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PGx/MDx Highlights from the 2013 San Antonio Breast Cancer Symposium

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The following are abstracts presented at the San Antonio Breast Cancer Symposium l held Dec 10-14 focused on pharmacogenomically guided treatment strategies and molecular diagnostics.


Sequencing

Exome sequencing reveals clinically actionable mutations in the pathogenesis and metastasis of triple negative breast cancer

Researchers led by the Duke Cancer Institute reported findings from a prospective exome sequencing study of 38 triple-negative breast cancers, showing the subtype is characterized by dramatic genetic heterogeneity.

In the study, funded by a Susan G. Komen Grant and led by Duke Oncologist Kimberly Blackwell, the team sequenced germline, primary tumor, and metatstatic tumor samples on an Illumina platform using Agilent solution-based exome capture methods. Overall, the effort generated over 10 GB of sequencing data, according to the team's abstract.

No single driver mutation was common to the metastatic tumors, the authors reported, but APC and MTOR mutations occurred more frequently in the metastatic than the primary tumors.

In addition, nonsense mutations of ER were detected in both primary and metastatic tumors but not in germline DNA. EGFR and HER2 mutations were not found in any of the primary or metastatic samples.

According to the group, the effort has revealed the "most comprehensive genetic portrait" of metastatic and primary triple-negative breast cancer to date and represents a "significant first step in identifying the genetic causes of the disease, drivers of recurrence, and potential therapeutic targets."


Whole exome and transcriptome sequencing of 120 primary breast cancer to discover novel therapeutic target

A team from Seoul National University Hospital presented a poster reporting whole-exome and whole-transcriptome sequencing of 120 breast cancer patients, which identified a range of potential therapeutic targets.

The study, led by Min Kyoon Kim, used the Illumina HiSeq2000 to sequence RNA and DNA from fresh-frozen primary breast cancer samples — excluding those with Stage IV disease or those who received neoadjuvant chemotherapy.

According to the group, the effort identified 11,684 putative somatic mutations in 7,373 genes, of which 6,547 were deemed to be a deleterious or damaging mutation based on analysis using the Provean and SIFT software tools.

The group found several mutations in potential drug target genes, including 25 PIK3CA mutations, three PTEN mutations, three AKT1 mutations, three AKL mutations, two ROS2 mutations, three FGRF alterations, two ERBB2 mutations, and single mutation in IDH1.

Excluding the previously confirmed therapeutic targets like PIK3CA, AKT1, and NOTCHs, and considering patients' clinical data, the researchers identified a group of primary target candidates for hormone-resistant breast cancer, which included NQO2, CELSR1, GLUD2, MYH9, PSMD2, NADK, IRS2, and MAP3K5. The group also identified potential targets for triple-negative breast cancer, including HSPG2, PHGDH, and MYLK.

The researchers are now validating the findings with Sanger sequencing and performing functional studies, according to their abstract.


Use of community-based next-generation sequencing (NGS) in advanced breast cancer: Identification of actionable targets to guide clinical trial selection

In a poster presentation, a team led by researchers from the Sarah Cannon Research Institute shared data from an SCRI community-based sequencing initiative to identify actionable mutation in breast cancer in order to guide treatment with approved or investigational drugs, which found potentially actionable mutations in 35 percent of the 93 breast cancers tested.

The researchers, led by Denise Yardley, reported on metastatic breast cancers profiled between October 2012 and May 2013. The group analyzed 35 cancer-linked genes in archival tumor specimens using targeted next-generation sequencing in a CLIA/CAP laboratory.

The team then reported sequencing results to treating physicians within 12 days, after which relevant mutations were used to identify patients appropriate for treatment with approved drugs or in clinical trials.

The researchers found that the community-based molecular profiling initiative was "well accepted by patients and physicians" and provided timely results.

According to the team, 65 percent of the tumors had no mutations detected, 28 percent had a single mutation, and seven percent had multiple mutations. PIK3CA mutations were the most frequently identified alteration, but the effort also identified alterations in RUNX and FGFR3, and even less frequently in PIK3R1, MET, KRAS, KIT, FGFR2, HER2, BRAF, SMO, MYC, DDR2, and AKT1.

The group also found that patterns and frequency of gene variations differed among different breast cancer molecular subtypes.

Six percent of the patients for whom potential targets were identified were enrolled into Phase I clinical trials with PI3K or mTORC1/2 inhibitors, the team reported. An additional 27 patients were potentially eligible for other ongoing trials at SCRI.


MammaPrint

MammaPrint ultra-high risk score is associated with response to neoadjuvant chemotherapy in the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657)

Researchers from the University of California and Genentech presented a poster evaluating how subdividing Agendia's MammaPrint high-risk group into a high-risk and "utra-high risk" subtypes might improve prediction of chemosensitivity and patient outcome.

In the study, the group looked at array data from 149 I-SPY 1 trial patients treated with neoadjuvant chemotherapy and computed a MammaPrint score and risk category.

Of these 149 patients, 138 were in the poor outcome group, or were in the good outcome group, but were HER2-positive.

After further stratifying these patients into two additional groups — MammaPrint high 1 and MammaPrint high 2 — the team found that the MP1 group was mostly hormone receptor-positive, HER2-negative, while the ultra-poor group was more evenly distributed among the four breast cancer subtypes.

The team saw a significantly higher percentage of pathological complete response in the MP2 patients to neoadjuvant chemotherapy than in the overall population, but no significant differences in recurrence-free survival between the two subsets. The authors reported that this is most likely due to the fact that "MP2 patients, who respond best, are also at the highest risk of relapse."

