Prostate Cancer (August 2018): Molecular Oncology Tumor Boards

ASCO University
Aug 08, 2018 7:15 AM

Participant 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 bi-monthly with discussions led by an expert pathologist and medical oncologist. This month’s topic is led by Drs. Gladell Paner (Pathologist from University of Chicago) and Alicia Morgans (Medical Oncologist from Northwestern).

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

15761

ASCO University
Re: Prostate Cancer (August 2018): Molecular Oncology Tumor Boards
Aug 08, 2018 7:16 AM

Patient Case

A 67-year-old man with a history of hypertension and hyperlipidemia presents to your oncology clinic after a new diagnosis of metastatic prostate cancer. He has bone metastases in the pelvis, his left femur, and T12, and a PSA of 137. Despite this he is relatively asymptomatic with only mild back pain and slight fatigue. 

After reviewing his case, you start him on androgen deprivation therapy (ADT) and abiraterone acetate per standard management for metastatic hormone sensitive prostate cancer. In your discussion with him and his wife, you learn that his sister was diagnosed with breast cancer at 42, and his mother had ovarian cancer at 48.

He has three children (son and two daughters), and he and his wife are wondering about whether he should undergo genetic testing as part of his clinical work up.

15766

ASCO University
Re: Prostate Cancer (August 2018): Molecular Oncology Tumor Boards
Aug 08, 2018 7:16 AM

Discussion Questions

1. Which men with prostate cancer should be referred to genetic counseling for consideration of genetic testing?

2. If we as oncologists are ordering the test ourselves due to the shortage of genetic counselors, which test should we order?  Is testing ordered on the tumor, or another way?

3. Which mutations are important to recognize and potentially act upon in genetic testing for men with prostate cancer?

4. What should be done if a patient has a genetic test that is positive for a mutation of interest?

15776

Anis Toumeh, MD
Re: Prostate Cancer (August 2018): Molecular Oncology Tumor Boards
Aug 08, 2018 3:37 PM

In my practice, I do pre-test genetic counseling on all men with metastatic prostate cancer and I typically order a panel testing to increase the chance of detecting germline mutations in multiple DNA repair pathway genes

15781

Re: Prostate Cancer (August 2018): Molecular Oncology Tumor Boards
Aug 12, 2018 8:46 PM

Nicholas Vogelzang MD

Comprehensive Cancer Centers of Nevada

Las Vegas, NV

 

I see about 20 new  metastatic prostate cancer patients per month (hormone sensitive and castrate resistant) and explain to each of them that the NCCN guidelines recommend germ line and somatic testing to detect mutations in the multiple DNA repair genes. Furthermore I explain that if they are identified as having a mutation they become eligible for one of the 3 clinical trials we have open studying PARP inhibitors. On occasion I have been able to have a 3rd party payer cover the cost of one the 3 currently approved drugs in ovarian cancer.I even had a federal judge rule that a Medicare patient, ineligible for the trial due to a prior gastric cancer, must receive the drug and that it had to be covered by Medicare. 

 I work closely with our full time genetic counselor who counsels the patient and then usually orders a multi-gene panel from Invitae (also available from Color, Myriad etc). Some 3rd parties only will pay for BRCA1 and 2 and I then explain to the patient that that is inadequate. I suggest that the cost of multi-panel testing, generally~ $250, is worth the out-of-pocket cost.

For somatic testing I try to obtain the Caris Molecular Intelligence profile on all patients (if insurance permits). I sit on their SAB and am very impressed with their independence, quality and responsiveness. Recently for example, one of my young hormone sensitive prostate cancer patients had a somatic BRCA1 mutation identified [c.5266dupC (p.Q1756fs) in 46% of the tissue sample. The Caris genetic counselor called me to remind me that NCCN guidelines recommend germ line testing in such individuals.

I've now treated abbout 10-15 prostate cancer patients with one of the 3 PARP inhibitors. There are some wonderful remissions and yet others have no response. It will be exciting to learn about which mutations predict benefit and resistance to which drugs.

