The discovery of the BRCA genes by Mary Claire King and Mark Skolnick in the 1990s provided immense insights.
It explained familial breast and ovarian cancer syndromes and established that the BRCA genes functioned by repairing DNA damage associated with lifelong injury.
It also showed that other cancers like melanoma and prostate could be associated.
Later it was recognized that BRCA mutations actually “sensitize” tumors to DNA damage like that caused by Cisplatin, culminating in the development of an entirely new class of drugs known as the PARP inhibitors.
BRCA mutations can now be identified by genomic analyses and many patients today are routinely screened. Good responses to platinum-based therapies have given hope to many.
What became puzzling however was that some patients who did not carry BRCA mutations nonetheless responded very well to BRCA-directed therapies. These patients have, what physicians have to come to call, “BRCA-ness”.
Stage 4 Uterine Cancer
A charming 63-year-old patient diagnosed with advanced uterine cancer underwent surgery followed by Carboplatin plus Taxol chemotherapy.
Relapse at one year led to a second surgery with a biopsy submitted to our laboratory.
Good activity for Carboplatin plus Doxil, identified by our EVA/PCD functional profile, provided the patient with a prompt complete remission but toxicity, principally low blood counts, made final completion of chemotherapy more difficult.
At this point, I re-examined the EVA/PCD analysis and noted sensitivity to the PARP inhibitor, Olaparib.
This drug had recently been FDA approved but only for BRCA (+) patients.
Hoping to qualify her for Olaparib, I submitted her tumor for genomic analysis. The results returned negative for both germ line (familial) and somatic (individual) BRCA mutations.
I offered to petition her insurer for Olaparib, but in the interim was able to provide a brief course of the drug.
During the first week the CA 125 rose. But then, as we achieved full dose, it fell to normal.
The patient who had virtually no side effects appeared to be achieving a remission with a drug that she would otherwise not have received.
Why might a patient found BRCA negative, at both the germline (familial) and somatic (individual) level, respond? The answer is a fascinating tale of insight and discovery.
Genes Are Only The Beginning
We must remember that genes are only a blueprint.
They make it possible for us to become the people we are but they are only the starting point. What each cell does with the genes it has been given, determines what we ultimately become.
After all every cell in the human body has the same genetic makeup. It is not what we have tucked away in that DNA attic but instead what we choose to pull out and utilize that makes us, us.
The process of selecting only those genes that we want is known as “gene-expression” and it is gene expression that distinguishes your genotype (DNA) from your phenotype (You).
As this patient had no evidence of a BRCA gene mutation, her cancer cells had the DNA template to make all the BRCA proteins they wanted. But instead of using the BRCA genes, her cancer cells chose to seal them off, preventing them from being expressed. Regardless of her gene profile at the DNA level she was “functionally” BRCA deficient.
We now recognize this as a process known as epigenetics (defined as “the study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself”).
Epigenetic modifications functionally silence normal genes leaving patients with the equivalent of an absent gene. This patient has all the features of a BRCA mutation (absent BRCA protein and BRCA function) but no BRCA mutation.
The concept of BRCA-ness has been the subject of numerous reviews.
It has been suggested that up to 25% of ovarian cancer patients with no measureable mutation or deletion in their BRCA genes may actually manifest this BRCA-like biology. Prostate, pancreas and some breast cancers are likely to behave exactly the same way.
By using functional analyses our laboratory has the unique ability to identify all patients with BRCA or other biological features, regardless of their genomic (DNA) makeup.
By doing this, we were able to identify an active drug that she would otherwise not have received. Her good response led to an approval by her insurer and she remains on this simple oral therapy.
It turns out that in cancer it’s what you is and not what you might be that counts.
As always, I appreciate your thoughts and comments.