HRD Times

When DNA double-strand breaks occur in a healthy individual, the homologous recombination (HR) pathway generates a new strand of DNA and inserts it into the previously damaged area. It’s a complicated process that involves multiple different proteins that first bind to the loose ends of DNA, then initiate DNA excision of the damaged area, exposing the single-strand. If one or more of these proteins malfunctions, then the pathway is disturbed and DNA repair cannot take place. There are other repair pathways that can compensate but, all too often, DNA damage accumulates, which can lead to the worst-case scenario: cancer.

It’s already known that mutations in BRCA1 and BRCA2 – genes whose resultant proteins play a prominent role in the HR repair pathway – are relatively common in ovarian and breast tumors. Otherwise, data regarding which tumors are more commonly affected by HR deficiency (HRD) are quite limited, and not large scale – which means some patients could be missing out on the best treatment.

Beyond BRCA

As a clinical fellow at the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC, I have been taking care of patients who are BRCA1/2 and PALB2 mutation carriers. During my two years of oncology training so far, I have witnessed the implementation of exciting new therapies (for example, PARP inhibitors) and unique drug combinations for these patients, and watched them respond remarkably well. I have also seen some of the negative impacts related to these mutations, including recurrent cancers and the need for prophylactic surgeries to minimize future cancer risk.

My work gave me a special interest in these patients, and so I participated in the design of a clinical trial looking more broadly at genetic mutations in the HR repair pathway. In the trial, which will be opening this fall, a PARP inhibitor will be combined with platinum chemotherapy for patients with advanced solid tumors and a somatic or germline mutation in one of the genes involved in the HR pathway.

Being involved in designing this trial opened my mind to the potential treatment possibilities for a larger group of patients than just BRCA mutation carriers. I wanted to find out how large the group of patients that could benefit from more tailored therapies truly might be. Although several groups have begun to define the prevalence of HRD within specific tumor lineages (1)(2) my colleagues and I decided to perform a study evaluating all tumor lineages – to our knowledge, the largest study evaluating the prevalence of HRD so far (3).

HRD definitions

To gain a better understanding of the prevalence of HRD, we reviewed molecular profiles from 53,619 solid tumor samples using several methods, including next generation sequencing. The tumors were taken from patients with a range of cancers, including breast, ovarian, pancreatic, lung, as well as unknown cancers. The aim was to identify somatic pathogenic mutations in HR genes, including BRCA1/2, ATM, PTEN and PALB2 (4). Overall, the frequency of HR mutations amongst all tested tumors was 13 percent, with some lineages having a much higher frequency than others (see Figure 1).

One of the main challenges we faced was deciding exactly how to define HRD, and therefore which mutations we thought would be impactful and should be included. We decided to include most genes involved in the HR pathway, but it’s important to bear in mind that some may not confer as much clinical significance as BRCA, for example. We were surprised to see the number of tumor lineages that were impacted by these mutations – with BRCA, PTEN, and ATM mutations seen quite widely. It could certainly expand treatment options for patients with, for example, lung cancer with a BRCA mutation.

Understanding the mutation landscape

One appealing feature of our study is that we were able to use commercially available technology to generate our results. The molecular profiling techniques we used can be performed on any solid tumor tissue, and are often covered by insurance. However, there is still work to be done. We don’t yet know how these results affect clinical outcomes – we would assume that patients with mutations in other genes involved in the HR pathway, beyond BRCA, will respond favorably to PARP inhibitors and platinum chemotherapy. Although this is just now starting to prove true in the literature (2)(5)(6), we have some way to go to ensure each mutation within the HR pathway carries a similarly weighted impact. Additionally, this testing evaluates for a mutation within the tumor itself, but not germline mutations. We also don’t know how this affects outcome; most of the previous work with BRCA, for example, was done using “BRCA mutation carriers” – patients with germline BRCA mutations. You could argue that knowing the somatic mutation landscape is actually more meaningful when it comes to predicting therapy response, but only time will tell.

To clinical trials, and beyond

When the planned multi-institutional trial valuating the use of PARP inhibitors with platinum chemotherapy in patients with both germline and somatic evidence of HRD is completed, we hope to couple this with our assessment of clinical outcomes to address the questions our study has raised. Doing so should help us to discover what the HRD response to PARP inhibitors and platinum chemotherapy will be, and to see which HRD mutations seem to cause the most striking effects in relation to therapy response – and mortality. Another exciting avenue is the potential to exploit the accumulation of DNA damage in tumors with HRD to achieve responses to immunotherapy via increased neoantigens and potentially increased tumor lymphocytes. A better understanding of HRD’s role in cancer has the potential to lead to many advances for patients, so it warrants much more exploration.

Arielle Heeke is a Clinical Fellow at Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., USA.