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Genomics Highlights from the American Society of Clinical Oncology's 2014 Meeting


The American Society of Clinical Oncology held its annual meeting May 30 to June 3 in Chicago. The following are abstracts presented at the meeting focused on genomically- informed treatment strategies.

Prognostic and predictive significance of PAM50 intrinsic subtypes in the NCIC CTG MA.21 phase III chemotherapy trial.

British Columbia Cancer Agency researchers and others from various US and Canadian institutions reported data from a study investigating the prognostic and predictive capabilities of Nanostring's 50-gene PAM50 breast cancer subtyping method.

Researchers retrospectively assessed samples of more than 1,000 study subjects with node-positive or high risk, node-negative disease using the PAM50 test. These patients were previously enrolled in a study comparing three regimens: dose-intense cyclophosphamide, epirubicin and flurouracil (CEF); dose dense and intense epirubicin, cyclophosphamide, and paclitaxel (EC/T); or three-weekly doxorubicin, cyclophosphamide, and paclitaxel (AC/T). The study's original results showed that patients receiving AC/T had reduced relapse-free survival compared to those receiving the other regimens.

Led by Karen Gelmon of BCCA, researchers in this study presented at ASCO, tried to gauge if they could identify, using the PAM50 test, which patients had worse prognosis and would benefit from a taxane-based regimen. The test identified 27 percent of subjects as luminal A, 23 percent has luminal B, 32 percent as basal-like, and 18 percent as HER2 breast cancer subtypes. Although the test results were significantly associated with relapse-free survival (disease prognosis), the interaction between subtypes and treatment outcomes was not significant.

"Subtype was not predictive of outcome amongst these chemotherapy regimens," the study authors concluded in their abstract. Several study authors reported receiving research funding from Nanostring, which markets Prosigna, a breast cancer subtyping test based on the PAM50 gene signature that runs on its nCounter platform.

A study of ovarian cancer patients tested with a 25-gene panel of hereditary cancer genes.

Investigators from Myriad Genetics and Northwest Cancer Specialists in Portland, Ore., conducted a study to assess where patients with hereditary breast and ovarian cancer and Lynch Syndrome are at heightened risk of other inherited cancer syndromes.

From September to December in 2013, researchers led by Lucy Langer of Northwest Cancer Specialists identified 263 patients within a database who a history of ovarian cancer and who were tested using Myriad's myRisk Hereditary Cancer test. In this cohort, 77 percent met National Comprehensive Cancer Network's guidelines hereditary breast and ovarian cancer testing, under 1 percent met guidelines for Lynch Syndrome testing, and 22 percent met guidelines for testing for both syndromes.

The myRisk test gauged deleterious or suspected deleterious mutations in at least one gene in approximately 16 percent of these patients. The mutations occurred in BRCA1 or BRCA2 (11%) and ATM (3.4%). Researchers also found positive mutations in APC in three patients, BRIP1 in two patients, and RAD51C, MSH6, CHEK2, and NBN mutations in single individuals.

In the study, researchers also detected 137 variants of uncertain significance in 263 patients. Some patients had as many as four VUS while the majority, nearly 62 percent had no VUS.

"Testing patients using a 25-gene hereditary cancer panel increased the number of positive test results in ovarian cancer patients by 48 percent over BRCA1 and BRCA2 testing alone, showing the benefit of using a panel approach in this population," Langer and colleagues concluded.

Circulating tumor DNA as a highly specific diagnostic marker for colorectal cancer.

Researchers led by Andre Marziali from Boreal Genomics in Mountain View, Calif., investigated whether circulating tumor DNA can aid in treatment decision making in colorectal cancer. Boreal currently markets the OnTarget assay as a research-use test and intends to validate it in a CLIA lab for clinical use. The company claims that OnTarget is able to separate with great accuracy mutant DNA in plasma or tissue from wild-type DNA, leading to improved detection of cancer upon sequencing patients' samples.

As described in the abstract presented at ASCO, researchers used this assay to analyze plasma samples from three cohorts: 13 normal subjects; 17 age-matched controls; and 17 colorectal cancer patients with all stages of disease who had their blood drawn before receiving treatment or surgery. Researchers also collected and tested primary tumor tissue samples from patients.

Marziali reported 92 percent concordance between patients plasma and tumor tissue profiles in early stage colorectal cancer patients. There were no false positives in the normal cohorts. The test was also able to detect which patients had metastatic disease by gauging mutations in plasma samples.

"Initial assay results from 30 healthy individuals and 17 colorectal cancer patients indicate that OnTarget detection of circulating tumor DNA provides an exceptionally specific assay for the presence of colorectal tumors and may have utility as a biomarker to guide colorectal cancer management across early-stage and metastatic disease," the study authors concluded.

Marziali's group at the University of British Columbia developed Boreal's Synchronous Coefficient of Drag Alteration or SCODA technology, the patent-protected electrophoresis method underlying its Aurora nucleic acid purification and concentration platform.

NRAS and KRAS testing by a new diagnostic method to detect point mutations in colorectal cancer specimens: Clart-NRAS iKRAS.

