Prostate (October 2017): Molecular Oncology Tumor Boards

ASCO University
Oct 11, 2017 9:00 AM

 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. Drs. Elizabeth Kessler, MD (Medical Oncologist, School of Medicine - University of Colorado) and John Tomaszewski, MD, MASCP (Pathologist, Jacobs School of Medicine and Biomedical Sciences - University of Buffalo) lead the discussion for the topic this month.

This discussion is based on a TAPUR, prostate patient case.

Do you have an interesting case in mind? Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.

Participants are encouraged to leave comments and post questions about the case in order to generate a wide discussion among the cancer care community. You can also receive email notifications when new comments are posted by clicking the “Follow this Conversation” option located at the bottom of this page.

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Comments

15061

ASCO University
Re: Prostate (October 2017): Molecular Oncology Tumor Boards
Oct 11, 2017 9:16 AM

Patient Case

Age/Sex: 66 year old male
Medical History: no significant history

Type of Tumor: prostate cancer

Relevant Markers:  current PSA of 35 ng/dL

Prior Treatment History/Response:

A 66 year old male with a history of controlled hypertension developed increased lower urinary tract symptoms and while undergoing urologic evaluation, was noted to have a PSA elevated to 10.8 ng/ml. A sextant prostate needle biopsy procedure is performed. 5/6 biopsies are diagnosed with prostatic adenocarcinoma.

The histology

figure 1 in  Schweizer and Cheng et al Oncotarget, 2016, Vol. 7, (No. 50), pp: 82504-82510

Figure 1: Schweizer and Cheng et al Oncotarget, 2016, Vol. 7, (No. 50), pp: 82504-82510

The histopathological features were not those of typical microacinar prostatic adenocarcinoma. Rather, approximately 65% of the cancer had a tubulopapillary architecture formed from glandular tumor cells which were large and composed of pseudostratified columnar epithelium with markedly atypical nuclei with clumped chromatin and prominent nucleoli most compatible with ductal prostatic adenocarcinoma. A biopsy of seminal vesicle was also positive.

T2 weighted endorectal MRI was performed and confirmed a large hypo-dense mass asymmetrically bulging the capsule of the prostate.

He was treated with 3 months of androgen deprivation therapy, then concurrent androgen deprivation therapy along with  IMRT to 6300Gy  followed by continued androgen deprivation therapy (ADT) for a total of 24 months of ADT.

He did not follow up regularly, and returned to the clinic with some back tenderness 2 years later.

He now had a PSA of 38 ng/ml and new bone and lymph node metastasis. Lesions were noted in the thoracolumbar spine, pelvis and left femoral neck. Patient was treated with 2 months of degarelix and then was started on docetaxel chemotherapy at 75mg/m2 give every 21 days for 6 cycles. His hormone therapy was continued throughout.

At six months after initiation of ADT, his PSA nadir was 2.85.

He subsequently developed a rising PSA and a new area of bone activity and was started on abiraterone acetate. He continued on this therapy for approximately 7 months until clinical and radiographic progression. He then started cabazitaxel chemotherapy with an excellent response in PSA and clinical status, but the development of grade 2 neuropathy and difficulties with treatment delays secondary to cytopenias. He received 5 cycles of chemotherapy.

After an 8-week period of stability, his PSA again began to rise with a doubling time of 4 weeks. He was started on enzalutamide. He remained on this therapy for 9 months prior to developing enlarging lymph node metastasis, rising PSA, and increase in pain at his known bone sites.

Co-morbidities:

Acid reflux and well-controlled hypertension

Images/Scans/Pathology:

 

 

15066

ASCO University
Re: Prostate (October 2017): Molecular Oncology Tumor Boards
Oct 11, 2017 9:18 AM

Discussion Questions

  1. What standard of care therapies would be available to this patient?
  2. What additional testing may help guide decision on the next line of therapy?
  3. What features of this patient’s current condition and treatment history would inform the timing of next therapy?

15071

Anis Toumeh, MD
Re: Prostate (October 2017): Molecular Oncology Tumor Boards
Oct 11, 2017 1:29 PM

A question I have is that, was the radiation dose of 6300Gy optimal for his disease? 

