Conventional wisdom used to hold that everyone with a tumor greater than 1 cm should be treated with chemotherapy, but now oncologists are realizing that genome testing could better tailor treatment to those it will help most. [© iQoncept - Fotolia.com]
This month, the Association for Molecular Pathology issued its “Opportunities and Challenges Associated with Clinical Diagnostic Genome Sequencing” report. The report noted that while molecular testing can be accomplished at greater speed and at high volume, “The potential impact on the diagnostic process and clinical correlations is extraordinary and clinical interpretation will be challenging.”
But despite these challenges, genomic testing, particularly in breast cancer, has already impacted physician and patient therapeutic decisions, albeit with some frustration on both sides.
Genomic Health currently markets its Oncotype DX breast cancer gene expression assay for use in women with early-stage (stage 1 or 2), node-negative, estrogen receptor-positive (ER+) invasive breast cancer who will be treated post-surgically with tamoxifen.
The real-time RT-PCR assay measures RNA expression in 16 cancer-related genes and five reference genes in paraffin-embedded breast tumor tissue. Results are expressed as a recurrence score (RS) between zero and 100, translated as low risk (a score of 18 or lower), medium risk (19 to 30), or high risk (31 or above). This score helps predict the chance that early-stage, estrogen receptor-positive, lymph-node-negative breast cancer will return within 10 years of the original diagnosis and provides additional information on the responsiveness of breast cancer tissue to chemotherapy.
A competing test, Agendia’s MammaPrint microarray assay, measures expression of 70 genes in fresh tissue, categorizing patients as either high risk (with a so-called poor signature) or low risk (with a so-called good signature) for recurrence, with no intermediate category.
There is no doubt that these tests have reduced the number of women being treated with chemotherapy whose tumors were unlikely to respond to further therapy. “When it comes to treating breast cancer, we used to throw the book at everyone,” said Christy A. Russell, a board member of the American Cancer Society’s California division and an associate professor at the University of Southern California Keck School of Medicine. “Now it’s much more targeted.”
Since its approval in 2004, Genomic Health says, multiple studies have established the test’s utility in providing information that improves patient selection for chemotherapy. One study reports that the test results changed the oncologist’s treatment recommendations, indicating that breast oncology specialists tended to overestimate the risk of tumor recurrence compared with RS. RS provided useful information that improved patient selection for chemotherapy and changed treatment recommendations in approximately 25% of cases, the investigators concluded.
Ongoing studies are likely to provide greater clarity for breast cancer patients with “low to intermediate” RS scores, who currently have to make treatment decisions with less definitive guidelines. For example, the ongoing TAILORx prospective randomized Phase III trial will determine the best individual therapy for women who have node-negative, estrogen receptor-positive breast cancer using Oncotype DX, to determine whether hormone therapy alone or hormone therapy together with combination chemotherapy is better for women with an RS score of 11–25, with final results expected in December 2017.
In January 2010, Genomic Health began offering a 12-gene Oncotype DX test for newly diagnosed stage 2 colon cancer. The test is performed on tumor tissue removed during the original surgery. As of June of 2012, it became available for colon cancer patients with stage 3 disease as well.
Without doubt, genomic testing of cancers has found favor with oncologists, despite the need for increasing definition of what their results really mean in the context of individual patients and other clinical parameters.
George Sledge, who will become director of the division of oncology in the department of medicine at Stanford University in January, commented that when the NIH held its consensus development conference on adjuvant therapy with breast cancer in 2000, oncologists were in general agreement that everyone with a tumor greater than one centimeter ought to be treated with chemotherapy.
“There’s no question that resulted in us hugely overtreating patients,” he said. “So I think a test that reduces the quantity of human suffering by half in that group is a useful test.”
But ultimately defining treatment for individual patient may evolve to rely on a complicated array on tests that goes beyond genomics to characterize tumor molecular patterns.
In the October 4 issue of Nature, investigator participants in the Cancer Genome Atlas Network described “Comprehensive molecular portraits of human breast tumors.”
While breast cancer has been categorized into four main types, these are based on whether the tumors express the estrogen receptor (ER positive) or the progesterone receptor (PR positive), overexpress one of the members of the epidermal-growth-factor receptor family (Her2 positive) or none of these, an extremely difficult to treat classification known as triple-negative breast cancer.
And although tumor morphology is often associated with the pattern of molecular aberrations in breast cancers, tumors of the same histological subtype display “remarkably different” clinical behavior.
The researchers, using data generated as part of The Cancer Genome Atlas (TCGA), based their studies of the four standard molecular subtypes on a comprehensive characterization of samples from 825 breast cancer patients.
The investigators combined data from five different platforms, including genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing, and reverse-phase protein arrays, to provide insights into previously defined gene expression subtypes, each of which shows significant molecular heterogeneity.
They also confirmed many “molecular commonalities” between basal-like breast tumors, or highly aggressive triple-negative tumors indicating a related etiology and similar therapeutic opportunities. This data suggests that patients with triple-negative breast cancer might benefit from therapies used to treat ovarian cancer.
“The molecular similarity of one of the principal subtypes of breast cancer to that found in ovarian cancer gives us additional leverage to compare treatments and outcomes across these two cancers,” commented Harold Varmus, NCI director. “This treasure trove of genetic information will need to be examined in great detail to identify how we can use it functionally and clinically.”
As molecular analysis of cancer goes beyond genomics to include a detailed molecular understanding of cancer, this knowledge will advance our understanding of the disease and improve the ability to diagnose, treat, and prevent it, according to the TCGA. But to recapitulate the American Society of Pathology’s report, the potential impact on the diagnostic process and clinical correlations will become more “extraordinary and clinical interpretation will be challenging.”