PCa Commentary | Volume 119 – Jan/Feb 2018

Posted by Edward Weber | Jan/Feb 2018

KNOW YOUR BRCA STATUS:
The Clinical Importance of Mutations in Genes that Repair Injury to DNA

The message is clear. At diagnosis, 6% of men carry mutations in the BRCA1 or BRCA2 gene.

At the stage of metastatic castration-resistant prostate cancer, nearly 12% of men exhibit these germline (inherited) mutations. Finally, as the course of the disease progresses through various therapies, the number of BRCA and BRCA-like mutations further increases and can be found in up to 23% of men. 

The field of genomic analysis for cancer mutations is complex and evolving. This Commentary will try to highlight several clinically relevant points accompanied by discussion and is a companion piece to PCa Commentary Vol 115 Sept 2017 “PARP Inhibition – An Emerging New Treatment” (ctrl+click link to follow). The current Commentary highlights expanded information regarding BRCA and BRCA-like mutations that can be identified with “next generation sequencing” (NGS) of circulating tumor DNA (ctDNA).

The identification of mutations in the family of DNA repair genes, notably BRCA 1 and 2 and ATM and their associates, is clinically important for three reasons: 

• When these mutations are found in the germline, they imply an increased risk for familial prostate cancer (as well as for breast, ovarian, and pancreatic cancer in family members). In certain situations, i.e. younger onset of prostate cancer, Gleason > 7, and in a family with several instances of prostate cancer, a conference with a genetic counselor may be in order. (Source: NCCN guidelines, Version 2.2017) 
• Having germline mutations in BRCA1 and especially BRCA2 implies more aggressive cancer at diagnosis, a higher risk for metastatic spread, and a worse outcome. One study1  found that 25% of men with germline mutations in BRCA 2 presented with metastatic disease. These mutations confer an additional risk factor to be considered when choosing active surveillance. The NCCN 2017 guidelines acknowledge this concern for aggressiveness and suggest that information about mutations in BRCA1/2 “should be discussed with such men if they are considering active surveillance.”
• Germline mutations and those additional mutations in the BRCA family that have evolved as a result of therapy (i.e. “somatic”) are termed “clinically-actionable mutations.” They render men candidates for novel therapies such as PARP inhibitors (i.e., olaparib and talazoparib); also for platinum-based chemotherapy, such as a combination of docetaxel and carboplatin.

How can a man learn if he harbors mutations in the BRCA1 and 2 genes and their helpers CHEK2, ATM, FANCA, PALB2, and the family of Rad 51 genes?

• Tissue Based Genomic Analysis Estimating the Prevalence of Germline Defects in

DNA Repair Genes:

• The conventional approach is having representative malignant tissue from the biopsy or

surgical specimen sent to a pathology lab that specializes in genome analysis. At many institutions this is an automatic referral after obtaining informed consent. The University of Washington’s UW-OncoPlex-Cancer Gene Panel, for example, employs NGS to detect mutations in tumor tissue in 262 cancer-related genes. Germline information can also be obtained by submitting blood, saliva, or buccal swabs for analysis since “germline” implies that all bodily cells contain the mutation (available at Color Genomics at color.com  $249).

Men with metastatic prostate cancer can enroll in the GENTleMEN study sponsored by the Seattle Cancer Care Alliance, Seattle WA, and have free testing of saliva using the Color Genomics kit. To learn more go to gentlemenstudy.org or call (877) 606-GENT (4368).

Tissue from biopsies from metastatic sites represents a select population of cancer cells, that is, ones that acquired the requisite characteristics that facilitate escape from the primary tumor and invasion of distant sites. It was with this arduous technique that a consortium of researchers (see below) established that the percentage of cells expressing BRCA and BRCA-like mutations in men who have metastatic cancer rose to about 12%.

• “Inherited DNA-repair gene mutations in men with metastatic prostate cancer” is a pivotal article compiled by an international consortium of researchers.2  
• Tissue from 692 men was analyzed with NGS for disabling mutations in 20 genes responsible for maintaining genomic stability by correcting double stranded breaks in DNA.
• “Our study showed that the frequency of mutations of [germline] genes involved in DNA repair was significantly greater among men with metastatic prostate cancer [i.e. 11.8%] than those with localized disease [4.6% – 6%],”2 predominantly occurring in high risk cancer patients. The most common alterations were BRCA1 and 2, ATM, and CHEK2 genes. They found no association of DNA repair mutations and age, and only marginal association with high Gleason scores.
• The authors note that therapy with drugs that inhibit PARP1 (i.e., olaparib & talazoparib) show “substantial objective response” in men with these DNA-repair defects [response rate reported at 88% by Mateo et al., NEJM Nov 20153]. The authors’ conclusion: “… it may be of interest to routinely examine all men with metastatic prostate cancer for the presence of germline mutations in DNA-repair genes”.2

This recommendation was further supported at the Philadelphia Prostate Cancer Consensus Conference, 2017, on the role of genetic testing for inherited cancer risk (JCO, 2017). There was strong consensus among panelists for factoring testing for BRCA1/2 and ATM into management discussions with men having high-risk/advanced cancer and metastatic CRPC.

