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Personalized Medicine Highlights from San Antonio Breast Cancer Symposium 2012

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The following is a summary of studies exploring personalized treatment strategies in breast cancer that were presented at the San Antonio Breast Cancer Symposium, held Dec. 4-8.


Myriad's HRD Score, BRCA Mutation Status Used to Predict Response to Platinum-based Chemo in TNBC

Researchers from Stanford University and Myriad Genetics presented data at SABCS showing that Myriad's homologous recombination deficiency assay can be used to predict which patients with early-stage triple-negative breast cancer and BRCA 1 and BRCA 2 mutations will likely respond to neoadjuvant, platinum-based treatments.

Myriad is developing the homologous recombination deficiency, or HRD, test as a tool that oncologists can use to determine which patients will likely benefit from DNA-damaging agents such as platinum therapies and PARP inhibitors. Myriad has companion diagnostic development agreements with several drug companies developing PARP inhibitors, including Abbott Pharmaceuticals, AstraZeneca, BioMarin Pharmaceuticals, as well as with Pharma Mar for a DNA-damaging agent (PGx Reporter 8/1/2012).

Myriad recently published data from a study in the British Journal of Cancer showing that the HRD score can gauge whether ovarian tumor cells have impaired ability to repair DNA function that cancer cells depend on for survival. Studies suggest that patients with BRCA 1- and BRCA 2-mutated tumors and other homologous recombination defects respond well to drugs that exploit double-stranded DNA breaks (PGx Reporter 10/17/2012).

In the study presented at SABCS, researchers led by Melinda Telli of Stanford University used the HRD score to analyze 77 tumor samples – 54 fresh frozen and 23 formalin-fixed paraffin embedded tissues – collected from 76 patients. The patients had stage I to stage IIIA, triple-negative breast cancer, and had tumors harboring BRCA 1 or BRCA 2 mutations. Study participants were treated with a regimen containing gemcitabine, carboplatin, and iniparib.

Researchers characterized patients' pathological response in terms of residual cancer burden (RCB), with RCB 1, 2, and 3 denoting, minimal, moderate, and extensive residual disease, respectively. Those that fell into RCB 0/1, 44 patients, were defined by researchers as responders to treatment and those in the RCB 2/3 category, or 33 patients, were classified as non-responders.

Study participants' genotype data were generated using Affymetrix MIP arrays for 15 patients, a custom Agilent SureSelectXT capture followed by sequencing by Illumina HiSeq 2500 for 21 patients, and both assays for 41 patients. In instances when data from both types of assays were available, researchers used data from the Illumina HiSeq.

The study authors reported that the HRD score correlated "significantly" with pathological response in patients treated with platinum-based chemotherapy who had BRCA 1/2 mutations and early-stage, triple-negative breast cancer. The data show that 70 percent of patients with an HRD score of 10 or greater responded to platinum-based treatment, while only 20 percent of patients with an HRD score under 10 responded to treatment.

A majority of triple-negative breast cancer patients (52 out of 74) scored 10 or higher by the HRD test, while 16 out of 19 patients with BRCA 1/2 mutations had such a score. Although the researchers noted no mean difference in HRD scores between those with BRCA 1/2 mutations versus those with normal gene function, the combination of the HRD score and BRCA mutations allowed differentiation between treatment responders and non-responders.

"Seventy percent of patients with a HRD score [greater than or equal to] 10 or BRCA1/2 mutation responded compared with 12 percent of patients with a HRD score [less than] 10 and intact BRCA 1/2," the study authors reported in the abstract.

Going forward, the researchers plan to further study the role of HRD in breast cancer in all 93 enrolled patients and conduct multivariate analysis to look at the role of the HRD score when BRCA 1/2 genotypes are factored in with patients' age, cancer stage, tumor grade, estrogen receptor and progesterone receptor status, and number of therapy cycles.

Researchers at Stanford are also looking at whether the HRD assay can be used to predict when triple-negative breast cancer patients will respond to anthracycline/taxane-based therapy. Myriad eventually plans to investigate prospectively whether the HRD score can be used to direct patients to either platinum-based or anthracycline/taxane-based therapy.


Researchers Compare Ability of Three Prognostic Tests to Gauge Late, Distant Breast Cancer Recurrence

Researchers from Massachusetts General Hospital, Queen Mary University, BioTheranostics, and Royal Marsden Hospital reported data from a study comparing how accurately three breast cancer prognostic tests – Oncotype DX, Breast Cancer Index, and IHC4 – gauged the risk of late, distant recurrence.

"Patients with estrogen receptor-positive, early breast cancer have a continuous yearly recurrence rate extending out to 15 years after having received adjuvant endocrine therapy for five years," the study authors said in the abstract, highlighting that more than 50 percent of breast cancer recurrences occur five years after diagnosis.

