Amanda Townsend

Impact of KRAS and BRAF Gene Mutation Status on Outcomes From the Phase III AGITG MAX Trial of Capecitabine Alone or in Combination With Bevacizumab and Mitomycin in Advanced Colorectal Cancer

PURPOSE Mutations affecting the KRAS gene are established predictive markers of outcome with anti-epithelial growth factor receptor (EGFR) antibodies in advanced colorectal cancer (CRC). The relevance of these markers for anti-vascular endothelial growth factor (VEGF) therapy is controversial. This analysis was performed to assess the predictive and prognostic impact of KRAS and BRAF gene mutation status in patients receiving capecitabine with bevacizumab (CG) or capecitabine without bevacizumab in the phase III AGITG MAX (Australasian Gastrointestinal Trials Group MAX) study. PATIENTS AND METHODS Mutation status was determined for 315 (66.9%) of the original 471 patients. Mutation status was correlated with efficacy outcomes (response rate, progression-free survival [PFS], and overall survival [OS]), and a predictive analyses was undertaken. RESULTS Mutations in KRAS and BRAF genes were observed in 28.8% and 10.6% of patients, respectively. KRAS gene mutation status (wild type [WT] v mutated [MT]) had no prognostic impact for PFS (hazard ratio [HR], 0.89; CI, 0.69 to 1.14) or OS (HR, 0.97; CI, 0.73 to 1.28). BRAF mutation status (WT v MT) was not prognostic for PFS (HR, 0.80; CI, 0.54 to 1.18) but was prognostic for OS (HR, 0.49; CI, 0.33 to 0.73; P = .001). By using the comparison of capecitabine versus capecitabine and bevacizumab (CB) and CB plus mitomycin (CBM), KRAS gene mutation status was not predictive of the effectiveness of bevacizumab for PFS or OS (test for interaction P = .95 and 0.43, respectively). Similarly, BRAF gene mutation status was not predictive of the effectiveness of bevacizumab for PFS or OS (test for interaction P = .46 and 0.32, respectively). CONCLUSION KRAS gene mutation status was neither prognostic for OS nor predictive of bevacizumab outcome in patients with advanced CRC. BRAF gene mutation status was prognostic for OS but was not predictive of outcome with bevacizumab.

Does the primary site of colorectal cancer impact outcomes for patients with metastatic disease

Previous reports have described differences in biology and outcome for colorectal cancer based on whether the primary is right or left sided. Further division by right, left, and rectum or even exact primary site has also been explored. Possible differences in response to biological agents have also been reported based on side of primary lesion.

Rising incidence of early‐onset colorectal cancer in Australia over two decades: Report and review

The average age at diagnosis for colorectal cancer (CRC) in Australia is 69, and the age‐specific incidence rises rapidly after age 50 years. The incidence has stabilized or is declining in older age groups in Australia during recent decades, possibly related to the increased uptake of screening and high‐risk surveillance. In the same time frame, a rising incidence of CRC in younger adults has been well‐documented in the United States. This rise in incidence in the young has not been reported from other countries that share long‐term exposure to westernised urban lifestyles. Using data from the Australian Institute of Health and Welfare, we examined trends in national incidence rates for CRC under age 50 years and observed that rates in people under age 40 years have been rising for the last two decades. We further performed a review of the literature regarding CRC in young adults to outline the extent of current understanding, explore potential risk factors such as obesity, alcohol, and sedentary lifestyles, and to identify the questions remaining to be addressed. Although absolute numbers might not justify a population screening approach, the dispersal of young adults with CRC across the primary health‐care system decreases probability of their recognition. Patient and physician awareness, aided by stool and emerging blood‐screening tests and risk profiling tools, have the potential to aid in identification of those young adults who would most benefit from a colonoscopy through early detection of CRCs or by removal of advanced polyps.

Colorectal Cancer Survival: An Analysis of Patients With Metastatic Disease Synchronous and Metachronous With the Primary Tumor