1- At this point, Radium 223 could be discussed with this patient. Although he has some LN metastasis but if those are not extensive or bulky, one coud consider this modality 

2- In a case like this, one also could consider genetic counseling and perhaps testing (germline or somatic) for mutations in DNA repair genes, such as BRCA1/2, which may make him eligible for a clinical trial with a PARP inhibitor. In that context, I am wondering how often investigators refer patients with metastatic prostate cancer for genetic counseling, especially after the paper by Pritchard et al. in NEJM 2016 

15076

Giovanni Lo Re, MD
Re: Prostate (October 2017): Molecular Oncology Tumor Boards
Oct 11, 2017 4:12 PM

The IMRT dose of 6300Gy can be considered ineffective for a radical treatment of prostate cancer.

Radium 223 is not recommended for the presence of lymph node metastases.

Consideration of PARP inhibitor therapy in the presence of a BRCA 1/2 mutation in DNA repair genes,  can be evaluated but the factor that could make this therapeutic chance impracticable is the ductal istotype of this prostate cancer patient.

This histotype can been considered  urothelial-like and it seems to present  similar  sensitivity to the drugs  employed on urothelial bladder cancer such as Carboplatin and gemcitabine. This has been reported by Kato T et al: International Journal of Urology (2007) 14, 1103–110; Y  Kamiyama et al: Tohoku J. Exp. Med., 2015, 237, 317-321 and conferred by unpublished personal experience. Finally, the search for MSI / MMR deficiency or the expression of PDL-1 might result in an effective treatment on urothelial cancer as anti PD-1 or anti-PDL-1 agents

15086

Elizabeth Riley Kessler, MD
Re: Prostate (October 2017): Molecular Oncology Tumor Boards
Oct 16, 2017 8:38 AM

Course Faculty Response

This patient has exhausted many of the standard of care approaches. He does have bone metastasis with very low burden of lymph node metastasis. One may consider treatment with Radium 223, although an assessment of volume of visceral disease would need to be undertaken. Some patients may receive mitoxantrone given its distant approval for palliation of advanced prostate cancer. Sipuleucel T is another drug approved in the US, but given the rapid rise in the PSA as well as the symptoms of disease, this therapy may not offer enough palliation soon enough.

Given the increased knowledge that there may be DNA repair defects or other drivers of prostate cancer growth, genomic evaluation of the tumor may aid in identifying agents both in clinical evaluation or approved that could offer some additional treatment activity.

This patient has had a rapid course of progression. The combination of worsening clinical symptoms, rapidly rising PSA and change in radiographic evaluation all are acceptable features for considering next lines of therapy. A change in therapy based on PSA alone is not often an adequate reason to alter a therapeutic course.

15091

ASCO University
Re: Prostate (October 2017): Molecular Oncology Tumor Boards
Oct 16, 2017 8:41 AM

Course Faculty Response: John E. Tomaszewski, MD

Molecular testing of prostate cancer after histopathological diagnosis may address either prognostic testing by evaluating the risk for metastasis of localized prostate cancer, or it may constitute predictive testing for the likelihood of response to proposed therapeutic options. Prognostic biomarkers include Ki-67 testing by immunohistochemistry; cell cycle related gene panels;  PTEN loss as measured by fluorescence in situ hybridization or immunohistochemistry; quantitative multiplex proteomics;  quantitative RT-PCR panels for androgen receptor pathways, proliferation, cellular organization, and stromal response; and genomic classifiers including genes related to cell proliferation, differentiation, androgen signaling, motility, and immune[1] regulation. Predictive biomarkers examine a tumor’s likelihood of response to a proposed therapeutic intervention. In metastatic prostate cancer tumors may be hyper mutated, and hyper mutated cancers have mismatch repair gene mutations and microsatellite instability . Next generation sequencing technology can be used to interrogate for such changes.  Mutations are frequently complex MSH2 or MSH6 structural rearrangements rather than MLH1 epigenetic silencing.


[1] Ross AE, et al. Prostate Cancer and Prostate Diseases 2016:19:1-6)

15096

ASCO University
Re: Prostate (October 2017): Molecular Oncology Tumor Boards
Oct 16, 2017 8:54 AM

Patient Case Update

The patient had an FNA of an enlarged pelvic lymph node and the biopsy was analyzed with IHC and sent for additional molecular profiling. This showed tumor cells with large amounts of cytoplasm and oval nuclei, which were arranged in papillary groups or flat and folded sheets. The edges of some groups showed peripheral nuclear palisading. A diagnosis of adenocarcinoma consistent with metastatic prostate adenocarcinoma and compatible with metastatic prostatic ductal adenocarcinoma was made.  