15786

Gladell P Paner,
Re: Prostate Cancer (August 2018): Molecular Oncology Tumor Boards
Aug 13, 2018 4:12 PM

Course Faculty Response

1. Some hereditary syndromes are associated with predisposition for prostate cancer and when suspected should prompt a referral for genetic evaluation. The hereditary breast and ovarian cancer (HBOC) and hereditary prostate cancer (HPC) syndromes are well-established risks. HBOC syndrome increases susceptibility to develop breast, ovarian, pancreatic, and prostate cancers. Also, Lynch syndrome patients may increase the risk for prostate cancer, and the rare multi-cancer Li-Fraumeni syndrome may infrequently develop prostate cancer in affected patients. Each of these syndromes has published criteria that requires familiarity (NCCN guidelines, Giri et al. 2018, Giri et al. 2016). But regardless of family history, the NCCN guideline considers germline genetic testing and counseling for high-risk to metastatic prostate cancer patients due to higher prevalence of mutations in DNA-repair genes (e.g. HBOC-associated BRCA2 and BRCA1) in these groups. The 2018 NCCN guideline now has a definition for “strong family history”, in relation to HBOC and Lynch, and that a strong family history would also prompt consideration for germline testing in the very low-risk to intermediate-risk prostate cancer patients.

In 2017, the Philadelphia Prostate Cancer Consensus Conference (PPCCC) for the first time provided multidisciplinary consensus statements addressing genetic evaluation of prostate cancer patients. (Giri et al. 2018) According to the PPCCC, genetic evaluation should be done in men with prostate cancer that: 1) are from families meeting criteria for HBOC, HPC, and Lynch; 2) have 2 or more close blood relatives on same side of the family having a cancer in the above syndromes (broader family history); 3) have metastatic castration-resistant prostate cancer (mCRPC); and 4) have tumor sequencing that shows mutations in cancer-susceptible genes. The last two can be attributed to the increased prevalence of prostate cancer susceptible gene variants in advanced and CRPCs, and the increased application of multi-gene next generation sequencing on tumor samples for targeted therapy, such as screening DNA-repair gene mutations for chemotherapy and clinical trials enrollment (e.g. PARP inhibitors). Detection of gene variants in the tumor would then require confirmation if the aberrations are germline in origin.

2.    The patient and his family are at risk for HBOC syndrome because of breast cancer (<45 years), ovarian cancer, and metastatic prostate cancer among first-degree members (per NCCN guideline). The genes associated with HBOC are BRCA2 and BRCA1 and should be tested in the patient. While some institutions and commercial laboratories offer targeted sequencing for BRCA2 and BRCA1 as combined or separate (single gene) tests, more prefer to request the small “prostate-specific panels” that include other known prostate cancer-susceptible genes for a little extra cost. Testing companies such as Ambry Genetics, Myriad Genetics, Color Genomics, and Invitae Corporation offer panels that may also cover other DNA-repair genes, mismatch repair genes (MMR) (Lynch), HBOX13 (HPC), or TP53 (Li-Fraumeni) (Zhen et al 2018).

Genetic counseling and testing can be costly. Many commercial laboratories are willing to submit pre-authorization to the insurance company upon receipt of the test sample. The patient is then informed of the cost and is asked whether to go ahead with the test. Most major insurance companies do not universally cover genetic testing and the coverage policy is neither uniform nor specific, with each company having their own criteria for approval of the test coverage. (Zhen et al 2018)

Germline genetic test must be done on non-tumor samples (e.g. saliva, buccal smear, blood, buffy coat). Of note, blood should not be used if there is past diagnosis of myelodysplasia or leukemia, or recent allogeneic bone marrow transplantation. Skin biopsy may also be accepted but it requires fibroblast culture that adds to the price and turnaround time. Testing prostate cancer tumor samples (primary or metastatic) also detect the mutations in BRCA2 and other DNA-repair genes. However, only less than half of these will have germline mutation findings, and as mentioned above in the screening criteria, germline testing confirmation should still be performed after a positive tumor testing.

