Small Cells, Big Worries

I have stated many times in this forum before that treating castration-resistant prostate cancer (CRPC) is analogous to trying to hit a moving target. The better we get at treating it, the more the disease is able to evolve and adapt and acquire new mechanisms of drug resistance and lethality.

Just as multi-drug resistant bacteria didn’t exist before the invention of antibiotics, neither did CRPC exist before the advent of ADT. The same applies to abiraterone and/or enzalutamide resistant disease - this biological entity did not exist before the advent of these drugs. And, until we actually develop therapies that cure metastatic disease, we must live with the specter of deadly iatrogenic tumor entities emerging during treatment with therapies that delay progression and induce temporary remissions but fall short of a cure.

One such treatment-emergent form of CRPC is small cell prostate cancer, frequently called small cell neuroendocrine tumor, or simply tSCNC. It is frequently lumped together with the rare, de novo ‘pure’ small cell prostate cancer, but is very different, and more common. Although they share histologic appearances, some new data have emerged on this concept, and it’s worth diving into the details a bit.  There are important biological as well as clinical clues that are going to be worth considering.

But first, two short cases.

1. A 70-year-old man develops urinary obstruction. His prostate is very enlarged. The biopsy reveals small cell carcinoma. His PSA is <1.0 and not rising. He is treated with Docetaxel plus Carboplatin as well as ADT and subsequently receives radiation therapy to the prostate gland and is rendered NED. He feels well for months until he develops a headache and is found to have a large and expansive brain metastases. Despite radiation to the brain metastases, they recur, and he ultimately succumbs to his disease.

2. A 58-year-old man has lymph node metastatic disease from Gleason 8 disease, responds to standard ADT for a number of years, then develops CRPC, still with only lymph nodes. His PSA is about 40. He is treated with abiraterone. PSA drops to <1.0 and he feels well. After about 2 months he calls feeling ill and is found to be jaundiced. A CT scan reveals new liver metastasis, and a biopsy reveals small cell carcinoma. His bilirubin climbs to over 13 and his liver function declines, precluding chemotherapy. He rapidly dies of liver failure.

These two dramatic cases both unfolded before my eyes in my clinic, under my care. Although histologically they both represent small cell, they differ in other critical aspects (besides the tragically rapid events that made them so memorable to me). These two cases were useful in my own understanding of the background and natural history of the distinct, yet closely related entities of de novo versus treatment-emergent small cell prostate cancer.

The first case was classic de novo Small Cell prostate cancer, which has nothing to do with ‘classic’ prostate cancer such as high PSA, sensitivity to ADT and taxane chemotherapy. The second case, on the other hand, is a more typical tSCNC. It ‘emerged’ in the context of CRPC and when the PSA was down while the patient took abiraterone and prednisone. We’re not exactly sure why or how it emerges in the context of CRPC, but we are learning a few new things about it through a major effort led by colleagues at my former institution and resulting in a recent important publication describing “what” treatment-emergent small cell is.

Rahul Aggarwal of UCSF authored the paper and, in doing so, helped us establish a new paradigm for thinking of the small cell emergence under the stress of ADT plus abiraterone and enzalutamide. The data come from upwards of 300 biopsies of metastases from the ‘West Coast Dream Team” a conglomeration of centers that banded together to obtain these samples from metastatic, treatment-resistant tumors. This was the first major publication from this effort, but more are definitely expected. The take-home messages from the paper have been nicely and succinctly summarized by Aggarwal in his lectures on the topic, and the paper itself.

My spin on some of these key take homes:
1. It is not rare. The Dream Team detected small cell carcinoma in approximately 15-20% of post abiraterone or post enzalutamide patients. They were found in the lymph node, bone, liver, not selective for any specific metastatic site. So, while it’s not the only way the disease can progress, it is a reasonably common one.
2. Treatment-emergent SCNC is clinically different from de novo SCNC. Unlike de novo small cell, many patients with tSCNC have high PSA’s (over 50) and many have lower volume disease than you’d think – lymph nodes only sometimes.
3. there is no ‘type of patient’ who is at greatest risk for tSCNC – thus far the data show no pattern in terms of age, race, prior treatment etc.
4. Perhaps most interestingly, the Androgen Receptor expression is retained but its activity is lower in t-SCNC. Aggarwal and colleagues have termed this to be “AR indifference” which is to imply that, even though the AR is there and may have some activity, it is not the critical driver of tumor survival, growth and metastasis. The AR remains as a vestige of the tumors’ past dependence on androgen signaling, but it is not driving it.
5. Overall survival is shorter from the time of diagnosis of tSCNC than in ‘regular’ prostate cancer.

All is well and good, and the final result of a herculean effort to collect tissue from challenging metastatic sites, but what do we do about it?

As the cases above demonstrate, definitive treatment recommendations are lacking.

We do know that platinum therapy works and it's generally accepted that when/if we do detect tSCNC that we should go to platinum in as feasible a manner as possible.  Our team participated in a trial a few years ago that looked at the combination of carboplatin and docetaxel in “anaplastic” prostate cancer which included, but was not limited to, small cell variants. We saw reasonable degrees of activity with this combination upfront but relatively little with the built-in second-line regimen of etoposide and cisplatin, which also proved a little rough for the prostate cancer population.

Moving forward,  we are going to be testing the upfront combination of cabazitaxel plus carboplatin plus ADT in high volume castration sensitive disease. The idea with this approach is to attempt to obliterate the platinum-sensitive small cell clones if they exist, while the tumor is receiving its first big dose of treatment. This study will be led by the University of Minnesota team and conducted through the prostate cancer clinical trials consortium.

In order to continue to make progress against this entity, however, we will also need to address the issue of whether large scale biopsies of metastatic lesions is feasible.

Much more work to do on this!

Written by: Charles J. Ryan, MD

References:
1. Aggarwal R, et al. Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study J Clin Oncol. 2018 Aug 20;36(24):2492-2503. doi: 10.1200/JCO.2017.77.6880. Epub 2018 Jul 9.
2. Aparicio AM, et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res. 2013 Jul 1;19(13):3621-30. doi: 10.1158/1078-0432.CCR-12-3791. Epub 2013 May 6.
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