Investigators from various institutions led by Maria Luisa Villahermosa from Genomica SAU in Spain presented a study using a multiplex diagnostic test for gauging rare KRAS and NRAS mutations in colorectal cancer patients' samples. The test, developed by Genomica, is an ARMS-PCR and microarray-based detection system, called CLART.

Approximately 40 percent of metastatic colorectal cancer patients harbor KRAS exon 2 mutations, which hinder their response to EGFR inhibiting treatments. However, recent studies have shown that patients with mutations in KRAS exons 3 and 4 and NRAS exons 2 and 3, also have a limited response to such agents.

As described in their ASCO abstract, Villahermosa and colleagues designed ARMS-primers and hybridization probes that could detect Q61H (183 A>C), K117N (351 A>C), K117N (351 A>T), A146T, and A146V mutations in KRAS; as well as G12D, Q61H (183 A>T), Q61L, Q61N and Q61R mutations in NRAS. They then tested 33 colorectal cancer patients' samples with these mutations, as well as samples that were wild-type, had KRAS exon 2 mutations, and BRAF mutations. The results were compared to Sanger sequencing.

The investigators reported that the CLART test had a sensitivity and specificity of more than 90% and 98%, respectively, for all mutations. Concordance between their assay and Sanger sequencing was 95 percent or greater.

"CLART NRAS iKRAS simultaneously detects the most prevalent mutations of NRAS and infrequent KRAS … [and is] capable of detecting mutations in samples with less than 5 percent mutated alleles," the study authors concluded. "Our data supports the use of this technology for clinical testing prior to anti-EGFR treatment, for both KRAS and NRAS status in human colorectal cancer samples."

Expression of immunologic genes in triple-negative and HER2-positive breast cancer in the neoadjuvant GEPARSIXTO trial: Prediction of response to carboplatin-based chemotherapy.

Carsten Denkert from Charité-Universitätsmedizin Berlin and colleagues from various institutions investigated whether immunological status of breast cancer patients in the previously reported GeparSixto trial could be informative for predicting response to neoadjuvant carboplatin-based chemotherapy. To do this, Denkert's team evaluated nearly 500 pre-treatment patients' samples for 12 immunologically relevant genes by rea- time PCR -- CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21, IDO1, PD-1, PDL1, CTLA4, FOXP3.

Statistical analysis separated patients' samples into three immune related subtypes, characterized by different expression of immunological genes and different amounts of tumor-infiltrating lymphocytes. All 12 immune markers, researchers reported, were significantly associated with with increased pathologic complete response rates in univariate analysis. Meanwhile, after multivariate analysis, 11 of the genes remained significantly associated with response.

"Some markers, such as CCL5, IDO1 and PDL1 provided predictive information even if controlled for tumor infiltrating lymphocytes," Denkert and colleagues reported. Moreover, CCL5, CD8A, CTLA4, IDO1 and PD1 were found to have a significant interaction with treatment (carboplatin vs. control) in the overall study cohort. In the triple-negative subset, CCL5 and CD8A were predictive for carboplatin response even after adjusting for tumor infiltrating lymphocytes.

"Expression of immune marker mRNAs in breast cancer is predictive for response to neoadjuvant chemotherapy," the study authors concluded. "In GeparSixto, these immunological parameters can be used in addition to tumor infiltrating lymphocytes to identify patients with increased response rates to carboplatin." The study authors noted the need for further validation of their results in other breast cancer trials evaluating carboplatin treatment.

A biopsy-based molecular diagnostic test for prediction of aggressive prostate cancer despite variability in pathology assessment.

Researchers from Genomic Health and the University of California, led by UCSF's Jeffry Simko, presented data from a retrospective study evaluating the ability of the company's prostate cancer risk prediction test, Oncotype DX prostate, to predict adverse pathology in samples assessed by different pathologists with a range of Gleason scores and pathologically assessed stage.

The group found that the assay was a robust predictor of adverse pathology despite stage and Gleason score, and that discordances were "consistent with previous studies," the authors wrote in their ASCO abstract.

Oncotype DX prostate was previously clinically validated in a study that relied on samples for which central biopsy and prostatectomy pathology review were performed by a single expert pathologist.

The new UCSF study assessed samples from 395 patients who underwent radical prostatectomy for low- or intermediate-risk prostate cancer between 1997 and 2011 at the University of California, San Francisco, comparing results of Genomic Health's Oncotype DX prostate with the biopsy gleason score, the prostatectomy gleason score, and the pathologic stage assessed originally by more than 15 UCSF pathologists.

According to the group's abstract, Oncotype DX was predictive of adverse pathology after adjusting for either central biopsy gleason score, or original biopsy gleason score, across the variably-assessed samples.

Simko and other authors of the study reported advisory relationships with and research funding from Genomic Health.

Validation of a 16-gene signature for prediction of recurrence after nephrectomy in stage I-III clear cell renal cell carcinoma (ccRCC).

