July 2013 Edition Vol.11, Issue 7

Breast and Lung Cancer Biomarker Research at ASCO: Changing Treatment Patterns

Breast and Lung Cancer Biomarker Research at ASCO:
Changing Treatment Patterns (cont.)

Genetic Heterogeneity

In addition to the breast cancer studies that examine the concordance and discordance between primary breast tumors and recurrence and survival, an abstract from the National University Cancer Institute of Singapore examined the prevalence of genetic heterogeneity of HER2, concordance or discordance within the primary tumor, and its impact on survival (Ho J et al. J Clin Oncol. 2013;31 [suppl]; abstr 586). The 158 primary breast tumor specimens in this study had similar distribution of HER2 status to SEER data.  

This study used immunohistochemistry (IHC) and the HER2:CEP17 ratio to classify tumors as HER2 genetically heterogeneous, according to the ASCO-CAP (College of American Pathologists) guidelines. The definition of genetic heterogeneity was 5% to 50% of tumor cells with a ratio of more than 2.2. 

Among the HER2-negative cases (n=106), 43.4% were genetically heterogeneous for HER2. All of the HER2 equivocal cases (FISH ratio 1.8-2.2) were genetically heterogeneous for HER2. In total, 36.1% of all 158 cases exhibited genetic heterogeneity for HER2 (Figure 2). HER2 genetic heterogeneity was associated with significantly higher stage (p=0.028), poorer overall survival (p=0.034) and higher grade, although this association was not statistically significant. 

Source: Ho J et al. J Clin Oncol. 2013;31 [suppl]; abstr 586.

This study calls for further prospective studies on HER2 genetic heterogeneity. It raises the importance of testing HER2-negative breast tumors for genetic heterogeneity because of the potential impact on treatment decisions. It also shows the importance of further investigation into the possible benefit of anti-HER2 therapy in HER2-negative breast cancers that have genetic heterogeneity.

Acquired Resistance in NSCLC

Acquired resistance in NSCLC provides an analogous example of the utility of predictive biomarkers and targeted therapies in oncology. Investigating acquired resistance raises the issues of testing, genetic heterogeneity and treatment decisions based on mutation status throughout the course of disease. In the presentation “The Clinical Perspective: Defining and Overcoming Barriers” in the session, “Beyond Progression: Treating EGFR or ALK-Positive Non-Small Cell Lung Cancer (NSCLC) after First-Line Therapy,” Dr. Howard J. West discussed acquired resistance to targeted lung cancer therapies and heterogeneous molecular patterns. The diverse molecular mechanisms of resistance led to diverse clinical patterns of progression. The central question of the presentation was whether clinicians should make changes in therapy based on progression. The data provided many examples of targeted therapy for EGFR and ALK-positive NSCLC, which continued to increase survival after progression and in disease with heterogeneous molecular profiles.

In NSCLC patients with an EML4-ALK translocation who developed resistance to an ALK inhibitor, recent data have shown that while one-half of the resistant patients continue to have tumors driven by ALK mutations, the other half have developed alternative mutations that may render them insensitive to further ALK inhibition. For example, 12% of ALK inhibitor-resistant tumor samples were shown to now possess an EGFR mutation, which may be best managed with an EGFR tyrosine-kinase inhibitor (TKI) (Doebele R. J Clin Oncol. 2012;30 [suppl]; abstr 7504).

Another study (Chen et al. Oncologist. 2012) demonstrated a variability of molecular markers over time and across anatomical sites of disease. They found that acquired resistance might be anatomically isolated, therefore illustrating a heterogeneity of tumor markers in one patient. Dr. West said that “a rogue satellite of disease” that is not responding to a TKI can be treated with local therapy or chemotherapy while the patient continues on the TKI. Oxnard et al. found that a combination of resistant and responsive disease usually exists throughout a patient’s course of disease (Clin Cancer Res. 2011).

The ASCO 2013 presentation on acquired resistance in EGFR- and ALK-positive NSCLC points out that biomarker analysis affects treatment throughout the course of disease. For cancers with a known driver mutation, continued inhibition of the target may be beneficial after progression if a population of cells that are sensitive to the targeted therapy remains. Treating with anti-HER2 therapy in breast cancer post-progression, for example, has been shown to increase the response rate and have a survival benefit. There is also evidence to suggest that NSCLC tumors may remain sensitive to TKI or may be resensitized following a course of chemotherapy (Heon S. J Clin Oncol. 2012;30 [suppl]; abstr 7525).

The resensitizing approach has been shown to be effective both in the preclinical and clinical settings, and it avoids the introduction of a new drug therapy. A study at the Dana Farber Cancer Institute and Massachusetts General Hospital followed 24 EGFR-mutant patients for approximately 10 years. The patients were treated with a TKI, resensitized to the TKI and then retreated with the same drug. Two-thirds of the patients had stable disease with a good median progression-free survival, supporting the practice of restarting the targeted therapy compared with introducing a new drug. Randomized clinical trials are currently ongoing to compare the relative efficacies of these different treatment approaches in NSCLC patients.

In order to determine the best course of action for a recurrent patient, it is critical to understand the molecular profile that is driving the recurrence. This may dictate repeat biomarker testing upon relapse. However, repeat biopsies are not yet commonly performed in NSCLC, in part due to the difficulty in obtaining sufficient lung cancer tissue. 

Pages: 1 2 3

Article Comments

Nguyen Nguyen

quotes Hello Ms. Katz, In the article "Breast and Lung Cancer Biomarker Research at ASCO", for breast cancer you wrote "...representing three of 11 unique biomarkers in oncology that are currently recommended to guide choice of drug regimen." Could you please list the names of these 11 biomarkers? Thank you very much, Nguyen quotes

Post a Comment

OBR Archives

To view previous issues of OBR green you can visit our archives. The entire library of OBR green articles is searchable.