2015 American Society of Clinical Oncology Annual Meeting:

Negative Drug Efflux Pump Expression Confers A More Favorable Outcome Than Positive Expression

Drug efflux pump expression was addressed by Rebecca Feldman, PhD, Research Scientist, Caris Life Sciences, Phoenix, AZ, at the 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, from May 29–June 2.

Multidrug Resistance Phenotype Impairs Chemotherapeutic Efficacy
The multidrug resistance phenotype reduces the efficacy of various chemotherapies. Multidrug resistance is linked to overexpression of adenosine triphosphate binding cassette (ABC) transporters in cancer cells, including P-glycoprotein (PGP/ABCB1), multidrug resistance protein (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2).

Protein Expression Patterns Were Assessed Across Tumor Types
Dr. Feldman and coinvestigators assessed protein expression patterns of drug efflux pumps across all tumor types for insight on how to exploit multidrug resistance status to circumvent treatment dilemmas.

“Data on drug efflux pumps and their significance in treating cancer patients is scarce,” said Dr. Feldman. “More preclinical research than translational research surrounds these transporters, and we need to understand the drug pump’s role in reducing efficacy of cancer treatment.”

A total of 51,939 patients were molecularly profiled using a commercial multiplatform approach developed by Caris Life Sciences. Protein expression was assessed by immunohistochemistry. The Caris Life Sciences registry was queried for patients in this analysis with available clinical outcomes.

Multidrug Resistance Protein 1 Was Found in 81% of Tumors
Across all 51,939 tumors profiled, multidrug resistance protein 1 positivity was highest at 81% (19,935/24,682). BCRP positivity was at 66% (8849/13,409) and PGP lowest at 23% (11,969/51,313).

Gastrointestinal cancers exhibited the most abundant expression of all three drug pumps (80%, 90%, 53%); with the highest average combined expression observed in liver cancers (81%).

In contrast, brain, thymic, and head and neck cancers exhibited the lowest average combined expression of all three drug pumps (39%, 40%, and 42%, respectively).

A total of 6002 patients were evaluable for coexpression with 29% (1728/6002) exhibiting positivity for all three drug pumps (ABC+, highest frequencies in colon, pancreas, ovary, breast, and lung).

Forty-two percent (2494/6002) were positive for 2/3 drug pumps and 21% (1263/6002) positive for 1/3 drug pumps. Only 9% of tumors (517/6002) were negative for all three drug pumps (ABC-, highest frequencies in breast, lung, ovary, skin, and endometrial tumors).

Drug Efflux Pump Expression Affected Survival
To determine the prognostic role of drug pumps on patient survival, differences in median survival were assessed between a cohort of ABC+ (n=31) and ABC – (n=27) patients with breast (n=6, 2, respectively); ovary (n=12, 6, respectively); and lung cancers (n=13, 19, respectively).

Median survival since specimen collection was 596 days for ABC + compared to 855 days for ABC – patients.  “This difference was not significant, probably because of the small sample size, the various cancer types studied, and multiple stages of these cancers,” Dr. Feldman noted. “It’s a cohort containing a wide variety of patients, cancer types, and stages. We will break down the results according to tumor types and stages in future investigations.”

Different tumor types exhibited broad and overlapping expression patterns for drug efflux pumps.

“The data demonstrated that drug pumps are abundantly expressed in this cohort of heavily treated, often refractory cancer patients,” said Dr. Feldman. “Some pumps were more overexpressed than others, and a favorable prognostic role surfaced in breast, lung, and ovarian cancer patients who do not express the three drug pumps tested.”

She continued,  “We also confirmed from previous (in vitro) data that expression of drug pumps is dynamic, and that of protein transporters goes up and down. This likely occurs in response to various chemotherapies.”

Future directions include the identification of more patients in whom we can examine drug efflux pump status in relation to prognosis.  In addition, several other ABC transporters exude chemotherapies, and examining their expression status in cancer patients is also important.”

Dr. Feldman added, “Further study will also determine how transporter expression may impact clinical outcomes. It would be helpful, for example, to confirm the role of simultaneous expression of multiple ABC transporters as a poor prognostic indicator.”

June 30, 2015

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