Despite recent advances in cancer drug development, most chemotherapeutic agents eventually fail in the metastatic setting. While some patients’ tumors respond to certain agents, the limited response rate in most patients places increasing importance on tailoring chemotherapeutic regimens for optimal response. Fewer than half of all patients respond to agents commonly used in the metastatic setting, and this fact has significant economic as well as medical ramifications (Figure 1).1,2 In addition, our incomplete understanding of tumor heterogeneity has made treating metastatic cancer difficult.
|Figure 1. High cost of non-responders in the metastatic setting|
In the near future, insurers and other stakeholders will want to see evidence that proposed regimens are likely to work in individual patients. At the same time, identifying regimens that are not likely to work can simplify the selection of agents to use in certain patients. Laboratory professionals can make use of advanced molecular profiling technologies to help clinicians identify biomarkers in patients’ tumors that are predictive of response (or non-response) to specific chemotherapeutic regimens.
Value of molecular profiling in detecting protein biomarkers
While DNA sequencing for known mutations is highly useful in therapeutic decision-making for lung cancer and other solid tumors, the power of this technology is limited by the lack of targeted agents known to work against aberrant sequencing events. Sole reliance on sequencing technologies denies the lab professional the opportunity to detect predictive and prognostic protein biomarkers in patients’ tumors. The true strength of these biomarkers derives from their negative predictive value (i.e., the ability to predict the likelihood of treatment failure). The presence of a biomarker associated with non-response to a specific chemotherapeutic agent may preclude use of that agent against a tumor lacking that biomarker. For example, except for the rare activating mutations in HER2, the absence of HER2 expression correlates with lack of response to trastuzumab and lapatinib.3 Furthermore, though we accept the protein biomarkers estrogen receptor (ER), progesterone receptor (PR), and HER2 for their response data in breast cancer, their possible application in other tumor sites is often overlooked.
As DNA sequencing has attracted increasing attention, many oncologists have drifted from focusing on the protein biomarkers to merely performing DNA sequencing. This trend leads to a loss of prognostication, as there is a limited choice of drugs for use with DNA mutations. Revisiting protein biomarkers in conjunction with DNA sequencing can yield a more complete molecular profile of an individual’s cancer, with significant implications for treatment and clinical trial selection.
Molecular profiling can help the lab professional identify protein biomarkers in tumor types for which their associations have not been well studied. For example, although HER2 amplification and combined TOP2A amplification and deletion are potentially valuable in predicting responsiveness to anthracycline-based adjuvant chemotherapy in patients with early breast cancer, findings from a recent meta-analysis do not support the use of anthracyclines only in patients with HER2-amplified or TOP2A-aberrated tumors.4 In addition, whereas the negative predictive value of BRAF is well-established in non-small-cell lung cancer (NSCLC), melanoma, and colorectal cancer, the presence of mutated BRAF genes makes patients less likely to respond to EGFR-targeted monoclonal antibodies and more likely to respond to BRAF inhibition.5 Finally, druggable mutations that are known to be common in certain tumor types may also be common in others; for example, BRAF mutations, commonly associated with melanoma, have now been reported in malignant peripheral nerve sheath tumors and are associated with response to vemurafinib.6,7
Choosing profiling techniques wisely
It behooves the oncologist to obtain a full molecular profile of the patient’s tumor. Table 1 lists several profiling technologies that can be used to detect and interrogate each biomarker in a tumor. When combined with an exhaustive, evidence-based literature review, the results of these profiling tests can help to individualize anticancer treatment.
|• Immunohistochemistry (IHC): determines level of protein expression|
|• Fluorescence/chromogenic in situ hybridization (FISH/CISH): detects gene deletions, amplifications, translocations, and fusions|
|• Next-generation sequencing (NGS): rapidly examines and more broadly detects somatic mutations across hundreds of hotspots in cancer genomes by determining the DNA sequence|
|• Quantitative polymerase chain reaction (qPCR): amplifies and quantifies a targeted DNA molecule|
|Table 1. Molecular profiling technologies|
In the metastatic setting, combining DNA sequencing, fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC) is useful for identification of phase I clinical trials, as these technologies can help clinicians identify targets that can increase the chances of finding an active agent. However, although treatment guidelines for NSCLC,8 colorectal cancer,9,10 and melanoma11 document a clear benefit for DNA sequencing, such a benefit is lacking for sarcomas and other less common cancers. DNA sequencing is also of limited benefit in breast cancer, which is still heavily reliant on the “classic” protein biomarkers for treatment decision-making. The medical consumer must therefore be savvy about ordering certain profiling technologies. Relying solely on sequencing is not in the patient’s best interest, given the lack of available drugs to target aberrant sequences.
In the future, the use of molecular profiling will likely expand to incorporate immunologic markers to predict response to cancer immunotherapy. The parameters for studying such markers, as well as their predictive and prognostic value, will need to be defined by clinical trials.
Additionally, biomarker data and treatment selection will increasingly be informed by results from so-called “basket” trials. These are studies that evaluate a drug targeting a specific molecular abnormality (e.g., a PI3KCA mutation) in patients with different tumor types, and group patients into separate study arms or “baskets” based on their tumor type. The “basket” trial design enables separate analyses of responses in tumor-specific patient cohorts as well as an overall analysis of response in all patients as a group.
Ultimately, molecular profiling will be used to prove a drug will not fail before it is administered to the patient. Such an approach will save significant resources due to the avoidance of ineffective therapies and unnecessary toxicities, without the loss of response.
- U.S. Food and Drug Administration. Individual drug labels. www.fda.gov.
- DataMonitor. Market and Product Forecasts: Top 20 Oncology Therapy Brands, 2011. http://www.datamonitor.com/store/Product/market_and_product_forecasts_top_20_oncology_therapy_brands_2011_21_avastin_fails_to_top_any_individual_market_in_2011?productid=HC00118-013. Accessed August 6, 2014.
- Bose R, Kavuri SM, Searleman AC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013;3(2):224-237.
- Di Leo A, Desmedt C, Bartlett JMS, et al. HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data. Lancet Oncol. 2011;12(12):1134-1142.
- Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26(35):5705-5712.
- Hirbe AC, Pekmezci M, Dahiya S, et al. BRAFV600E mutation in sporadic and neurofibromatosis type 1-related malignant peripheral nerve sheath tumors. Neuro Oncol. 2013 Dec 22 [Epub ahead of print].
- Kaplan HG. Vemurafenib treatment of BRAF V600E-mutated malignant peripheral nerve sheath tumor. J Natl Compr Canc Netw. 2013;11:1466-1470.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer, version 2.2014. http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed August 6, 2014.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer, version 2.2014. http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed August 6, 2014.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Rectal Cancer, version 2.2014. http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed August 6, 2014.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Melanoma, version 2.2014. http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed August 6, 2014.