A FFPE cellblock was made from the aspirate. Immunohistochemistry on the cellblock for P53 showed upregulation of nuclear labels. Fresh tissue from the aspirate was saved in transport media for subsequent molecular testing. Targeted deep sequencing that included capture of both intronic and flanking DNA sequences for mismatch repair genes and associated MSI was performed. Copy loss in MSH2 and MSH6 was found. Activating mutations in the of thePI3K/Akt/mTOR pathway were also observed. The patient developed increased fatigue and malaise, as well as new right shoulder pain. Imaging was preformed, which revealed increase in the size and number of his lymph node metastasis as well as a new bone metastasis in the right scapula. PSA had risen from 18 to 35 ng/mL in a 7-week period.

15101

ASCO University
Re: Prostate (October 2017): Molecular Oncology Tumor Boards
Oct 16, 2017 8:56 AM

Discussion Questions


1.    What are the therapy options at this point?
2.    Should other counseling or testing be recommended for the patients based on the genomic data provided?

15106

Lowell Frank Inhorn, MD
Re: Prostate (October 2017): Molecular Oncology Tumor Boards
Oct 16, 2017 3:05 PM

Perhaps time to consider pembro.

Lemery et al. N Engl J Med 2017; 377:1409-1412

15121

Elizabeth Riley Kessler, MD
Re: Prostate (October 2017): Molecular Oncology Tumor Boards
Oct 20, 2017 10:37 AM

Course Faculty Response

Based on the information from the genomic sequencing data, this patient’s tumor has multiple alterations including MSH2 which would suggest microsatellite instability high status. These features taken together may inform the use of a checkpoint inhibitor in the treatment of the prostate cancer. Pembrolizumab has been approved for any tumor type based on MSI status alone and could be considered in this case.

In addition, the patient also has a TP53 alteration and an AKT hotspot mutation. Each of these are targeted in clinical trials. The patient may be eligible for a study using AZD5363, an inhibitor of AKT. In addition, the number of alterations, may suggest a sensitivity to platinum-based therapy should he have progression on a checkpoint inhibitor. Certainly, his clinical neuropathy and overall performance status would require reassessment at each decision point.

15126

ASCO University
Re: Prostate (October 2017): Molecular Oncology Tumor Boards
Oct 20, 2017 10:53 AM

Course Faculty Response: John E. Tomaszewski, MD

Immunohistochemistry for PDL-1 was also performed on the tumor cells from the aspirate. The tumor cells were positive for membrane labels in approximately 20% of cells. While the predictive modeling operating characteristics for PDL-1 immunohistochemistry in prostate cancer are not well established, the level of labeling was considered to be significant.

15136

Elizabeth Riley Kessler, MD
Re: Prostate (October 2017): Molecular Oncology Tumor Boards
Oct 25, 2017 11:45 AM

Course Faculty Summary

  • The progression of metastatic prostate cancer is variable, and therapies should generally be altered based on a combination of features rather than PSA alone. Change in clinical status, radiographic progression, or a very rapid change in PSA may all be indicators for new therapy.
  • Genomic testing may identify other agents with potential activity in solid tumors
  • Immunotherapy may be a viable option in patients that have features suggestive of a good response (high mutational burden, Microsatellite Instability high status).

15141

Christina Goodwin
Re: Prostate (October 2017): Molecular Oncology Tumor Boards
Oct 25, 2017 11:46 AM

Course Faculty Summary: John E. Tomaszewski, MD

  • MSI molecular testing in prostate cancer has not been common; however, a significant subset of patients may be MSI high and testing may be warranted if immune checkpoint inhibitor therapy is being considered.
  • PDL-1 testing by immunohistochemistry may be an additional testing modality that could help make the case for immune checkpoint inhibitor therapy in prostate cancer.

15146

ASCO University
Re: Prostate (October 2017): Molecular Oncology Tumor Boards
Oct 25, 2017 11:47 AM

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