• A second article, “Integrative clinical genomics of advanced prostate cancer,”4 presented the work of another international consortium. The researchers assayed genomic data from “bone or soft tissue tumor biopsies from a cohort of 150 metastatic CRPC affected individuals” in the search for somatic alterations that had developed under the selective pressure of therapy during the course of the disease. Loss of BRCA2 was noted in 12.7% of cases. Combining alterations in BRCA1, 2, and ATM, that aggregate loss was 19.3% overall, making them candidates for PARP inhibition therapy.
• Genomic Analysis of Fragments of Circulating Tumor DNA (ctDNA) with Next Generation Sequencing:
• Malignant cells release DNA into the bloodstream through natural death (apoptosis) or tumor destruction (necrosis). NGS is a sophisticated and evolving technique that can analyze blood and capture the commingled gene mutational data arising from body-wide tumor sites. This technique has gained the term “liquid biopsy” and offers the possibility of sequential sampling of the evolving mutational landscape. This information may allow the selection of therapy to match new target opportunities.

Analysis of prostate biopsies and surgical specimens can capture germline data, and biopsies of specific metastatic sites can add data about somatic mutations. However, these sources of information are limited by the heterogeneity of prostate cancer. Liquid biopsies assayed by NGS have the capacity to query the entire evolving mutational landscape representing multiple sites metastases. The amount of ctDNA in blood has been found to be proportional to the aggregate tumor mass. Hence,“repeat liquid biopsies therefore offer unparalleled  opportunity for monitoring tumor burden and response to therapy in real-time.”5  

• Guru P. Sonpavde reported results of analysis using the Guardant360 platform for assaying ctDNA from 514 men with metastatic CRPC.6 Their findings showed the power of this new technique. The Guardant 70-gene panel found at least one alteration in 94% of the specimens. 

Mutations in BRCA1 and BRCA2 each were found at baseline in 5%. After treatment, serial testing recorded an increase in the number of mutations in these genes. “A higher number of ctDNA alterations was associated with a shorter time to treatment failure. Because these mutations in the BRCA family indicate a specific vulnerability, the results suggested to them that “PARP inhibitors hold promise.”6

• Based on their review of ctDNA profiling, Parimi and Ko confirm the high number, 22.7%, of men with metastatic CRPC who harbor “clinically actionable” defects in BRCA-like genes responsible for DNA repair.7 These mutations offer treatment opportunities with PARP inhibitors. 
• Optimism about the promise of NGS is reflected in the quote from Vanderkerhove: “The unique opportunity to learn about basic tumor biology and drug resistance in large patient cohorts combined with the potential clinical impact means that the liquid biopsy is poised to revolutionize the treatment of advanced prostate cancer.”6

[NGS of ctDNA is commercially available at Guardant360.com (Guardian Health, Inc). Their panel analyzes for mutations in 73 genes in 10 cc blood, including the genes highlighted in this Commentary: BRCA1 and 2, and ATM.]

Of interest: In January 2018, olaparib (“Lynparza”) received FDA approval for treatment of women with a special subtype of breast cancer who had BRCA-mutated genes. A clinical trial had shown a 42% reduction of the risk of death compared to standard chemotherapy. It can be reasonable to hope that an approval might be gained for men with prostate cancer having BRCAness mutations on the basis of results of ongoing trials. Currently olaparib is only available for protocol use. See Vol. 115 for details of ongoing protocols.

BOTTOM LINE: It is to a man’s advantage to be aware of his BRCAness status at diagnosis and during the course of his disease.

References

1. Gleicher S, et al. Implications of high rates of metastatic prostate cancer in BRCA2 mutation carriers. Prostate. Sep 2016.
2. Pritchard CC, Nelson PS, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. NEJM. Dec 2016.
3. Mateo J, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. NEJM. Nov 2015.
4. Robinson D, et al. Integrative clinical genomics of advanced prostate cancer. Cell. May 2015.
5. Vandekerkhove G, Chi KN, Wyatt AW. Clinical utility of emerging liquid biomarkers in advanced prostate cancer. Cancer Genetics. 2017.
6. Sonpavde GP (February 2017). Abstract 149. Genitourinary Symposium, Orlando Florida.
7. Parimi S, Ko JJ. Recent advances in circulating tumor cells and cell-free DNA. Expert Review of Anticancer Therapy. 2017.

“I want to thank Dawn Scott, Staffperson, Tumor Institute Radiation Oncology Group, & Mike Scully, Librarian, Swedish Medical Center for their unfailing, timely, and resourceful support of the Commentary project. Without their help this Commentary would not be possible.”