In another Genomic Health-funded study, a team including researchers from several French hospitals, led by Bernard Escudier, presented results of a validation study of the company's 16-gene Oncotype DX renal cell carcinoma risk prediction test, concluding that the test provides "significant information beyond conventional clinical and pathologic characteristics as a predictor of clinical outcome in patients with stage I-III clear cell renal cell carcinoma."

The group set out to validate the test, which was previously developed in a cohort of 931 patients from the Cleveland Clinic, in an independent group of patients treated with nephrectomy between 1995 and 2007 at a consortium of French hospitals. Patients in this cohort had a median follow up of five and a half years.

According to the group's ASCO presentation, the test strongly predicted renal cancer-specific survival, disease-free survival, and overall survival. In multivariable analyses, the assay also continued to predict recurrence after adjustment for tumor size, Fuhrman grade, and necrosis.

The assay identified 39 percent of stage I patients as having two percent average risk of five-year recurrence and 15 percent of stage I patients as having a 23 percent recurrence risk. In stages II-III, the score found 19 percent to have a two percent recurrence risk and 44 percent to have a 39 percent recurrence risk.

Overall, the researchers reported that the study successfully validated the Oncotype DX assay as a predictor of clinical outcome in patients with stage I-III ccRCC. The assay "may be useful to select patients for adjuvant treatment trials, for active surveillance of small renal masses, and for surveillance strategies after surgery," the authors wrote.

Comparison of test results and clinical outcomes of patients assessed with both MammaPrint and Oncotype DX with pathologic variables: An independent study.

In a comparison of Genomic Health's Oncotype DX breast, and Agendia's MammaPrint tests, an independent group of researchers from several Pittsburgh medical centers, led by David Dabbs, found that "real differences in risk assignments" between the two assays that "may affect treatment decisions."

In their study, the Pittsburgh researchers compared Oncotype DX results for 437 patients with ER-positive cancer who had a minimum of five years of follow up with results of Agendia's MammaPrint, BluePrint, and TargetPrint test suite.

Of 301 patients who were classified as low risk by MammaPrint, the group found that 191 were also low risk according to Oncotype DX, a 63 percent agreement.

Of 136 patients deemed high risk by MammaPrint, 63 were also high-risk by Oncotype DX — a 46 percent agreement.

Among 161 Oncotype DX intermediate risk cases 104 of were MammaPrint low risk and 57 were high risk. Of 287 tumors deemed low risk by BluePrint, 188 (66 percent) were Oncotype DX low-risk, 95 (33 percent) were intermediate, and four cases were Oncotype DX high risk

According to the authors, four percent of the Oncotype DX low-risk patients, 34 percent of the intermediate-risk patients, and 77 percent of the high-risk patients received chemotherapy. Among 7 distant recurrences in this chemo-treated group, four had a MammaPrint high-risk result and three had a MammaPrint low-risk result. Five were Oncotype DX intermediate-risk, one was Oncotype DX high, and one was Oncotype DX low.

One study researcher, Adam Brufsky reported holding a consultant or advisory role with both Agendia and Genomic Health.

Chemosensitivity and endocrine sensitivity predicted by MammaPrint and BluePrint in the Neoadjuvant Breast Registry Symphony Trial (NBRST).

A team from Agendia and researchers from different cancer centers, led by Pat Whitworth of the Nashville Breast Center, presented data from the prospective Neoadjuvant Breast Registry Symphony Trial, which is tracking chemosensitivity in different breast cancer subgroups.

Sharing data from 336 patients, the researchers concluded that molecular subtyping using MammaPrint and BluePrint led to a reclassification of 23 of the tumors in the NBRST cohort from their status based on IHC and FISH, and that "BluePrint reclassification resulted in better grouping of patients into expected response groups compared to local surrogate subtyping with immunostains."

According to the group, among the 336 subjects analyzed, 167 were ER/PR-positive and HER2-negative by IHC/FISH. Of these, 32 were re-classified by BluePrint, 31 of which tested into the Basal subgroup.

Among 95 patients classified by IHC/FISH as HER2-positive, 43 were re-classified by BluePrint; 25 as Luminal and 18 as Basal-type, and of 74 IHC/FISH triple-negative patients, BluePrint found three not to be Basal-type as expected.

Tracking responses in patients treated with neo-adjuvant chemotherapy and endocrine therapy, the researchers found that only one Luminal A patient among 45 treated with neo-adjuvant chemotherapy had a partial complete response, while nine of 13 Luminal A patients on endocrine therapy had a partial response

Of 111 patients classified as Luminal B who received chemo, 7 had a partial complete response. The rate of response among patients who were IHC/FISH ER/PR-positive andHER2-negative patients was higher, about 11 percent, the authors wrote.

Finally, the study also found that response rates seemed to be higher for Blueprint-classified HER2 subgroup patients, than those found to be HER2-positive by IHC/FISH. According to the study authors, 49 percent of BluePrint HER2 patients had a partial complete response compared to 37 percent of IHC/FISH HER2-positive patients. Response rates of BluePrint Basal-type patients, meanwhile, were similar to those seen in patients designated triple-negative by IHC/FISH.