Small-Cell PCa.

[pjoshea13]

New paper below [1].

Typically, I look for additions to PubMed that can be translated into action. The brief text below is more of a heads-up warning not to be too eager for treatment.

The options we have for metastatic PCa are palliative rather than curative. With a relatively short mean-time-to-failure, the downside to early use is that (a) an option is used-up too early, & (b) we move to a more aggressive form of the disease ("treatment-emergent") too soon. This is of great concern to younger men (as I was 14 years ago & BigRich 19 years ago).

With a greater array of options today & with BigPharma hoping to expand the use of their wares, we need to know more about the risks. Johan de Bono of the Royal Marsden has expressed his concern that, as wonderful as the new drugs are, doctors all ill-prepared for some of the forms that drug resistance may take.

"Small-Cell Prostate Cancer Variety Surprisingly Common."

"... treatment-emergent small-cell neuroendocrine prostate cancer occurs in 17% of patients with the metastatic, castration-resistant form of the disease. This small-cell variety of prostate cancer shows a distinct gene expression signature and reduces patients' survival by nearly 20%."

In another recent study [2]:

"Constitutively active androgen receptor splice variants AR-V3, AR-V7 and AR-V9 are co-expressed in castration-resistant prostate cancer metastases."

"Out of 25 CRPC metastases that expressed any AR variant, 17 cases harboured expression of all three of these AR-Vs."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/300...

Cancer Discov. 2018 Aug 2. doi: 10.1158/2159-8290.CD-NB2018-101. [Epub ahead of print]

Small-Cell Prostate Cancer Variety Surprisingly Common.

[No authors listed]

Abstract

A recent study finds that treatment-emergent small-cell neuroendocrine prostate cancer occurs in 17% of patients with the metastatic, castration-resistant form of the disease. This small-cell variety of prostate cancer shows a distinct gene expression signature and reduces patients' survival by nearly 20%.

PMID: 30072408 DOI: 10.1158/2159-8290.CD-NB2018-101

[2] ncbi.nlm.nih.gov/pubmed/299...

Br J Cancer. 2018 Jul 10. doi: 10.1038/s41416-018-0172-0. [Epub ahead of print]

Constitutively active androgen receptor splice variants AR-V3, AR-V7 and AR-V9 are co-expressed in castration-resistant prostate cancer metastases.

Kallio HML1, Hieta R2, Latonen L2, Brofeldt A2, Annala M2, Kivinummi K2, Tammela TL3, Nykter M2, Isaacs WB4, Lilja HG5,6,7,2, Bova GS2, Visakorpi T2,8.

Author information

Abstract

BACKGROUND:

A significant subset of prostate cancer (PC) patients with a castration-resistant form of the disease (CRPC) show primary resistance to androgen receptor (AR)-targeting drugs developed against CRPC. As one explanation could be the expression of constitutively active androgen receptor splice variants (AR-Vs), our current objectives were to study AR-Vs and other AR aberrations to better understand the emergence of CRPC.

METHODS:

We analysed specimens from different stages of prostate cancer by next-generation sequencing and immunohistochemistry.

RESULTS:

AR mutations and copy number variations were detected only in CRPC specimens. Genomic structural rearrangements of AR were observed in 5/30 metastatic CRPC patients, but they were not associated with expression of previously known AR-Vs. The predominant AR-Vs detected were AR-V3, AR-V7 and AR-V9, with the expression levels being significantly higher in CRPC cases compared to prostatectomy samples. Out of 25 CRPC metastases that expressed any AR variant, 17 cases harboured expression of all three of these AR-Vs. AR-V7 protein expression was highly heterogeneous and higher in CRPC compared to hormone-naïve tumours.

CONCLUSIONS:

AR-V3, AR-V7 and AR-V9 are co-expressed in CRPC metastases highlighting the fact that inhibiting AR function via regions common to all AR-Vs is likely to provide additional benefit to patients with CRPC.

PMID: 29988112 DOI: 10.1038/s41416-018-0172-0

[cesanon]

"he brief text below is more of a heads-up warning not to be too eager for treatment.

The options we have for metastatic PCa are palliative rather than curative. With a relatively short mean-time-to-failure, the downside to early use is that (a) an option is used-up too early, & (b) we move to a more aggressive form of the disease ("treatment-emergent") too soon. "

Tall_Allen, can you explain the connection between the above and the study? I don't quite get it.

[Kat95]

When you say ‘not to be too eager for treatment’ Is that because with this type of cancer it spurs the cancer into resistance and greater strength?

[pjoshea13 in reply to Kat95]

With palliative treatments, we select for cells that can survive. With more sophisticated drugs, we select for more sophisticated cancer survival mechanisms.

A few years ago, it looked as though BigPharma was moving away from a single agent solution to a two- or three-pronged approach. That's what we need for durable remissions. Cancer meds should have a component that combats resistance (adaptation).

-Patrick

[dave2]

Treatment-emergent, aggressive PCa variants are definitely an issue to pay attention to. For more on treatment-emergent small cell NE PCa, see Ed Weber's August 2018 PCa Commentary: prostatecancerfree.org/pca-...

Research is underway in an effort to reduce emergence of this difficult-to-treat variant. It turns out that Monoamine Oxidase A (MAOA) can become over-expressed in PCa and facilitate expression of NEPC. Article here: ncbi.nlm.nih.gov/pmc/articl...

We already have long-ago approved MAO inhibitors (for both MAO A & B), the first type of antidepressant developed. In 2014 a phase II study began of MAO inhibitor phenelzine to assess its ability to lower PSA in BCR PCa patients: clinicaltrials.gov/ct2/show... While this study isn't specifically focused on reducing emergence of PCa variants, an interim analysis found that 7 of 12 patients in the noncastrate group experienced some PSA decline.

[pjoshea13 in reply to dave2]

Dave,

Ed Weber does an excellent job of explaining the problem, IMO. My wariness of Lupron 14 years ago pales in significance when compared to potential PCa adaptations to modern treatment options.

I'd have less concern if there was a drug combo with prolonged effectiveness - a decade or two. Not holding my breath.

-Patrick

[paulofaus]

I followed my oncologist advice, zoladex, Docetaxel, Enzalutamide. I recently had a TURP and when the tissue was sent to pathology, it seems I'm now dealing with small cell PCa. I just can't seem to catch a break.