Postoperative Circulating Tumor Cells

[pjoshea13]

New Korean paper below [1].

The study was on "203 patients with undetectable {PSA} who had undergone radical prostatectomy".

Over a third had circulating tumor cells [CTCs] ("at a median of 4.5 months after surgery.")

"CTC detection was independently associated with an increased risk of biochemical recurrence (HR=5.42 ...)"

My prostatectomy was an immediate failure. I wonder what the incidence of CTCs is when PSA is not zero after surgery?

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/318...

J Urol. 2019 Dec 17:101097JU0000000000000704. doi: 10.1097/JU.0000000000000704. [Epub ahead of print]

Association Between Postoperative Detection of Circulating Tumor Cells and Recurrence in Patients with Prostate Cancer.

Pak S1, Suh YS1,2, Lee DE3, Kim SH1, Joung JY1, Park WS4, Lee SJ5, Lee KH1.

Author information

1

Department of Urology, Center for Urologic Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea.

2

Seoul Urology Clinic, Seoul Urology Group, Seoul, Korea.

3

Biostatistics Collaboration Team, Research Core Center, Research Institute and Hospital, National Cancer Center, Goyang, Korea.

4

Department of Pathology, Research Institute and Hospital, National Cancer Center, Goyang, Korea.

5

Division of Cancer Immunology, Research Institute and Hospital, National Cancer Center, Goyang, Korea.

Abstract

PURPOSE:

The clinical implications of postoperative detection of circulating tumor cells (CTCs) in prostate cancer are largely unknown. This study aimed to investigate the association between postoperative CTC detection after radical prostatectomy and disease recurrence in prospectively enrolled patients with prostate cancer.

METHODS:

A total of 203 patients with undetectable prostate-specific antigen (PSA) who had undergone radical prostatectomy for prostate cancer were prospectively enrolled. CTC sampling was performed at a median of 4.5 months after surgery. The primary endpoint was biochemical recurrence-free survival. Detection of CTCs in the blood of patients was performed using a novel approach with a replication competent adenovirus controlled by PSA/prostate-specific membrane antigen transcription regulatory elements (Ad5/35E1aPSESE4).

RESULTS:

CTCs were detected in 73 (36.0%) patients with undetectable PSA concentrations after surgery. The 3-year biochemical recurrence-free survival rate from the time of surgery was significantly higher in CTC-negative patients than in CTC-positive patients (81.6% vs 48.9%, log rank p<0.001). Multivariable analysis showed that postoperative CTC detection was independently associated with an increased risk of biochemical recurrence (HR=5.42; 95% CI, 3.24-9.06; p<0.001). C-index was increased in the combination of multivariable model and postoperative CTC detection compared with multivariable model alone.

CONCLUSIONS:

CTCs in the blood were frequently detected in patients with undetectable PSA levels after radical prostatectomy for localized prostate cancer. Furthermore, CTC detection was associated with an increased risk of biochemical recurrence, suggesting that CTC detection precedes PSA rise after surgery in case of prostate cancer recurrence. Large-scale validation is needed in the future.

KEYWORDS:

biomarkers; circulating tumor cells; prostate cancer; recurrence

PMID: 31845840 DOI: 10.1097/JU.0000000000000704

[Philly13]

How is CTC measured? If the answer is in the article, then I missed it. Is it possible that evidence of systemic disease, travelling through the blood is available.

I never thought of the term instant failure. That term fits for me as .58 was my 90 day reading and 1.12 was 120 days. 120 days was April and by the middle of the month, the RO convinced United Healthcare to authorize an Auximen Scan, which was positive for 3 lesions that were not evident in conventional scans.

[GP24 in reply to Philly13]

This was my first question too. It says in the abstract: "Detection of CTCs in the blood of patients was performed using a novel approach with a replication competent adenovirus controlled by PSA/prostate-specific membrane antigen transcription regulatory elements (Ad5/35E1aPSESE4)."

With other words, you cannot go to the next hospital and ask for this test to be done. Question is if you will get the same results with a different CTC test.

[FCoffey in reply to Philly13]

CTCs are amazing technology, they detect 1-10 cancer cells in a volume of blood containing 5 million or more white blood cells and a 7-10 billion red cells. CellSearch is currently the only FDA-approved assay.

An interesting future study would be to check for CTCs before performing RP. If there are a significant number of CTCs, this study suggests the RP may not be very effective.

[Graham49]

This paper seems to give a good reason to target these CTCs after RP using recognised anti cancer drugs, supplements or off label drugs even if the PSA is not detectable. Current UK standard medical practice is to do nothing until the PSA starts rising.

[pjoshea13 in reply to Graham49]

My understanding is that the body does an amazing job of zapping 'free' CTCs, but that CTCs that dock on circulating micro-clots escape destruction. Some have said that altered coagulation (which occurs in many cancers) may be required for metastasis. Even though I have metastatic disease, I target micro-clots via nattokinase. I test D-dimer, which should generally be zero when there is no clot activity.

