Prostate Cancer (July 2015): Molecular Oncology Tumor Boards

ASCO University
Jul 15, 2015 10:53 AM

User Instructions: Welcome to the Molecular Oncology Tumor Board Series! This educational initiative is a collaboration between the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Association for Molecular Pathology (AMP).

A new case will be presented each month with discussions led by an expert pathologist and medical oncologist. This month’s topic is led by Drs. Daniel Petrylak (Yale University) and George Netto (Johns Hopkins University).

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Comments

10896

ASCO University
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 15, 2015 11:00 AM

Patient Case

Age/Sex: 72 Male

Medical History: History of Gleason Score 4+3= 7 adenocarcinoma diagnosed by prostate biopsy after the patient was found to have an elevated PSA of 212.

Type of Tumor: Adenocarcinoma of the prostate

Relevant Markers:  The patient had circulating tumor cells measured for ARV7 expression

Prior Treatment History/Response: The patient was initially treated with androgen blockade with leuprolide and bicalutamide starting in July of 2012.  His initial PSA was 212 ng/ml and he has multiple bony metastases on technetium bone scan.  He had a CT scan of the chest/abdomen/pelvis which demonstrated no evidence of visceral disease.  Six months after the initiation of androgen blockade, his PSA decreased to  0.4 ng/ml.  At that time his testosterone level was 28 ng/dl He continued on leuprolide and bicalutamide, and in August of 2013, his PSA rose to 3.  The patient had a testosterone level of 30 ng/dl, and his bicalutamide was discontinued. He entered on a clinical trial to evaluate serial measurement of ArV7 splice variants in circulating tumor cells.  He was treated with abiraterone/prednisone and his PSA declined to 3.0, 6 months after treatment initiation. Eight months later, the patient’s PSA began to rise and his circulating tumor cells converted from negative for ArV7 to positive.

Co-morbidities: Diabetes mellitus, hypertension

Images/Scans/Pathology:
Bone scan demonstrates multiple metastasis in the scapula, thoracic (T2 and T7) and lumbar spine (L1)

Prostate needle biopsies reveal the presence of Gleason Score 4+3= 7 adenocarcinoma in 6 of 12 cores. The extent of involvement ranged from 30% to 90% of the positive cores. The Gleason pattern 4 component was focally “cribriform” in architecture (See Figure GN1). Foci of intraductal carcinoma, perineural involvement and extraprostatic extension were also identified.

 

 

10901

ASCO University
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 15, 2015 11:19 AM

Discussion Questions

1.    What is the role of Arv7 in the resistance to hormonal therapy?
2.    What are the potential treatment implications of patient who possess the ARV7 splice variant?

3.    What is the role of ArV7 in the response to cytotoxic agents such as docetaxel?

 

Anis Toumeh, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 15, 2015 3:46 PM

1- The presence of AR-V7 in circulating tumor cells predicts resistance to Abiraterone Acetate and Enzalutamide in men with metastatic castration-resistant prostate cancer due to the lack of the ligand-binding domain targeted by thses hormonal agents.

2- Due to the likely resistance in patients who possess the variant to the above hormonal agents, different therapeutic approaches should be considered such as taxane therapy, Radium-223 (which may be a good option for the presented patient) and Sipuleucel-T if known prior to initiating first line treatment for mCRPC.

Could you please comment about any data regarding the predictive role of ArV7 in patients treated with Radium-223 and Sipuleucel-T (if any available)?

3- So far it does not seem that patients with ArV7 variant are resistant to taxanes ( as reported in a small study; Antonarakis ES et al. JAMA Oncology 2015). 

10911

Daniel Peter Petrylak, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 16, 2015 9:04 AM

Dr. Toumeh, thanks for your responses.  To address your question, currently, there is no data which evaluates Arv7 to predict outcome in patients treated with Provenge or radium 223.

 

10926

Travis John Osterman, DO, MS
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 16, 2015 10:36 PM

Hello all, and thanks to everyone for taking time to prepare this case and participating in the discussion.  Two questions came up for me.

