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The Exceptional Responders Initiative: Feasibility of a National Cancer Institute Pilot Study
Barbara A Conley1, Lou Staudt2, Naoko Takebe3
1Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.
Background:
Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses.
Methods:
Exceptional response was defined as partial (PR) or complete (CR) response to a systemic treatment with population PR or CR rate less than 10% or an unusually long response (eg, duration >3 times published median). Cases proposed by patients' clinicians were reviewed by clinical and translational experts. Tumor and normal tissue (if possible) were profiled with whole exome sequencing and, if possible, targeted deep sequencing, RNA sequencing, methylation arrays, and immunohistochemistry. Potential germline mutations were tracked for relevance to disease.
Results:
Cases reflected a variety of tumors and standard and investigational treatments. Of 520 cases, 476 (91.5%) were accepted for further review, and 222 of 476 (46.6%) proposed cases met requirements as exceptional responders. Clinical data were obtained from 168 of 222 cases (75.7%). Tumor was provided from 130 of 168 cases (77.4%). Of 117 of the 130 (90.0%) cases with sufficient nucleic acids, 109 (93.2%) were successfully analyzed; 6 patients had potentially actionable germline mutations.
Conclusion:
Exceptional responses occur with standard and investigational treatment. Retrospective identification of exceptional responders, accessioning, and sequencing of pretreatment archived tissue is feasible. Data from molecular analyses of tumors, particularly when combining results from patients who received similar treatments, may elucidate molecular bases for exceptional responses.
Insights
Identifying exceptional responders retrospectively and analyzing their tumor tissue is feasible. This approach may reveal molecular insights into why some patients respond unusually well to cancer treatments.
Area of Science:
- Oncology
- Translational Research
- Genomics
Background:
- Exceptional responses to cancer therapy offer insights into tumor biology and personalized treatment strategies.
- Retrospective analysis of exceptional responders can identify potential molecular drivers of treatment efficacy.
Purpose of the Study:
- To evaluate the feasibility of retrospectively identifying exceptional responders.
- To obtain and molecularly analyze pre-treatment tumor tissues from these patients.
- To uncover potential molecular explanations for exceptional treatment responses.
Main Methods:
- Exceptional response defined by partial/complete response rates <10% or unusually long duration.
- Clinical and translational expert review of proposed cases.
- Comprehensive molecular profiling including whole exome sequencing, RNA sequencing, and methylation arrays.
- Analysis of potential germline mutations.
Main Results:
- 46.6% of proposed cases met criteria for exceptional responders (222/476).
- Molecular analysis was successfully performed on 93.2% of cases with sufficient nucleic acids (109/117).
- Potentially actionable germline mutations were identified in 6 patients.
Conclusions:
- Exceptional responses are observed with both standard and investigational cancer treatments.
- Retrospective identification and molecular profiling of exceptional responders' archived tumor tissue is feasible.
- Combined molecular data may elucidate the biological basis of exceptional treatment responses.