(Too bad I knew nothing about this 15 years ago. I could have avoided the double DVT that occurred ~5 years later.)

-Patrick

[FCoffey]

Interesting, thanks for posting. I can't download the full paper, so these comments are based on my reading of the abstract.

This could be interpreted as 36% of men undergoing RP already had distant metastases that the surgery didn't touch. Perhaps too small to detect, or perhaps they didn't do a sensitive imaging scan before the RP.

Another interpretation is that surgery disturbs the capsule enclosing the tumor and allows cells to enter the bloodstream. There's ample evidence for that happening in breast cancer needle biopsies. It's not much of a stretch to apply to findings to prostate cancer.

The abstract doesn't mention if they checked for an association between positive margins after RP and recurrence. Positive margins will certainly increase the risk of failure.

[pjoshea13]

Nala,

I was slow off the mark & left myself open. My radio-oncologist was of the opinion that the lesions at L5 & T6 were probably due to very early mets. I'm not unhappy with how things turned out, but I could have done better.

Was the CTC test expensive? Did Medicare pay?

-Patrick

[Graham49]

This recent study, although for breast cancer may be relevant to discussion. Patrick - Does this support what you said about micro clots?

Neutrophils escort circulating tumour cells to enable cell cycle progression

Barbara Maria Szczerba, Francesc Castro-Giner, Marcus Vetter, Ilona Krol, Sofia Gkountela, Julia Landin, Manuel C. Scheidmann, Cinzia Donato, Ramona Scherrer, Jochen Singer, Christian Beisel, Christian Kurzeder, Viola Heinzelmann-Schwarz, Christoph Rochlitz, Walter Paul Weber, Niko Beerenwinkel & Nicola Aceto

Nature volume 566, pages553–557(2019)

Abstract

A better understanding of the features that define the interaction between cancer cells and immune cells is important for the development of new cancer therapies1. However, focus is often given to interactions that occur within the primary tumour and its microenvironment, whereas the role of immune cells during cancer dissemination in patients remains largely uncharacterized2,3. Circulating tumour cells (CTCs) are precursors of metastasis in several types of cancer4,5,6, and are occasionally found within the bloodstream in association with non-malignant cells such as white blood cells (WBCs)7,8. The identity and function of these CTC-associated WBCs, as well as the molecular features that define the interaction between WBCs and CTCs, are unknown. Here we isolate and characterize individual CTC-associated WBCs, as well as corresponding cancer cells within each CTC–WBC cluster, from patients with breast cancer and from mouse models. We use single-cell RNA sequencing to show that in the majority of these cases, CTCs were associated with neutrophils. When comparing the transcriptome profiles of CTCs associated with neutrophils against those of CTCs alone, we detect a number of differentially expressed genes that outline cell cycle progression, leading to more efficient metastasis formation. Further, we identify cell–cell junction and cytokine–receptor pairs that define CTC–neutrophil clusters, representing key vulnerabilities of the metastatic process. Thus, the association between neutrophils and CTCs drives cell cycle progression within the bloodstream and expands the metastatic potential of CTCs, providing a rationale for targeting this interaction in treatment of breast cancer.

[pjoshea13]

Graham,

Good find!

Nothing comparable so far for PCa.

Here is a new non-PCa study:

Cooperative and Escaping Mechanisms between Circulating Tumor Cells and Blood Constituents

mdpi.com/2073-4409/8/11/138...

My interest in clotting is based on the studies of men on anticoagulants. Long-term use appears to protect against mets.

The big complication with such studies is that the first symptom of PCa can be a DVT. Healthy men with DVTs should be screened for PCa. Therefore, men who have just been put on anticoagulants have an increased risk for mets. It is assumed that long-term use before PCa diagnosis is unrelated to PCa.

-Patrick

[tallguy2]

I will add to this discussion that, while oncologists order CTC and mine showed "zero" it really made no difference. My cancer progressed anyway.

[Rfs1975]

Is the CTC test recommended as a follow up test after RP? I had RP in June of 2016 and had a BCR 22 months later, PSA .06. I immediately started Salvage radiation in June and finished on Aug 19 2019. I had a follow up PSA mid october, .03 and scheduled for another PSA on January 21st.

Should I ask my oncologist for a CTC or any other test?

Thanks

[pjoshea13 in reply to Rfs1975]

It looks as though the CTC test should be standard after RP - but it isn't. I'd ask for the test, but take a copy of the paper with you.

-Patrick

[Rfs1975 in reply to pjoshea13]

looked at my past chart and only test ordered by my oncologist was a lactate dehydrogenase, this was prior to my radiation. My oncologist suggested that I start ADT prior to my radiation and following my radiation but I opted for no ADT at this time.

[Rfs1975]

Thanks for the information, I will request the test.

Richard