It is imperative that the patient should be referred to a genetic councilor for (pre and post test) counseling and interpretation of results, particularly when gene variants of uncertain significance are identified.

3.    Men from families with women who had breast and ovarian cancers due to BRCA mutations have 5X relative risk (RR) for prostate cancer when they carry germline BRCA2 mutation. The RR increases up to 7X if men in the family develop prostate cancer at <65 years. (Thompson et al. 2001) For BRCA1 mutation carrier however, association with prostate cancer predisposition has been inconsistent with a RR of 1.8 to 3.7. The NCCN guideline for prostate cancer does not provide separate prostate cancer screening recommendations for men who are BRCA2 mutation carrier. However, the NCCN guideline for breast and ovarian cancer do recommend that men with BRCA2 mutation start prostate cancer screening at age 45 years and that men with BRCA1 mutations should consider the same.

Germline DNA-repair gene mutations are identified at a much higher rates in metastatic (11.8%) than in localized (4.6%) prostate cancer, and men without cancer diagnosis (2.7%). (Pritchard et al. 2016) Among these genes in metastatic prostate cancer, BRCA2 mutation has the highest (5.3%) incidence and with lower frequency for others such as BRCA1, ATM, CHECK2, RAD51D, and PALB. In mCRPCs, mutations (somatic and germline) are higher for DNA-repair genes overall (23%) and for BRCA2 (12%). (Robinson et al. 2015) Unlike BRCA2 and maybe with BRCA1, risk for prostate cancer susceptibility is not established with the other DNA-repair genes.

Preliminary findings from the IMPACT study in men - with known germline BRCA 1/2 mutation status biopsied for elevated PSA level (>3 ng/ml) on regular screening - showed higher detection of intermediate- or high-risk prostate cancer in BRCA2 mutation carriers. (Bancroft et al. 2014) Germline mutations on BRCA 1/2 confer a more aggressive prostate cancer with higher chance of nodal and distant metastasis and poor survival. (Castro et al. 2013) Germline mutations on BRCA 1/2 and ATM is significantly higher in lethal PCA (6%) than in localized PCA patients (1.4%) and is associated with early age at death. (Na et al. 2017)

BRCA2 and other DNA-repair genes such as BRCA1, ATM, and RAD51 are important for repair of DNA double-strand break (DSB) in a mechanism known as homologous recombination. Another mechanism of DNA repair is by base excision repair of DNA single-strand break (SSB) mediated by poly(ADP-ribose) polymerase (PARP) enzymes that bind to the broken DNA, and through PARylation recruits other DNA factors that replaces the damage region with normal DNA. Defect in one of these mechanisms of repair still allow DNA repair and cell survival, however, simultaneous loss of both mechanisms will be lethal to the cell (synthetic lethality). The presence of mutations in homologous DNA-repair genes with defective DSB repair in cancers has been exploited by blocking the PARP catalytic activity (SSB repair) with use of inhibitors. Several PARP inhibitors are now being tested in phase I or II clinical trials for mCRPC such as olaparib (AstraZeneca), veliparib (AbbVie), niraparib (Tesaro). The phase II trial with olaparib given to patients with heavily pre-treated metastatic prostate cancer (TOPARP-A), showed a remarkable response rate (88%) in those with homozygous and/or deleterious mutations in DNA-repair genes including BRCA2, BRCA1, ATM, FANCA, and CHECK2. (Mateo et al. 2015) The FDA has now given olaparib a breakthrough therapy designation.