BACKGROUND Whether metastatic colorectal cancer (mCRC) that presents synchronously with the primary lesion behaves differently from mCRC that appears metachronously to the primary disease is not clear. PATIENTS AND METHODS The South Australian Clinical Registry for mCRC collects data for patients diagnosed after February 2006. Data from 2502 patients, available on October 22, 2012, were analyzed according to stage at initial diagnosis (SAID) to compare outcomes between metachronous tumors (MTs) (stages I, II, III) and synchronous tumors (STs) (stage IV). Overall survival (OS) was calculated from the date of mCRC diagnosis. RESULTS Patients with ST had more liver-only metastases, and patients with MT had more lung-only, non-lung and non-liver, and non-lung metastases. The median time to recurrence differed significantly according to SAID: stage I, 49.3 mo (n = 29), stage II, 25.2 mo (n = 346) and stage III, 18.4 mo (n = 497). The median OS was longer for patients with MT than for those with ST (19.0 vs.14.9 mo, P = .003). For patients who received any treatment for mCRC, the OS was longer for patients with MT than for those with ST (19.2 vs. 15.3 mo, P = .005). In patients who received only chemotherapy for mCRC, the median OS was longer for patients with MT than for those with ST (15.2 vs. 9.9 mo, P < .0001). No difference in OS between the MT and ST groups for patients who did not receive treatment for mCRC (1.6 vs. 2.6 mo; P = .95). CONCLUSION Patients with MT have a longer OS than those with ST, independent of treatment. Classification of patients according to whether they have metachronous or synchronous presentation of mCRC is prognostic. These results may add further support for population screening with the aim to reduce de novo metastatic disease.

Metastatic Carcinoid Tumor Changing Patterns of Care Over Two Decades

Background Metastatic carcinoid tumors (MCTs), an important subgroup of neuroendocrine tumors, occur infrequently and often have an indolent course, limiting data on long-term treatment outcomes. We aimed to assess treatment trends at a single center over time and the impact on the outcome. Study Patients diagnosed with carcinoid tumors in the North West Adelaide Health Service between January 1, 1985 and March 1, 2007 were identified from the South Australian Cancer Registry. Results We identified 92 patients with carcinoid tumors; 49 had MCT. Although treatment options increased over time, the most significant change was to access octreotide therapy, with 24 receiving long-acting somatostatin analogs. Survival improved over time and the median overall survival for patients receiving long-acting somatostatin analogs was 112 months compared with 53 months for those who did not (P=0.021, hazard ratio: 2.46). Ten year survival was 40% and 22%, respectively. About 75% of evaluable patients had a biochemical response to initial therapy and a measurable response occurred in 3 of 24 (13%) patients. Conclusions This single center experience has provided insight into current treatment options for MCT, and suggests the use of long-acting somatostatin analogs may impact on disease control and survival. However, the uptake of other treatment options seems limited and there is a need for agents that target tumor progression.

A population-based study of metastatic colorectal cancer in individuals aged ≥ 80 years: findings from the South Australian Clinical Registry for Metastatic Colorectal Cancer

Life expectancy is increasing, and more patients are presenting with cancer at an advanced age (≥80 years). Optimal management for this group of patients has not been well defined.

Impact of age on choice of chemotherapy and outcome in advanced colorectal cancer

BACKGROUND Age is a major risk factor for development of sporadic colorectal cancer but elderly patients are underrepresented in clinical trials and are potentially offered chemotherapy less often. METHODS Data were obtained from South Australian Clinical Registry for advanced colorectal cancer between 1st February 2006 and 9th September 2010. Patients who received chemotherapy were analysed to assess the impact of single versus combination chemotherapy and to assess the outcome in two age cohorts, age < 70 years and ≥ 70 years. RESULTS Out of a total of 1745 patients in the database during this time period, 951 (54.5%) received systemic chemotherapy. 286 (30%) received first line therapy (median age 74 years) with single agent fluoropyrimidine and 643 patients (68%) received first line combination chemotherapy (median age 64 years). The median overall survival of patients receiving first line combination chemotherapy was 23.9 months compared to 17.2 months for those who received single agent fluoropyrimidine (p<0.001). Combination chemotherapy was given to 81% of patients aged < 70 years compared to 53% of those ≥ 70 years. There was no significant difference in median overall survival of patients receiving chemotherapy by age cohort, 21.3 months for age <70 years and 21.1 months for age ≥ 70 years (p = 0.4). CONCLUSION Treatment outcomes are comparable in both the elderly and younger patients. Patients who received initial combination chemotherapy were younger and had a longer median overall survival. In our study, age appeared to influence the treatment choices but not necessarily outcome.

