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ASCO and Biomarkers: Changing the Course of Disease

Biomarkers played a prominent role in the research presented at the 2013 American Society of Clinical Oncology (ASCO) annual meeting. The Biomarkers France study (Barlesi F. J Clin Oncol. 2013;31 [suppl]; abstr 8000), the largest biomolecular study ever conducted, analyzed the mutation status of 10,000 advanced non-small cell lung cancer (NSCLC) patients and provided molecular profiling of EGFR, HER2, KRAS, BRAF and PIK3CA mutations as well as EML4-ALK translocation and demonstrated the feasibility of genetic tumor profiling. Data presented at ASCO 2013 showed novel clinical implications of biomarkers, including estrogen receptor (ER), progesterone receptor (PR) and HER2 in breast cancer, and EGFR and EML4-ALK in lung cancer. In our post-ASCO discussion, we illustrate the genetic changes throughout the course of disease, acquired resistance, and the influence of biomarkers on testing and treatment.

Genetic Changes throughout Disease Course

Biomarker status agreement was investigated in multiple breast cancer studies. A study of 117 consecutive cases investigated changes in biomarkers ER, PR, HER2 and Ki-67 between the primary tumor and a recurrence after breast-conserving surgery (Okumura Y et al. J Clin Oncol. 2013; 31 [suppl]; abstr 1116). The PR+ rate decreased significantly (p=0.01) and the mean Ki-67 index increased significantly (p=0.047) from the primary tumor to the recurrence. Discordance in the Ki-67 index between the primary tumor and IBTR was associated with a lower distant disease-free survival (DDFS).

A study of 193 patients (Shin HC et al. J Clin Oncol. 2013; 31 [suppl]; abstr 1039) compared the primary breast tumor and a metastatic recurrence. Investigators looked at the triple receptor status (ER, PR and HER2) and divided the patients into three groups: concordant non-triple-negative (TN), concordant TN and a discordant group. The highest overall survival (OS) rate from the primary tumor was among the concordant non-TN group and the concordant TN group had the lowest OS rate. The relative risk of 2.5 (95% CL: 1.2 to 5.3) among the discordant group showed it to be an independent prognostic factor for death after metastasis.

Another breast cancer study (Ho J et al. J Clin Oncol. 2013; 31 [suppl]; abstr 586) examined the prevalence of genetic heterogeneity of HER2, concordance or discordance, within the primary tumor in 158 breast tumor specimens and its impact on survival. Thirty-six percent of the 158 cases exhibited genetic heterogeneity for HER2. HER2 genetic heterogeneity was associated with significantly higher stage (p=0.028), significantly poorer overall survival (p=0.034) and higher grade. These studies raise important questions. When re-biopsying a patient’s tumor, should multiple disease sites be biopsied to best understand discordance and heterogeneity? Are we using the appropriate testing cut points for HER2, for instance?

Acquired Resistance

Acquired resistance in NSCLC provides an analogous example of the utility of predictive biomarkers and targeted therapies in oncology.  An ASCO 2013 presentation, “Beyond Progression: Treating EGFR or ALK-Positive Non-Small Cell Lung Cancer (NSCLC) after First-Line Therapy,” on acquired resistance in EGFR- and ALK+ NSCLC points out that for cancers with a known driver mutation, continued inhibition of a sensitive target may be beneficial even after progression, even when a heterogeneity of tumor markers exists in one patient.

Plasma DNA Testing

A study of breast cancer patients (Beaver J. J Clin Oncol. 2013; 31 [suppl]; abstr 11019) evaluated PIK3CA mutation rates in both tumor specimens and pre-surgery plasma samples using polymerase chain reaction (PCR). The results showed both a high sensitivity (92.3%) and specificity (100%) between the FFPE samples and the pre-surgery plasma.

Similarly, Mok et al., reporting on the detection of EGFR mutations from plasma DNA of NSCLC patients, showed that when using tissue as a comparator, the sensitivity of plasma test was 76% (68 of 89 patients) and the specificity of plasma test was 96% (130 of 135 patients) (J Clin Oncol. 2013:31 [suppl]; abstr 8021). This study concluded that an EGFR blood test can be used to reliably detect EGFR mutations in plasma and is a potent predictor of survival outcomes.


Established biomarkers including ER, PR, HER2, EGFR and ALK hold great potential for the continued development of new targeted therapies and have repercussions for future treatment decisions. Genetic changes over time, acquired resistance, and genetic heterogeneity all have the potential to change a tumor’s behavior and sensitivity throughout the course of the disease. The plasma DNA studies could indicate improvements in diagnostics and advancements in therapeutic decision-making. They also raise the question of the effectiveness of the plasma DNA test if there is discordance between the primary tumor and a recurrence.  What is the acceptable and clinically meaningful level of agreement between plasma DNA testing and tumor DNA testing in order to establish plasma DNA as a surrogate tissue for biomarker testing in the case of PIK3CA, for instance? These studies also raise important questions about companion diagnostics – when and how often should the testing occur? It is clear that the impact of biomarkers on treatment will continue to grow and improve the capacity to provide targeted therapy to cancer patients safely and effectively.

By Julie Katz, MPH, MPhil, Associate Consultant, Clinical & Scientific Assessment, Kantar Health

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