15791

Alicia K. Morgans, MD, MPH, BA
Re: Prostate Cancer (August 2018): Molecular Oncology Tumor Boards
Aug 13, 2018 4:15 PM

Course Faculty Response

1.  To answer #1, it can be helpful to review the NCCN guidelines for men with high risk localized prostate cancer with a family history, and metastatic disease regardless of age or family history.  Because 11.8% of men with metastatic prostate cancer can have heritable mutations in DNA repair defect genes and because this is not associated with age at diagnosis or family history, all men with metastatic prostate cancer should be tested.  For men with high risk localized prostate cancer (defined by Gleason ≥7), referral to a genetics counselor is recommended with  ≥1 first degree relative with ovarian, pancreatic, or metastatic prostate cancer at any age, or breast cancer under 50 years old, or ≥2 first degree relatives with ovarian, pancreatic, prostate, or breast cancer at any age, or Ashkenazi Jewish ancestry.   His family history suggests that there is a heritable aspect to his case, but only testing can say for sure.  Some centers are making efforts to take genetic counseling into a neutral space, outside of women’s health, to make men feel more comfortable, and other centers are taking it completely out of cancer centers to make cascade testing less scary for family members without cancer.

4.  Patients and their families to consider cascade testing if a patient with cancer tests positive for a DNA repair defect.  This is important for all first-degree relatives, including children of the patient, and siblings.  If those individuals test positive, their children may also consider testing.  Screening programs can be implemented for family members without cancer, focusing on breast and prostate cancer screening, counseling regarding ovarian cancer, and consideration of screening protocols for pancreatic cancer.

15796

ASCO University
Re: Prostate Cancer (August 2018): Molecular Oncology Tumor Boards
Aug 13, 2018 4:15 PM

Patient Case Update

The patient is referred to a genetic counselor who discusses the tests available and sends off a germ line test.  The test results confirm that he is a BRCA2 carrier, and he counsels his family, including his three children and brother, to undergo cascade testing after discussing this with his genetic counselor and oncologist.  He is tolerating treatment with abiraterone and ADT well, and his PSA has decreased to 12.

15801

ASCO University
Re: Prostate Cancer (August 2018): Molecular Oncology Tumor Boards
Aug 13, 2018 4:16 PM

Discussion Questions

1.  Is the front line approach to management of patients with DNA repair defects different than the treatment algorithm for patients without? Are there approved medications or clinical trials for patients with DNA repair defects?

2.  Should I biopsy the cancer or use circulating DNA testing for somatic mutation testing?  If biopsying the cancer, should it be the primary tumor or a metastatic site?

3. Does “BRCAness” come into play for men with prostate cancer the way that it does for patients with ovarian cancer?

15806

Anis Toumeh, MD
Re: Prostate Cancer (August 2018): Molecular Oncology Tumor Boards
Aug 14, 2018 7:53 PM

In regards to question #2: with most patients having bone predominant disease and the challenges that can come up with doing somatic testing on bone biopsies, what is the role/data with using liquid biopsies? 

15811

Gladell P Paner,
Re: Prostate Cancer (August 2018): Molecular Oncology Tumor Boards
Aug 17, 2018 7:43 AM

Course Faculty Response

1. Advanced and mCRPC are enriched with biallelic inactivation of DNA-repair genes. In metastatic prostate cancers with germline DNA-repair gene mutations, ~60% have somatic alterations in the second allele. (Pritchard et al. 2016) In the TOPARP-A trial, ~80% of those with DNA-repair gene mutations that responded to the PARP-inhibitor olaparib had biallelic aberrations and only 36% of which had germline findings. Although germline mutations in one allele may show response to PARP inhibition, additional somatic DNA-repair gene abberations are likely important to predict a response. Biallelic inactivation of BRCA2 has also been shown in 3 cases of platinum-sensitive mCRPC tumors, 2 of those had germline findings. (Cheng et al. 2016) Thus, sequencing the tumor for mutations in DNA-repair genes is important upon progression of mHSPC for potential targeted therapy with PARP inhibitor, or perhaps for platinum-based therapy, in addition to enrollment in clinical trials. It is also possible that homologous recombination DNA-repair defects may sensitize prostate cancer cells to platinum-based therapy, a drug which induces DNA damage. In 2017, the Advanced Prostate Consensus Conference (APCC) recommended that BRCA1, BRCA2, and ATM mutations in tumor biopsy in advanced prostate cancer should be reported because the knowledge will likely influence management decisions. (Gillessen et al. 2018)