They added that "current multi-gene signatures have significant prognostic performance in predicting early recurrence (zero to five years post-diagnosis), however, such signatures have limited performance in predicting the risk of late recurrence (greater than five years)."

Genomic Health's Oncotype DX, the market leader in breast cancer recurrence diagnostics, analyzes the expression of 21 genes by RT-PCR. IHC4, developed by Royal Marsden Hospital and Queen Mary University, is an immunohistochemistry test that derives a recurrence score based on quantifying estrogen receptor, progesterone receptor, Ki67, and HER2. BioTheranostics' Breast Cancer Index combines two indices that evaluate endocrine signaling and mitogenic pathways: A two gene expression ratio biomarker associated with estrogen signaling and a five cell cycle-linked gene index that gauges tumor grade.

According to the abstract presented at SABCS, the investigation revealed BioTheranostics' test to be superior compared to the other diagnostics in assessing which patients will likely experience disease recurrence five years after they've been diagnosed with breast cancer. "Breast Cancer Index, unlike IHC4 and [Oncotype DX] RS, is a significant prognostic factor for late recurrence and enables the assessment of individual recurrence risk for estrogen receptor-positive patients [who are] recurrence-free after five years of endocrine therapy," the study authors concluded, noting that this study is the first to compare the ability of multi-gene assays to gauge late residual recurrence risk in breast cancer patients after treatment with endocrine therapy.

In the investigation presented at SABCS, researchers led by Dennis Sgroi of MGH used the Breast Cancer Index to analyze tissue samples from approximately 1,000 patients with node-negative disease previously enrolled in the TransATAC study in order to evaluate their risk of early recurrence in the first five years after diagnosis and late recurrence between five and 10 years post-diagnosis. In TransATAC, patients were treated with the aromatase inhibitor anastrozole or tamoxifen.

Using previously reported data on Oncotype DX and IHC4 analysis of TransATAC samples, the study authors compared the determinations made by the three diagnostics in terms of distant recurrence, any recurrence, breast cancer death, and overall survival.

Although all three tests provided "significant prognostic performance for early distant recurrence (zero to five years)" and provided more prognostic information over standard clinical assessments for the period of 10 years post diagnosis, "only BCI was significant beyond clinical treatment score for late distant recurrence," Sgroi et al. reported. "Similar comparative results of Breast Cancer Index, [Oncotype DX] recurrence score, and IHC4 for late recurrence were observed for the other clinical endpoints."

PAM50, a multi-gene assay that gauges the risk of 10-year distant recurrence in breast cancer, was not included in the comparison. In a previous study, NanoString compared prognostic data from its version of the PAM50 test against Oncotype DX and IHC4 and found that PAM50 provided significantly more information than the other tests about patients' risk of distant recurrence-free survival (PGx Reporter 12/14/2011).


NanoString Presents Data from PAM50 Studies

At SABCS, NanoString Technologies reported positive results from a second validation trial involving its PAM50 test.

The trial, led by Michael Gnant from the Comprehensive Cancer Center in Vienna, investigated the prognostic value of the PAM50 risk score compared to standard clinical measurements. Researchers analyzed more than 1,400 samples from hormone receptor-positive early stage breast cancer patients previously enrolled in the ABCSG8 trial and treated with tamoxifen or tamoxifen plus anastrozole.

PAM50, operating on NanoString's nCounter platform, measures mRNA expression levels of 58 genes to classify patients' intrinsic breast cancer subtypes as Luminal A, Luminal B, Her2-enriched, or Basal-like46, and provides a risk of relapse score.

The validation study revealed that the risk of relapse score adds statistically significant prognostic data beyond standard measures in all patients. Additionally, the study showed that Luminal A patients had better outcomes than Luminal B patients when receiving tamoxifen alone. The ability of PAM50 to distinguish between Luminal A and Luminal B subtypes adds significant information regarding distant relapse-free survival beyond clinical measures, the study authors reported.

The company holds an exclusive worldwide license to use the PAM50 gene signature to develop commercial tests and research products on its nCounter Analysis System.

The ABCSG8 study, alongside results of the TransATAC study, which the company reported at SABCS last year, "together provide Level 1 evidence for the clinical validity of the PAM50 test for predicting the risk of distant recurrence in postmenopausal women with HR+ EBC treated with endocrine therapy alone," Gnant et al. wrote in a poster presented at this year's symposium.

In September, NanoString achieved CE Mark self certification for PAM50 in the European Union. The test is for research use only in the US. The validation studies for PAM50 are intended to support regulatory approval for the test in the US and in other markets.

The company is planning to conduct additional validation studies comparing PAM50 against other breast cancer recurrence signatures and is investigating the test's ability to gauge distant recurrence in patients receiving various chemotherapy regimens.

