For the First Time, Origins of Lethal Prostate Cancer TrackedFran Lowry
October 25, 2013
medscape.com
For the first time, researchers have traced the development of lethal prostate cancer, from the primary cancer to metastases, in a patient who died from the disease. The innovative effort was enabled by whole-genome sequencing and molecular pathological analyses.
The research provides "proof-of-concept of the potential importance of molecular staging and grading strategies, in conjunction with existing pathological criteria, to accurately inform clinical decision making in precision medicine," write the authors, led by Michael C. Haffner, MD, from Johns Hopkins University in Baltimore.
The work was published in the November issue of the Journal of Clinical Investigation.
Dr. Haffner and his group note that prostate cancer is highly heterogeneous, with manifestations that range from indolent localized tumors to widespread metastases.
"Given recent controversies surrounding overtreatment of prostate cancer, there is a critical need to understand the features of the primary tumor that are associated with progression to lethal disease," they write.
Death 17 Years After Initial Diagnosis
The patient in question was diagnosed with prostate cancer when he was 47 years old. His entire primary tumor and a single involved lymph node metastasis was removed with radical prostatectomy, but an elevated prostate specific antigen level 5 years after the surgery suggested the disease was systemic.
The patient received the investigational prostate cancer vaccine GVAX, androgen ablation, systemic chemotherapy, and localized radiation. Despite these treatments, the patient died at the age of 64 from castrate-resistant prostate cancer, 17 years after his initial presentation.
The researchers used tissue samples taken throughout the progression of the cancer and at the time of death to identify the origin of the lethal clone.
They were surprised to find that the lethal clone originated from a small low-grade focus in the primary tumor, and not from the larger higher-grade primary tumor or from the lymph node metastasis resected at prostatectomy.
The generalizability of the findings from this work are not clear, because this is the first prostate cancer case in which it was possible to carry out such detailed longitudinal characterization of the lethal cell clone, from the primary cancer to distant metastases, the authors note.
In an accompanying commentary, A. Rose Brannon, PhD, and Charles L. Sawyers, MD, from the Memorial Sloan-Kettering Cancer Center in New York City, commend Dr. Haffner and his group for reporting "such a fascinating anecdote." They note that the effect of this work "will only be realized if we can collect and assemble this type of data across hundreds of cases."
The Potential Importance of "N of 1" Studies
Drs. Brannon and Sawyers note that enthusiasm for reporting single cases is on the rise. They cite, as an example, a clinical trial testing the mTOR kinase inhibitor everolimus in metastatic bladder cancer. Only 1 person enrolled in that trial had a complete remission (Science. 2012;338:221).
That patient's tumor had a mutation in TSC1, a tumor suppressor gene known to regulate mTOR kinase activity. Three other patients in the trial whose tumors had TSC1 mutations had partial responses. The rest of the patients had wild-type TSC1 tumors, and did not respond to everolimus.
Even though the number of patients in this trial was small, the results were sufficient to prompt a clinical trial of everolimus in TSC1-mutant cancers.
"Such biomarker-based clinical trials (called 'basket studies') are becoming increasingly common in oncology and reflect growing confidence that molecular diagnostics can predict treatment response," Drs. Brannon and Sawyers write.
In fact, the National Cancer Institute recently began the Exceptional Cases Initiative to identify and sequence tumors from 100 extraordinary responders to any form of cancer therapy.
"If successful, this initiative could legitimize a new field of 'N of 1' science," they write.
A comprehensive database of such studies will be needed to identify common patterns in cancer progression, Drs. Brannon and Sawyers note.
"The growing penetration of genomic sequencing into clinical medicine has led to increased calls for the creation of various types of medical 'data commons' that will allow comparisons between individual cases. Perhaps we are entering an era in which 'N of 1' cases are here to stay," they conclude.
Dr. Haffner and Dr. Brannon have disclosed no relevant financial relationships. Dr. Sawyers reports serving on the board of directors for Novartis Pharmaceuticals and on scientific advisory boards for Agios, Beigene, Blueprint, Housey Pharmaceuticals, Nextech, and Tracon.
J Clin Invest. 2013;123:4918-4922, 4568-4570. Abstract, Commentary |
