Dr. Nagourney's Blog

Recurrent BRCA Positive Ovarian Cancer: An Unexpected Opportunity

By Robert A. Nagourney, MD

For the over 22,000 women in the United States diagnosed each year with ovarian cancer outcomes have improved slowly, yet the majority of these women still do not survive five years.

Despite these statistics, ovarian cancer remains one of the most chemo-responsive diseases treated by medical oncologists and there is renewed reason for hope.

We now recognize that the responsiveness of ovarian cancer cells to platinum-based (Cisplatin and Carboplatin) chemotherapy is actually a “hard-wired” feature of this disease. The term applied is Homologous-DNA-Repair (HDR) deficiency and the most common inheritable form of this abnormality is known as BRCA mutation.

Patients with BRCA-related cancers share features with a rare childhood illness known as Fanconi’s anemia (see picture of FA cells above), named after first being described by Guido Fanconi (1892-1979). This syndrome is also caused by DNA repair deficiency.

Indeed, an older diagnostic test for Fanconi’s anemia exposed bone marrow cells of affected children to the chemotherapy drug Mitomycin-C to identify the characteristic DNA damage under the microscope. Cisplatin and carboplatin affect the DNA in much the same way, thus a connection between this childhood illness and these adult cancers.

Case in Point:  BRCA Positive Stage 4 Ovarian Cancer

This bit of history recently came into focus when I was asked to see a 66-year-old woman with rapidly progressive BRCA-positive stage 4 ovarian cancer who had failed all therapy.

After progressing on Carboplatin plus Taxol she went on to Doxil plus Avastin and then in June of 2017 began treatment with Niraparib, a member of the newest class of drugs for BRCA (+) tumors known as the PARP inhibitors.

Things went from bad to worse as the CA 125 tumor marker rose from 1122 to 5968 in just under 6 weeks and all areas of measureable disease worsened.  A biopsy of a chest wall mass was conducted by our surgeon and provided ample cells for EVA/PCD study.

Her Functional Profiling Results

The results were extremely interesting, as the patient’s tumor revealed utter resistance to the currently fashionable PARP inhibitors yet a striking degree of sensitivity to Mitomycin-C (the drug used to diagnose Fanconi’s anemia in children) and very good activity for the related combination of Cisplatin plus Gemcitabine.

It seemed that the patient’s tumor still remembered its heritage as a DNA repair deficient cancer (like Fanconi’s anemia) but didn’t much care for the current crop of “targeted” PARP inhibitors.

While the new drugs appeared useless, a simple and readily available drug doublet appears highly likely to work.

Functional analyses, like the EVA-PCD assay, enable us to explore drugs, both new and old.

I tested Mitomycin-C, in part, to probe this patient’s tumor.

In essence, I used this potent DNA damaging agent to confirm the presence of Fanconi's anemia-like biology.  Just like that pediatric test of old, this patient’s result informed us that DNA-damaging combinations still held promise.

While it is too early to be sure that this ovarian cancer patient will respond I am optimistic.

Impressed by the results with Mitomycin-C and it’s similarity to Cisplatin plus Gemcitabine our functional analysis not only confirmed resistance to the PARP inhibitor but also identified sensitivity to drugs that might otherwise not have been tried.

While the new classes of signal inhibitors revealed no activity, a readily available chemotherapy doublet can now be administered:

A simple solution to a complex problem.

As always, I appreciate your thoughts and comments.

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