According to the abstract, the results suggest MammaPrint score stratification within the high-risk biology group might be useful for developing companion diagnostics for neoadjuvant therapies, and the team is testing this hypothesis further in the I-SPY 2 clinical trial, which is evaluating several investigational drugs for breast cancer in the neoadjuvant setting using an adaptive randomization design.


Chemosensitivity and endocrine sensitivity of MammaPrint and BluePrint in the prospective neo-adjuvant breast registry symphony trial (NBRST)

A team from Agendia's NBRST trial presented data in a poster suggesting that breast cancer patients in different risk and subtype groups based on the MammaPrint and BluePrint stratification tests have different outcomes and responses to therapy, and that the Agendia tests might predict chemotherapy response more accurately than IHC/FISH.

The NBRST trial is comparing BluePrint/Mammaprint testing to IHC/FISH subtyping to predict neoadjuvant chemosensitivity and neoadjuvant endocrine therapy response.

The poster presentation, led by Pat Whitworth of the Nashville Breast Center, covered data on 191 patients from the trial and showed that molecular subtyping using MammaPrint and BluePrint differed from IHC/FISH results in about 24 percent of tumors.

Overall, the team found that BluePrint predicted chemosensitivity more accurately than IHC/FISH in those patients for which the test gave different results than IHC/FISH status.

According to the researchers, patients with Luminal A-type breast cancer according to BluePrint had a relatively high (71 percent) response to neo-adjuvant endocrine therapy and low (four percent) pathological complete response to neoadjuvant chemotherapy.

Patients with BluePrint HER2-type and Basal-type breast cancer meanwhile, had a high pathological response rate to neoaduvant chemotherapy.


Biomarkers

Potential biomarkers of long-term benefit from single-agent trastuzumab or lapatinib in HER2-positive metastatic breast cancer

An international research team from the randomized Phase II HERLAP trial presented a poster analyzing molecular patterns in the 19-patient cohort in order to identify possible biomarkers that could identify a subset of patients that derived the longest lasting benefit from HER2-targeting therapy without chemotherapy.

HERLAP, which closed early due to slow accrual, evaluated trastuzumab or lapatinib (GlaxoSmithKline's Tykerb) without chemotherapy as first line therapy in patients with HER2-positive metastatic breast cancer.

In the presented study, the HERLAP group — led by Filippo Montemurro, of the Piedmont Oncology Foundation in Italy — performed gene expression analysis of 105 genes on formalin-fixed paraffin-embedded primary tumor samples from the trial, and also evaluated the samples for PAM50 intrinsic subtypes (Luminal A, Luminal B, HER2-enriched and Basal-like) and HER2 status.

According to the team, the gene expression analysis revealed that high expression of the 17q12-21 amplicon genes HER2 and GRB7, and membership in the the PAM50 HER2-enriched intrinsic subgroup were both significantly associated with longer success rates on targeted therapy alone before a switch to chemotherapy.

Conversely, high expression of luminal-related genes such as PGR, MDM2 and PIK3CA, or the PAM50 luminal intrinsic profile, were found associated with worse outcomes on targeted therapy, the group reported.

According to the researchers, the results suggest that tumors belonging to the PAM50 "HER2-enriched" subtype and/or those with high H2T/p95 protein expression ratio are "exquisitely sensitive" to anti HER2-agents.

"[Patients] with these tumors may be candidates for studies aimed at establishing chemotherapy-free approaches," the authors wrote.

The groups results were also published online in Molecular Oncology in September.


Neoadjuvant trial of bevacizumab (B) and trastuzumab (T) in combination with weekly paclitaxel (P) as neoadjuvant treatment in HER2-positive breast cancer: A phase II trial (AVANTHER). Analysis of biomarkers

Researchers from a group of Spanish institutions shared biomarker analysis results from the Phase II AVANTHER trial, showing that expression of IGFR could be correlated with trastuzumab resistance.

AVANTHER is a trial evaluating Avastin (bevacuzimab) in combination with trastuzumab and paclitaxel chemotherapy as a neoadjuvant treatment in HER2-positive breast cancer.

In a poster, the team shared results of gene expression analysis in 44 patients of PI3KCA, TOPO 2α, VEGF, and activation of insulin growth factor 1-receptor (IGF1R), and analysis of how these markers were correlated with pathological complete response in the study subjects.

According to the group, PTEN expression was normal in all patients who had pathological complete response, while only one patient in the group with no pCR had a PTEN deletion.

PI3KCA was mutated in three patients in the pCR group, and four patients in the no-pCR group, while Topo 2α was amplified in eight patients in both groups. IGFR 1 expression was negative in 44.4 percent of the pCR group and 15.4 percent of the no-pCR group, and VEGF was positive in seven pCR group patients and 10 no-pCR patients.

Based on the results, IGFR 1 appears to be a potential marker of trastuzumab resistance, and should be evaluated in future studies, the authors wrote.

The Scan

Highly Similar

Researchers have uncovered bat viruses that are highly similar to SARS-CoV-2, according to Nature News.

Gain of Oversight

According to the Wall Street Journal, the Biden Administration is considering greater oversight of gain-of-function research.

Lasker for mRNA Vaccine Work

The Scientist reports that researchers whose work enabled the development of mRNA-based vaccines are among this year's Lasker Award winners

PLOS Papers on Causal Variant Mapping, Ancient Salmonella, ALK Fusion Test for NSCLC

In PLOS this week: MsCAVIAR approach to map causal variants, analysis of ancient Salmonella, and more.