  1. How do we determine progression while following Arv7?  In this scenario, Arv7 was undetectable and then began to rise along with PSA.  What if Arv7 was rising without PSA or vice-versa?
  2. If Arv7 fails to become undetectable, is there a consensus for progression as an increase from best response (ie: lowest level)?

-- T

Daniel Peter Petrylak, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 18, 2015 8:48 AM

Dr. Osterman,

Thanks for your questions.  

1- The clinical response of the agent would be the parameter to use to determine whether the drug should be continued. In the future, if we have further validation of Arv7 as a marker for the lack of response of further hormonal manipulations, it could be used to steer patients towards chemotherapy or other investigational agents.

2 - There is no consensus at this time.

10931

Abhishek Tripathi, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 17, 2015 3:51 PM

hi everyone,

                  The intracellular domain of the receptor variant is ligand independent  and is constitutively active as transcription factors leading to activaton of target proteins. In addition to conferring resistance to Abiraterone and Enzalutmide (due to lack of ligand binding site), could there be a role of this variant in emergence of castration resistance and possbly prognostigating patients at the time of initial diagnosis ?

thanks 

Daniel Peter Petrylak, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 18, 2015 8:53 AM

Dr. Tripathi, thanks for your question.  Arv7 is one of several pathways to castration resistance including androgen receptor amplification, intracrine synthesis of testosterone, Since approximately 25% of patient who are treated with androgen blockade who do not normalize their PSAs (<4ng/ml)  at 7 months post therapy have a median survival of 13 months, it would be interesting to see if these patients have the Arv7 splice variant de novo or if they develop it within the 7 month time period.  

10946

Abhishek Tripathi, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 18, 2015 1:53 PM

Thank you for the response Dr Petrylak. 

 

For an oncologist in clinical practice, would this tool be available as a predictive biomarker of response considering the cost of these drugs? 

 

thanks

Daniel Peter Petrylak, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 20, 2015 9:22 AM

The answer to this question is not known. Validation of these findings is clearly needed. 

George Netto, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 22, 2015 4:39 PM

Our lab ( and I imagine others will) is working on bringing ARV7 assay to a CLIA approved laboratory for clinical use once additional clinical validation data are in.

10961

George Netto, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 20, 2015 11:58 AM

Course Faculty Response

In response to the discussion question above, Androgen receptor (AR) splice variants are AR isoforms that lack the ligand-binding domain and remains constitutively active and thus retain their transcriptional activity in a ligand-independent manner. Recently, Antonarakis et al. (N Engl J Med. 2014 Sep 11;371(11):1028-38) found that detection of AR variant-7 (ArV7) in peripheral blood CTC in castration- resistant prostate cancer patients to be associated with primary resistance to abiraterone and enzalutamide. 

10966

Daniel Peter Petrylak, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 20, 2015 12:02 PM

Course Faculty Response

I address the initial discussion questions below:

1.)    After an initial response to androgen blockade, men develop resistance to primary hormone ablation after a median of approximately 18 to 24 months of treatment. . In these patients, prostate cancer cells adapt to surviving in an environment where serum testosterone levels are less than 50 ng/dl.  The androgen receptor maintains its effect on cellular growth through multiple mechanisms including gain of function mutations, aberrant receptor modifications, alternative splicing of the receptor, cofactor perturbation, and receptor amplification/overexpression. Intracrine synthesis of androgen also plays a role in castration resistance. Therapeutic approaches to castration resistance include inhibition of androgen receptor function/translocation (enzatamide) as well as inhibition of intracrine androgen synthesis (abiraterone).    The androgen receptor consists of DNA-binding domain, a hinge region, and a ligand binding domain. The AR-V7 splice variant encodes for a truncated version of the androgen receptor, which lacks the ligand binding domain, and is constitutively activated. Antonarakis et al. evaluated 31 patients treated with enzalutamide as well as 31 patients treated with abiraterone for AR-V7 expression in circulating tumor cells. Shorter PSA progression-free survival, radiographic progression-free survival and overall survival were noted in those patients who were ARV7 positive and treated with either drug compared to those who were ARV7 negative. The emergence of circulating tumor cells while patients were being treated with either enzalutamide or abiraterone was associated with the development of resistance to therapy