2. Biopsy of cancer at the metastatic site is important for phenotypic and genotypic characterizations, findings in both, may have implications to therapy. Histologic examination of the metastasis is essential, besides diagnostic confirmation, to identify neuroendocrine differentiation (small cell carcinoma), which occurs with greater frequency in advanced prostate cancers, particularly mCRPC. Immunostaining for neuroendocrine markers such as synaptophysin and chromogranin can be done on the tissue sample. At the genomic level, testing of the metastatic tumor will provide insights to alterations and clonal evolution that are more relevant to the latest disease state. This is supported by the findings of more frequent mutations in DNA-repair genes in metastatic (11.8%) compared to localized (4.6%) prostate cancers. In the 2017 APCC meeting, more experts preferred a fresh tumor biopsy sample from the mCRPC.

Analysis of circulating tumor DNA (ctDNA) in blood samples, a non-invasive or “liquid biopsy” procedure, is showing promise. There are emerging data on the role of liquid biopsies as a predictive, prognostic, response, and resistance biomarker in metastatic prostate cancers. (Goodall et al. 2017) In the TOPARP-A trial, targeted and whole exome sequencing of serial circulating cell-free (cfDNA) samples was able to detect all corresponding tumor tissue somatic DNA-repair mutations. Further, cfDNA concentration and allele frequency of somatic mutations were shown to decrease in the responding patients. Interestingly, multiple subclonal aberrations that reverted the germline DNA-repair mutations back in frame were identified in the cfDNA as possible mechanism for resistance. (Goodall et al. 2017)

Use of ctDNA though has disadvantages. Morphologic evaluation including use of ancillary immunohistochemistry to identify clonal phenotypic evolution can only be done on biopsy tissues. The average size of ctDNA fragments is ~160 base pairs. Detection of amplication or translocations can be limited. Only moderate size panels <100 genes are performed on ctDNA. Use of ctDNA test for routine clinical setting is hindered by the lack of a standardized method. A 70-gene NGS panel by Foundation Medicine (Foundation Act Assay) was recently granted a breakthrough device designation by the FDA.

3. “BRCAness” is a phenocopy of BRCA1 and BRCA2 mutations and describes situations in which a homologous DNA repair defect exists in a tumor without a germline BRCA1 or BRCA2 mutation. (Lord and Ashworth. 2016) mCRPC has been shown to be significantly enriched with mutations in other DNA repair pathway genes. One study of 150 mCRPC detected DNA-repair aberrations in 34 (23%) tumors. Of the 34 tumors, 14 (41%) had mutations in genes other than BRCA2 and BRCA1. Mutations in ATM were identified in 8 (23%) of the tumors. (Robinson et al. 2015) In the TOPARP-A trial, among 16 men with homozygous deletions and/or deleterious mutations in DNA-repair gene, 14 (88%) had a response to olaparib. These 16 included all 7 men with BRCA2 loss and 4 (of 5) men who exhibited ATM aberration. Three of the responders had mutations in BRCA1, PALB2 and HDAC2. (Mateo et al. 2015) These findings highlight the potential relevance of the other DNA-repair genes in targeted treatment with PARP-inhibitors.

A recent preclinical study demonstrated that enzalutamide was able to suppress the expression of homologous recombination genes in CRPC, thus creating a “pharmaceutically-induced” BRCAness. Enzalutamide treatment followed by olaparib, promoted DNA damage-induced cell death and inhibited clonal proliferation of prostate cancer cells in culture and suppressed growth of prostate cancer xenografts in mice. (Li et al. 2017)

15816

Alicia K. Morgans, MD, MPH, BA
Re: Prostate Cancer (August 2018): Molecular Oncology Tumor Boards
Aug 17, 2018 7:47 AM

Course Faculty Response

1.  Front line treatment for mHSPC is standard and not affected (yet) by DRD status.  Testing the tumor and having the germline information can be useful in clinical trials for front line mCRPC, second line mCRPC, and for patients to consider off-label use of a PARPi for advanced disease after that.  The TOPARP study (Mateo et al NEJM 2015) demonstrated an OS benefit to use of PARPi in patients with DRD, but this was a single arm phase 2 study and is not standard of care.  Additional clinical trials are being done combining PARPi and checkpoint inhibitors, many opportunities to engage in trials or consider PARPi off label.  Trials are the best option so we can learn from what we find.

