represent systemic inflammation. In 396 eligible patients identified, there was a non‐significant inverse relationship between local and systemic inflammation. Increased CIC density was significantly associated with improved overall (HR 0.45, p = 0.001) and recurrence‐free survival (HR 0.37, p = 0.003). High NLR was significantly associated with poorer overall survival (HR 2.56, p < 0.001). The combination of these markers further stratified prognosis independent of standard high‐risk criteria, with a dominant systemic inflammatory response (low CIC/high NLR) associated with the worst outcome (5‐year overall survival 55.8%). With further validation this simple, inexpensive combined inflammatory biomarker might assist in patient selection for adjuvant chemotherapy in Stage II colon cancer.

Primary Tumor Resection in Patients With Metastatic Colorectal Cancer Is Associated With Reversal of Systemic Inflammation and Improved Survival

BACKGROUND The true survival benefit of noncurative primary tumor resection in patients with de novo metastatic colorectal cancer (mCRC) remains uncertain. The present study examined the effect of primary tumor resection on systemic inflammation and survival in patients with mCRC. MATERIALS AND METHODS Consecutive patients with de novo mCRC who had undergone primary tumor resection were identified from a prospective database. Patients were excluded if they had undergone resection of metastases, had undergone delayed primary resection, or if blood samples were unavailable. The neutrophil/lymphocyte ratio (NLR) was used as a biomarker of systemic inflammation. Overall survival (OS) was compared between patient groups according to the pre- and postprimary resection NLR. The associations between the reversal of an elevated NLR and primary tumor bulk or performance status were explored. RESULTS A total of 145 eligible patients were identified from the database, with a median age of 70 years. The baseline NLR was elevated (> 5) in 65 patients, 36 (55%) of whom had a low NLR after surgery. The reversal of an elevated NLR was associated with significantly improved OS (hazard ratio, 0.53; P = .017). A similar benefit was seen after excluding patients undergoing emergency primary resection. NLR reversal was more frequent in patients with larger primary tumors or good performance status. CONCLUSION The present study is the first to demonstrate a relationship between the reversal of a systemic inflammatory response and the improved survival after primary resection in those with mCRC. A greater effect was seen in patients with large primary tumors. If validated, these observations could guide clinical decision-making in patients with mCRC at presentation.

Treatment and outcomes of metastatic colorectal cancer in Australia: defining differences between public and private practice

Prior studies have suggested improved outcomes for cancer patients managed in private centres, despite universal healthcare within Australia.

Docetaxel in very elderly men with metastatic castration-resistant prostate cancer

Purpose To evaluate the use of docetaxel in very elderly men with metastatic castration-resistant prostate cancer (mCRPC) treated in routine clinical care. Methods A retrospective case series of men with mCRPC aged ≥80 years and treated with docetaxel between July 2006 and June 2012 at three community hospitals in Melbourne, Australia. Results Twenty patients were identified, with a median age of 83 years (range 80–93 years). Aside from one patient treated weekly, all patients were treated with a 3-weekly regimen of docetaxel with a median of six cycles (range 1–10 cycles) delivered. Eight patients (40%) had an initial dose reduction and 11 patients (55%) had subsequent dose delays or reductions. Eight patients (40%) completed planned treatment. Grade 3/4 hematologic toxicity was observed in nine patients (45%), and five patients (25%) were admitted to hospital with chemotherapy-related complications. Prostate-specific antigen (PSA) response was assessable for 16 patients, of whom nine (56%) had a PSA response of ≥50% and one (6%) had a PSA-complete response. The median overall survival in this cohort was 13.4 months. Conclusions Very elderly patients (80 + years) with mCRPC are infrequently included in clinical trials, yet the use of chemotherapy in this population is likely to increase. Our series demonstrates significant response rates to docetaxel chemotherapy, but that a substantial number of patients had treatment-related complications. This highlights the need for careful patient selection and optimization of chemotherapy dosing.

Patterns of care and outcomes for elderly patients with metastatic colorectal cancer in Australia

OBJECTIVES The elderly accounts for a large proportion of patients with metastatic colorectal cancer (mCRC). This study reviews patterns of care and outcomes for elderly patients with mCRC in the community setting. MATERIALS AND METHODS Elderly patients (≥ 65 years) with mCRC on the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) registry were identified. Treatment, bevacizumab-related adverse events, and overall survival (OS) were analysed by age cohorts, comparing those aged 65-74 vs. 75-84 vs. ≥ 85 years and correlated with potential prognostic factors. Factors affecting chemotherapy and bevacizumab administration were analysed using logistic regression analysis. RESULTS Of 1439 patients, 363, 352, and 106 were aged 65-74, 75-84, and ≥ 85 years, respectively. 584 (71%) patients received first-line chemotherapy, with chemotherapy use declining with advancing age (84%, 69%, and 34% in 65-74-, 75-84- and ≥ 85-year-olds, respectively). Seven (10%) patients aged ≥ 85 years were not treated with chemotherapy on the basis of age alone. Only 10 of 36 very elderly patients who received chemotherapy also received bevacizumab. Factors affecting bevacizumab administration included age, treatment location, and comorbidities. There was no impact of age on bevacizumab-related adverse events. Resection of metastatic disease occurred in 173 (21%) patients overall, with rates declining with age (26% vs. 21% vs. 6%). CONCLUSION Chemotherapy usage and resection of metastatic disease decline with advancing age. A minority of patients are not treated with systemic therapy due to advanced age alone. Our cohort suggests underutilisation of bevacizumab in older patients, but where given, toxicity rates did not increase with age.

Impact of Diabetes Status and Medication on Presentation, Treatment, and Outcome of Stage II Colon Cancer Patients

Diabetes is a risk factor for colorectal cancer and several reports suggest worse cancer-specific outcomes in diabetes patients. Recent studies in multiple tumour types indicate metformin may positively impact on cancer-specific and overall survival. A population-based series of stage II colorectal cancer patients treated and followed from 2000 to 2013 were analysed for baseline characteristics, treatment, and outcomes. 1116 patients with stage II colon cancer were identified, 55.5% were male and median age was 70.9 years (range 20.5–101.2). The diabetes patients (21.6%, n = 241) were older than nondiabetes patients (median 74.0 versus 69.6, p = 0.0001). There was no impact of diabetes on cancer presentation or pathology. Diabetes patients were less likely to receive adjuvant treatment (13.7 versus 24.8%, p = 0.002) but were equally likely to complete treatment (69.7 versus 67.7%, p = 1.00). Diabetes did not significantly impact cancer recurrence (HR = 1.07, 95% CI 0.71–1.63) or overall survival (HR = 1.23, 95% CI 0.88–1.72), adjusted for age. Diabetes medication did not impact cancer recurrence or survival. Cancer presentation and outcomes in diabetes patients are comparable to those of nondiabetes patients in those with stage II colon cancer. The effect of metformin merits further evaluation in patients with colon cancer.