2.)    There are four classes of approved agents for the treatment of castration resistant prostate cancer (CRPC). These include 1) immunotherapy  2) hormonal manipulations   3) cytotoxic chemotherapy  4) isotope therapy. Currently, only clinical parameters can be used to help the clinician decide the appropriate therapy. For example, patients who have asymptomatic non-visceral disease are appropriate for immunotherapy with Sipeuleucel-T.  Although data now suggested chemotherapy should be used along with androgen blockade as the initial treatment for metastatic disease, the trend in the past had been to delay chemotherapy until symptoms developed. Isotope therapy with radium 223 is only appropriate for patients with bone metastases who do not have visceral disease or bulky adenopathy. The potential use of ArV7 could potentially help decide whether a hormonal agent such as enzalutamide or abiraterone should be used rather than the other three classes of drugs for castration resistant prostate cancer

3.)    Although docetaxel-based chemotherapy has been associated with arrest of cells at G2M and inhibition of the anti-apoptotic protein BCL-2, docetaxel also inhibits the translocation of the androgen receptor into the nucleus. Thus, it may have both cytotoxic and hormonal effects. In vitro translocation of the ArV7 mutant appears to be unaffected by taxane treatment, whereas the ARv567 mutant is sensitive to docetaxel treatment. Tumors xenografts expressing the ARv7 mutant are resistant to docetaxel. However, this in vitro observation does not appear to translate clinically. A recent study by Antorakis et al of 37 docetaxel-treated CRPC patients detected ARv7 mutations by PCR in 17(45.9%) of patients. Although a non-significant difference was seen in PSA declines of 50% and progression-free survival, in the ARV7+ patients, when compared to a cohort of 62 patients treated with abiraterone or enzalutamide, docetaxel appears to be more efficacious in this population. There appeared to be comparable activity of docetaxel to either abiraterone or enzalutamide the ArV7 negative population. Further studies need to be performed as to whether a similar pattern of efficacy is observed with the second-line taxane, cabazitaxel. If these findings are confirmed, this will aid in the selection of both initial and subsequent treatments for castration resistant prostate cancer
  

James A. Knost, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 24, 2015 8:05 AM

Three questions:

1) ARV7 is one of many "splice variations" i.e. AR5,6,7 as an example. Of the splice variations what perecentage is ARV7?

2) Any correlation with TMPRSS2:ERG, pTEN and splice variations?

3) The Universit of Edmonton was working on a compound that would bind to the N-terminal end of the Androgen receptor, how are these compounds coming along?

10971

ASCO University
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 20, 2015 12:07 PM

Patient  Case Update

A  laboratory developed  (LDT) quantitative reverse-transcriptase–polymerase-chain-reaction (qRT-PCR) assay was used for the detection of ArV7 mRNA in circulating tumor cells (CTC) in 5 ml freshly obtained (within 2 hours of collection) lavender top BD vacutainer tube of peripheral blood sample. 

Analysis of circulating tumor cells for ArV7
The assay used in the initial Antonarakis et al. study is categorized as an LDT (laboratory developed test).
CTC analyses were conducted using the ProstateCancerSelect kit to enrich CTC from 5ml blood using magnetic particles coated with a combination of antibodies recognizing prostate cancer cells, while the ProstateCancerDetect kit was used to make cDNA for detection of prostate cancer-associated RNA transcripts using multiplexed polymerase chain reaction (PCR). The test was adapted for detection and quantification of Full length AR (AR-FL) and AR-V7 by quantitative real-time PCR using custom primers specific for AR-FL and AR-V7. The ratio of AR-V7 / AR-FL. The relative AR-V7 transcript abundance is then determined in each blood sample by calculating the ratio of AR-V7 to AR-FL.  A Rise in that ratio, like the one detected in current patient reflects the development of a resistant CTC population.

ASCO University
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 20, 2015 12:09 PM

Discussion Questions 

1.    Where any pathologic features in the biopsy predictive of aggressive disease
2.    What are some of the clinical parameters associated with response/progression on hormonal therapy?

