Women with invasive breast cancer can benefit from new genomic test

[News]

A new genomic test combining multiple signatures - a patient's estrogen receptor status, endocrine therapy response, chemotherapy resistance and sensitivity - shows promise as a predictor of chemotherapy response and survival benefit in women with invasive breast cancer, according to research led by The University of Texas MD Anderson Cancer Center.

More... (http://www.news-medical.net/news/20110511/Women-with-invasive-breast-cancer-can-benefit-from-new-genomic-test.aspx)

[gdpawel]

In this prospective study, genomic testing that was prognostic for response to anthracycline and taxane therapy in women with newly diagnosed invasive breast cancer was shown to have improved on predictions based on clinicopathologic parameters.

Here's the fatal flaw: It's just like all similar studies (including OncotypeDX). It's not a real world situation. What they are doing is to collect and freeze specimens and batch process them. This is similar to virtually all of the breast cancer studies, using IHC for ER and Her2 (where studies are performed by batch processing archival, paraffin-embedded specimens).

This is not real world, in which specimens are received daily, in real time, and processed in a clinically relevant time frame. In the real world, when patient gets a biopsy, the specimen gets processed and reported within a few days to a couple of weeks. Each specimen is processed and tested individually, by whomever happens to be working on the days in question. It's not the same team of technicians, working with the same pathologist, with the same reagents and the same microarrays, doing it all at the same time.

With cell culture assays, it is a real world situation. Specimens are received over days, weeks, months, years. They are processed and completed as they come in through the door.

With the NEJM OncotypeDX study, all of the specimens were batched processed within the same 2 week time segment (for hundreds of specimens). Had the specimens been processed and studied under real world conditions (months and years), the correlations would certainly not have been nearly as good.

The same thing goes with ER and Her2. These are "batch processed" studies. This is the only study of which there was reasonably real world (specimens processed and tests completed as specimens were received). Note the poor correlations, particularly with regard to false negatives.

I don't know how one could really deny any breast cancer patient with metastatic disease a trial of hormonal therapy, given the 20% response rate for ER negative patients, with ER performed using IHC in "real world" conditions. But we think that ER negative patients have only a 10% or less response rate, based entirely on non-real world "batch processed" studies.

But that's how all these multi-gene studies are done. Batch processed and retrospective. Utterly non-real world.

[gdpawel]

Private laboratory oncologists have been making this point for years...finally validated -- in the JCO, no less!

All of these marker studies (including Her2, ER, KRAS, EGFR mutations, OncotypeDx, etc.) are highly artificial, non-real world studies. Everything gets batch processed by the same crack team of technologists, same reagents, same platforms, same pathologists, etc. over a brief period of time. In cell culture studies, they are constrained to "real world conditions." Specimens processed and tested as accessioned, in real time, over days, weeks, months, years.

In this study, the authors got null results, which didn't agree with previous findings, and blamed this on the fact that the present study was "real world," while all the prior studies were "batch processed."

From their discussion:

"Finally, it is important to note, that our study required real- time processing of tumor specimens for ERCC1 and RRM1 in situ protein levels. All prior investigations of these molecules utilized batch processing of tumor samples. Thus, day-to-day variations in the assay reliability may have not affected prior investigations, whereas our investigation suffered from this. During the entire trial, all specimens were processed by one of two investigators using a standardized operating procedure, device, and image anal- ysis application. Reagents were from similar sources and prepared identically; however, different lots of reagents were used during the 3.5-year patient accrual period. In an analysis of ERCC1 and RRM1 values over time, we noticed nonrandom trends in marker levels, suggesting that reagent and processing procedures may have influ- enced the biomarker levels.

In summary, we believe that the survival results and possibly the disease response results are false negative. However, the trial clearly demonstrates feasibility of treatment assignment for patients with advanced NSCLC across countries and academic, nonacademic, and private practice settings. We conclude that further assay development with special attention to reagent specificity, day-to-day assay conditions, and site-specific specimen processing is desirable before another trial is launched."

Randomized International Phase III Trial of ERCC1 and RRM1 Expression–Based Chemotherapy Versus Gemcitabine/Carboplatin in Advanced Non–Small-Cell Lung Cancer

Gerold Bepler, Charles Williams, Michael J. Schell, Wei Chen, Zhong Zheng, George Simon, Shirish Gadgeel, Xiuhua Zhao, Fred Schreiber, Julie Brahmer, Alberto Chiappori, Tawee Tanvetyanon, Mary Pinder-Schenck, Jhanelle Gray, Eric Haura, Scott Antonia, and Juergen R. Fischer

Abstract

Purpose:

We assessed whether chemotherapy selection based on in situ ERCC1 and RRM1 protein levels would improve survival in patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods:

Eligible patients were randomly assigned 2:1 to the trial’s experimental arm, which consisted of gemcitabine/carboplatin if RRM1 and ERCC1 were low, docetaxel/carboplatin if RRM1 was high and ERCC1 was low, gemcitabine/docetaxel if RRM1 was low and ERCC1 was high, and docetaxel/vinorelbine if both were high. In the control arm, patients received gemcitabine/ carboplatin. The trial was powered for a 32% improvement in 6-month progression-free sur- vival (PFS).

Results:

Of 331 patients registered, 275 were eligible. The median number of cycles given was four in both arms. A tumor rebiopsy specifically for expression analysis was required in 17% of patients. The median time from informed consent to expression analysis was 11 days. We found no statistically significant differences between the experimental arm and the control arm in PFS (6.1 months v 6.9 months) or overall survival (11.0 months v 11.3 months). A subset analysis revealed that patients with low levels for both proteins who received the same treatment in both treatment arms had a statistically better PFS (P = .02) in the control arm (8.1 months) compared with the experimental arm (5.0 months).

Conclusion:

This demonstrates that protein expression analysis for therapeutic decision making is feasible in newly diagnosed patients with advanced-stage NSCLC. A tumor rebiopsy is safe, required in 17%, and acceptable to 89% (47 of 53) of patients.

J Clin Oncol 31:2404-2412. 2013 by American Society of Clinical Oncology

http://www.ncbi.nlm.nih.gov/pubmed/23690416