In another trial, also presented at SABCS, researchers from the Mayo Clinic College of Medicine and elsewhere used the multi-gene assay to analyze more than 1,300 samples from patients previously enrolled in the CALGB9741 trial, which compared in four treatment arms the efficacy of sequential versus concurrent chemotherapy, and conventional dosing versus dose dense administration.

The primary endpoint was relapse-free survival, and researchers led by Minetta Liu of Mayo Clinic investigated whether patients' intrinsic subtypes were linked to how well they benefited from dose dense chemotherapy. Researchers also looked at whether patients' subtypes, risk of relapse scores, and proliferation scores were associated with recurrence.

In the study, the researchers found that patients' intrinsic subtypes were associated with relapse-free survival regardless of the type of chemotherapy dose or schedule they received.

"The prognostic value of PAM50 subtype, risk of relapse score, and proliferation score remains highly significant in patients treated with contemporary adjuvant anthracycline and taxane-based chemotherapy," the study authors concluded.

Since patients' intrinsic subtypes did not seem to be associated with better survival by either dosing schedule, Liu et al. hypothesized that "the prognostic differences by subtype outweighed the modest but significant clinical benefit of dose dense chemotherapy administration for the overall population."

Additionally, in comparing the prognostic value of measuring patients' intrinsic subtypes versus IHC subtypes, the study authors found intrinsic subtypes to provide more prognostic data.


Phase III Study Shows TNBC Patients Don't Benefit Significantly by Adding Avastin to Chemo

Results from the Phase III BEATRICE trial show that triple-negative breast cancer patients who received one year of Genentech's Avastin (bevacizumab) in combination with chemotherapy did not experience significantly longer disease-free survival than those receiving just chemotherapy.

“This study did not confirm the hypothesis that adding bevacizumab to chemotherapy would improve patients’ outcomes,” David Cameron, professor of oncology at Edinburgh University in Scotland, said at SABCS in a presentation announcing results from BEATRICE. “Therefore, sadly for patients, we have nothing extra to add to chemotherapy for early, triple-negative breast cancer.”

At an hearing last year to consider whether the US Food and Drug Administration should revoke Avastin's metastatic breast cancer indication, many women with triple-negative breast cancer — a hard-to-treat and virulent form of the disease where tumors do not express estrogen receptor, progesterone receptor, or HER2 — said they had had a robust response to Avastin. The patient stories, as well as a biomarker strategy proposed by Genentech, failed to sway FDA, however, and Avastin's breast cancer indication was pulled last November (PGx Reporter 11/30/2011)

In BEATRICE, more than 2,500 triple-negative breast cancer patients with operable, invasive disease were randomized to receive Avastin with either anthracycline-based or taxane-based chemotherapy or receive chemo alone. After 32 months of treatment, the hazard ratio was 0.87 in favor of patients receiving the Avastin-containing regiment, with 107 deaths in the chemotherapy alone arm versus 93 deaths in the Avastin arm.

“Bevacizumab clearly does something in this setting, but the effect is not sustained, and therefore, adding bevacizumab to chemotherapy for all these patients is not the way to improve their chances," Cameron said in a statement released by the American Association for Cancer Research.

Although Avastin didn't increase the risk of fatal adverse events in BEATRICE, researchers reported increased grade 3 or greater hypertension, left ventricular dysfunction, and congestive heart failure in patients receiving the bevacizumab-containing regimen.

Cameron noted the need for further research to better understand the triple-negative breast cancer population.

In a pilot project to assess the feasibility of using 23andMe's direct-to-consumer genomics service to collect patient-reported genetic data and outcomes information for genome-wide association studies, Genentech is recruiting metastatic breast cancer patients treated with Avastin for the InVite study. The partners hope to enroll 1,000 patients, and recruitment is taking place through 23andMe's online customer base as well as referrals from patient advocacy organizations, such as the Avon Foundation for Women, Facing Our Risk for Cancer Empowered, and the Triple Negative Breast Cancer Foundation (PGx Reporter 8/1/2012).

The Scan

Study Finds Few FDA Post-Market Regulatory Actions Backed by Research, Public Assessments

A Yale University-led team examines in The BMJ safety signals from the US FDA Adverse Event Reporting System and whether they led to regulatory action.

Duke University Team Develops Programmable RNA Tool for Cell Editing

Researchers have developed an RNA-based editing tool that can target specific cells, as they describe in Nature.

Novel Gene Editing Approach for Treating Cystic Fibrosis

Researchers in Science Advances report on their development of a non-nuclease-based gene editing approach they hope to apply to treat cystic fibrosis.

Study Tracks Responses in Patients Pursuing Polygenic Risk Score Profiling

Using interviews, researchers in the European Journal of Human Genetics qualitatively assess individuals' motivations for, and experiences with, direct-to-consumer polygenic risk score testing.