3.  At ASCO 2018, Noel Clarke presented data on a phase 2 study in men with mCRPC that combined abiraterone + olaparib and demonstrated prolonged radiographic PFS in all-comers (both men with documented DRD and without).  This is still being evaluated further, and has not been clearly demonstrated in other studies of men with prostate cancer as of yet.

15821

Pashtoon Murtaza Kasi, MD
Re: Prostate Cancer (August 2018): Molecular Oncology Tumor Boards
Aug 18, 2018 8:16 AM

Similar to how things have evolved for pancreas cancer, genetic testing should be considered or at least discussed with ALL patients regardless of family history. It has bearing for not only the family, but also the individual patient. 

 

15826

Gladell P Paner,
Re: Prostate Cancer (August 2018): Molecular Oncology Tumor Boards
Aug 22, 2018 8:55 AM

Case Summary

  • There is an emerging significance of BRCA2 in screening, prognostication, and therapy of prostate cancer.
  • Men from families with HBOC syndrome have greater (5X) relative risk for prostate cancer when they carry BRCA2 mutation.
  • Germline BRCA2 testing and thorough family history on BRCA2-associated tumors (breast, ovarian, pancreatic, or prostate cancers) may identify family members who can be offered genetic counseling.
  • Men who are BRCA 1/2 mutation carriers biopsied for elevated screening PSA levels have higher detection rates of intermediate- or high-risk prostate cancers.
  • Germline mutations on BRCA 1/2 confer a more aggressive prostate cancer with higher chance of nodal and distant metastasis and poor survival.
  • Advanced and mCRPC have higher incidence of BRCA2 mutations (5.3-12%) and are also enriched with mutations in other DNA-repair genes such as BRCA1, ATM, CHECK2, RAD51D, and PALB.
  • BRCA2 and other DNA-repair genes are involved in DNA DSB repair and another mechanism of DNA repair is mediated by PARP enzymes; simultaneous loss of both mechanisms will be lethal to the cell.
  • The presence of mutations in homologous DNA-repair genes with defective DSB repair has been exploited by blocking the PARP catalytic activity with inhibitors such as olaparib.
  • Sequencing the tumor for mutations in DNA-repair genes is important upon progression of metastatic prostate cancer for potential targeted therapy (with PARP inhibitor) and enrollment in clinical trials.
  • There is potential for liquid biopsies of ctDNA as a predictive, prognostic, response, and resistance biomarker in metastatic prostate cancers.

15831

Alicia K. Morgans, MD, MPH, BA
Re: Prostate Cancer (August 2018): Molecular Oncology Tumor Boards
Aug 22, 2018 8:56 AM

Case Summary

  • Consideration of a referral to a genetic counselor is recommended in the NCCN guidelines for men with metastatic prostate cancer, regardless of age or family history.
  • The presence of DNA repair defects may provide opportunities for treatment for men with mCRPC if ongoing clinical trials in this patient population demonstrate benefit from treatment.  Phase 2 single arm trials suggest that patients with these abnormalities may benefit from treatment with a PARP inhibitor.
  • Families of patients with DNA repair defects should consider cascade testing to identify these abnormalities in family members and enable them to undergo screening protocols for prostate and other cancers, including breast, ovarian, and pancreatic cancers.
  • It is important for patients with prostate cancer to consider enrolling in clinical trials to enable us to understand DNA repair defects more completely, to continue development of therapeutics and enhance our understanding of patient selection for men with prostate cancer.

15836

ASCO University
Re: Prostate Cancer (August 2018): Molecular Oncology Tumor Boards
Aug 22, 2018 8:57 AM

Thank you to Drs. Paner and Morgans for 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 credit on ASCO University by clicking here.

Please check back in mid-October for a new case in this series related to breast cancer.


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