N of 1 Study Insightful to Prostate Cancer Evolution, Therapy?
Updated: Apr 26
18 November 2013
Cancer is a microcosm of evolution, the most lethal versions of which are bestowed with an immense reservoir of genetic heterogeneity, providing the raw resources to adapt to changing environments. The physical manifestations of this are the same that thwart treatment: chemotherapy resistance and metastasis (1).
Tumor heterogeneity over time is difficult to study, owing to a rarity in genomics-grade longitudinal samples in cancer patients. Last week I had the pleasure of presenting a curious N=1 study to our weekly journal club here at the Moores Cancer Center. Haffner and colleagues performed genomic and histological analyses on unusually well-preserved specimens collected over a man’s 17 year disease course with prostate cancer (2). (article available for free here)
The ensuing analyses revealed a few interesting pieces of information:
The region of the prostate surveyed that likely gave rise to a wave of lethal metastases 17 years after diagnosis (and radical prostatectomy) was of low histological grade compared to the rest of the prostate tumor region.
The lymph node metastasis removed the same time as the radical prostatectomy differed in molecular signature to the lethal metastases 17 years later, indicating a diverging evolution and suggesting, at least in this patient, that the palpable lymph node tumor did not act as a way station for the lethal, visceral metastases 17 years later in the lung, liver, and thoracic lymph nodes. This gives weight to the “embolization” theory of metastasis in prostate cancer, which posits that lymphatic and hematogenous dissemination are two separate paths, the lethal one being hematogenous. In breast cancer, this distinction was the subject of much debate until clinical trials very clearly demonstrated that aggressive removal of regional lymphatics does not reduce the risk of distant organ dissemination in breast cancer (3, 4). Perhaps the same could be true for prostate cancer? While not “essential” organs, aggressive surgical removal of regional lymphatics is far from innocuous. Even small hints at tumor evolution can glean valuable information for the most effective, least invasive means to treat prostate cancer.
Lastly, the metastatic clones that aggressively arose 17 years after diagnosis were all highly similar in both driver and passenger mutations, indicating a temporally recent progenitor. The questions that I would like to ask are:
Where were these metastatic clones hiding out for 17 years? The patient had multiple gaps without detectable disease. Also, what caused re-immergence from metastatic latency? Why then and not 10 years prior or 10 years in the future? Was there an undetected watershed moment mutation after decades of genomic Russian roulette and genomic instability that enabled the emergence of a lethal clone? Or, were there coordinated changes in many tissues at once that could have given rise to a more favorable environment for metastasis (i.e. perhaps some threshold related to aging)?
These questions cannot be answered with the current study, and I agree with Brannon and Sawyers (5) that N=1 studies could be immensely more powerful if we are able to better transpose genomics to the spatial and temporal disease course of many patients. At this point we have the technology; the real challenges in implementation are clinical and logistical, which can be overcome.
Ryon References: 1. Klein CA. Selection and adaptation during metastatic cancer progression. Nature. 2013 09/19/print;501(7467):365-72. 2. Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA, et al. Tracking the clonal origin of lethal prostate cancer. The Journal of clinical investigation. 2013 Nov 1;123(11):4918-22. PubMed PMID: 24135135. Pubmed Central PMCID: PMC3809798. Epub 2013/10/19. eng. 3. Donker M, Straver ME, van Tienhoven G, van de Velde CJ, Mansel RE, Litiere S, et al. Comparison of the sentinel node procedure between patients with multifocal and unifocal breast cancer in the EORTC 10981-22023 AMAROS Trial: Identification rate and nodal outcome. Eur J Cancer. 2013 Mar 19. PubMed PMID: 23522754. Epub 2013/03/26. Eng. 4. Fisher B, Redmond C, Fisher ER, Bauer M, Wolmark N, Wickerham DL, et al. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. The New England journal of medicine. 1985 Mar 14;312(11):674-81. PubMed PMID: 3883168. Epub 1985/03/14. eng. 5. Brannon AR, Sawyers CL. “N of 1” case reports in the era of whole-genome sequencing. The Journal of clinical investigation. 2013 Nov 1;123(11):4568-70. PubMed PMID: 24135144. Pubmed Central PMCID: PMC3809802. Epub 2013/10/19. eng.