Prognostic impact and the relevance of PTEN copy number alterations in patients with advanced colorectal cancer (CRC) receiving bevacizumab

Loss of phosphatase and tensin homologue (PTEN) expression may be prognostic in colorectal cancer (CRC) and may have a correlation with vascular endothelial growth factor (VEGF) expression via hypoxia‐inducible factor 1 (HIF‐1) alpha, and the PI3K/mTOR pathways. We therefore have explored the prognostic association of PTEN loss and the potential that PTEN loss may be predictive of outcome with bevacizumab. Patients enrolled in the AGITG MAX trial, a randomized Phase III trial of capecitabine (C) +/− bevacizumab (B) (+/− mitomycin C [M]) with available tissues were analyzed for PTEN expression (loss vs. no loss) as assessed using a Taqman® copy number assay (CNA). Of the original 471 patients enrolled, tissues from 302 (64.1%) patients were analyzed. PTEN loss was observed in 38.7% of patients. There was no relationship between PTEN loss and KRAS or BRAF mutation. PTEN status was not prognostic for progression‐free survival (PFS) or overall survival (OS) in multivariate analyses adjusting for other baseline factors; loss versus no loss PFS hazard ratio (HR) 0.9 (0.7–1.16), OS HR 1.04 (0.79–1.38). PTEN was not prognostic when assessed by KRAS and BRAF status. By using the comparison of C versus CB+CBM, PTEN status was not significantly predictive of the effectiveness of B for PFS or OS. PTEN status was not prognostic for survival in advanced colorectal cancer, irrespective of KRAS or BRAF status. PTEN status did not significantly predict different benefit with bevacizumb therapy.

Rechallenge with oxaliplatin and fluoropyrimidine for metastatic colorectal carcinoma after prior therapy

Objectives:Patients with advanced colorectal cancer (CRC) who have received oxaliplatin, 5-fluoropyrimidine, and irinotecan chemotherapy (with or without bevacizumab) and antiepidermal growth factor receptor therapy (if KRAS is wild type) have no further standard treatment options. Although repeating a prior chemotherapy [in particular, oxaliplatin and fluoropyrimidine (FOX)] is an option, there is very little evidence in the literature for this approach; thus, we reviewed our registry to assess the frequency and outcome of rechallenging with FOX. Methods:Patients who had been rechallenged with FOX were identified from the South Australian metastatic CRC database. Patient characteristics were analyzed, and tumor response was retrospectively assessed using Response Evaluation Criteria in Solid Tumors criteria. Results:Twenty patients were eligible for inclusion in this analysis. The number of prior lines of therapy received for metastatic CRC was 4 lines for 2 patients, 3 lines for 6 patients, 2 lines for 7 patients, and 1 line for 3 patients, with 3 patients having received oxaliplatin as adjuvant therapy. Four patients had received bevacizumab previously, 7 patients had undergone antiepidermal growth factor receptor treatment, and 4 patients had undergone liver resection earlier. Response rate was 18%, and 47% had stable disease. The median progression-free survival was 3.7 months, median overall survival was 7.8 months, and 1-year survival was 37%. Conclusions:In this selected population, there is evidence of modest activity of rechallenge with FOX chemotherapy, although radiologic response is uncommon.

Correlation of extended RAS and PIK3CA gene mutation status with outcomes from the phase III AGITG MAX STUDY involving capecitabine alone or in combination with bevacizumab plus or minus mitomycin C in advanced colorectal cancer

Background:Mutations affecting RAS genes are now established predictive markers of nonresponse to anti-EGFR antibodies in advanced CRC. This analysis assessed the prognostic and predictive impact of extended RAS and PIK3CA gene mutation status in patients receiving capecitabine plus or minus bevacizumab (±mitomycin C) in the randomised phase III MAX study.Methods:DNA was extracted from archival macrodissected formalin-fixed paraffin-embedded tumour tissue. Mutation status was determined using pyrosequencing, confirmed with Sanger sequencing (for equivocal RAS) and correlated with efficacy outcomes. Predictive analyses were undertaken using a test for interaction involving both C vs CB+CBM.Results:Of the available 280 of the 471 (59.4%) patients, mutations in KRAS exons 2, 3 and 4 and NRAS 2, 3 and 4 were as follows: 32%, 2.9%, 2.2%, 1.4%, 0.7% and 0% (total RAS MT 39%). The PIK3CA MT rate was 7.5% exon 9 and 3.6% exon 20. Extended RAS gene mutation status (WT vs MT) had no prognostic impact for PFS (HR 0.91 (0.71–1.17)) or OS (HR 0.95 (0.71–1.25)). The RAS gene mutation status was not predictive of the effectiveness of bevacizumab for PFS (HR 0.56 (0.37–0.85) for RAS MT and HR 0.69 (0.5–0.97) for RAS WT; P for interaction 0.50). The PIK3CA mutation was neither predictive for bevacizumab effect nor prognostic.Conclusion:Of KRAS exon 2 WT patients, 10% had additional RAS mutations. Neither all RAS gene mutation status nor PIK3CA mutation status was prognostic for PFS or OS, or predictive of bevacizumab outcome in patients with advanced CRC.