 

11001

George Netto, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 24, 2015 2:26 PM

Dr. Knost,

Thanks for your questions.  When present, ARv7 is about 20% of total AR transcripts. All the others, including ARv567 are less than 4% of total AR.  Regarding the correlation, the association between ERG and AR variants is unknown.

 

11006

Daniel Peter Petrylak, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 24, 2015 2:35 PM

Dr. Knost,

I have not seen anything published about the compounds mentioned.

 

11016

George Netto, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 24, 2015 3:10 PM

Course Faculty Response

Several histopathologic findings in the initial biopsy pointed to potentially aggressive biologic behavior.

  • The Gleason Score 4+3=7 will place the biopsy findings in a “Grade Prognostic Group III of V “ according to the soon to be proposed system by the International Society of Urologic Pathology (ISUP); Epstein et al. AmJ Surg Path (in press).
  • The presence of cribriform architecture Gleason Pattern 4 has been recently suggested to be associated with worse pathologic outcome on radical prostatectomy compared to “poorly formed glands”. The same may be true for the presence of intraductal carcinoma.
  • The biopsy revealed evidence of extraprostatic extension.

11021

Daniel Peter Petrylak, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 24, 2015 3:19 PM

Course Faculty Response

There have been clinical and laboratory parameters associated with poor prognosis in patients treated with androgen blockade, however this patient demonstrates only one of these characteristics. Hussain et al demonstrated that, as in this case, patients who achieve a PSA of <4.0 ng/ml after 7 months of androgen blockade had one third the risk of death that those who PSA did not nadir below that level; patients who achieved a PSA of <0.2 ng/ml have one fifth the risk of death when compared to those patients whose PSA level remained above 4.0 ng/ml.

Serum testosterone levels in patients treated with androgen blockade also appear to be prognostic for survival. Retrospective studies in prostate cancer patients treated with androgen blockade suggest that patients who attain a serum testosterone level 6 months after the initiation of androgen blockade of <25 ng/dl have a better survival than those who do not.  In non-metastatic patients, Klotz et al also demonstrated a decreased survival and decrease in time to castration resistance in patients who do not attain a serum testosterone level of <25 ng/dl 6 months post initial of androgen blockade.
Paradoxically, in the COUGAR 302 trial, which compared abiraterone/prednisone to placebo/prednisone, high baseline androgen levels were associated with longer median overall survival whether the patient received abiraterone or not, compared with men who had low baseline levels. In patients treated with abiraterone/prednisone, men with high testosterone levels who received abiraterone had almost double the median overall survival compared with men who had low levels and received placebo.   – 17.8 versus 9.3 months, respectively.

11031

George Netto, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 29, 2015 2:03 PM

Thank you everyone for the interest in this discussion.  Below are my summary points from this case based on the information:

  • Multiple histopathologic findings in the initial biopsy suggested an aggressive biologic behavior
  • Androgen receptor (AR) splice variant 7 is an AR isoforms that lack the ligand-binding domain and remains constitutively active and thus retain their transcriptional activity in a ligand-independent manner. 
  • A laboratory developed test (LDT) for the detection of AR variant-7 (ArV7) in peripheral blood CTC in castration- resistant prostate cancer patients is being further validated to identify tumors associated with primary resistance to abiraterone and enzalutamide. 

 

 

11036

Daniel Peter Petrylak, MD
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 29, 2015 2:05 PM

Thank you everyone for the interest in this discussion.  These are my take away points based off of the information: 

  • Prospective confirmation of the role of ARV7 in selecting treatment for men with castration resistant prostate cancer is ongoing.
  • The role of testosterone monitoring needs to be further elucidated in the treatment of both androgen sensitive and insensitive disease. 

 

11041

ASCO University
Re: Prostate Cancer (July 2015): Molecular Oncology Tumor Boards
Jul 29, 2015 2:20 PM

Thank you to Drs. Petrylak and Netto leading the discussion of this case and also to all of those who contributed to the conversation! The forum is now closed to further comments but users have the opportunity to claim CME credit on ASCO University by clicking here.

Please check back in mid-Aug for a new case in this series related to CUP  


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