HRD-Positive Ovarian Cancer

HRD stands for homologous recombination deficiency. Homologous recombination is the cell's precise way to fix double-strand breaks in DNA. When that system breaks, the tumor falls back on sloppier methods. Damage then builds up that the cell cannot fix.

That weakness is the point. A tumor that cannot repair DNA well is more vulnerable to drugs that create DNA damage or block the remaining repair routes.

NCI puts the mechanism plainly for the best-known genes. BRCA1 and BRCA2 make proteins that help repair damaged DNA. When those proteins fail, chemotherapy that damages DNA can work well. Cisplatin is one example. PARP inhibitors can work well too. NCI lists four approved for cancers with harmful BRCA1 or BRCA2 changes. They are olaparib, rucaparib, niraparib, and talazoparib.

This is the part most summaries skip. FDA's approved wording defines HRD-positive status as a deleterious or suspected deleterious BRCA mutation, and/or genomic instability.

That means your report can be HRD-positive for either reason.

Route one: a BRCA finding. The test detects a harmful or likely harmful change in BRCA1 or BRCA2.

Route two: a genomic instability score. The test measures scarring across the whole genome. That pattern is left behind by years of failed repair. A tumor can score positive with no BRCA mutation at all. Some other part of the repair machinery failed instead.

Ask which route produced your result. The two mean different things for your relatives.

FDA keeps a list of approved companion diagnostics. It names Myriad myChoice CDx for ovarian cancer with olaparib. The listed biomarker matches the two-route definition. It covers deleterious or suspected deleterious mutations in BRCA1 and BRCA2, and/or a positive Genomic Instability Score.

FoundationOne CDx also appears on that list for ovarian cancer with olaparib. The biomarker listed there is BRCA1 and BRCA2 alterations. That is a narrower question than a full HRD check.

So the name of the assay matters. Say your test reports BRCA only. A negative result then says nothing about genomic instability.

FDA approved olaparib with bevacizumab on May 8, 2020. The setting is first-line maintenance in adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients must be HRD-positive. They must also have had a complete or partial response to platinum-based chemotherapy.

The supporting data came from PAOLA-1. The HRD-positive subgroup held 387 patients. Median progression-free survival was 37.2 months with olaparib plus bevacizumab. It was 17.7 months with placebo plus bevacizumab. The hazard ratio was 0.33, with a 95% confidence interval of 0.25 to 0.45.

The dosing in that approval is specific. Olaparib is 300 mg by mouth twice daily. It runs up to two years, or until the disease grows or side effects stop it. Bevacizumab is given by vein every three weeks, at an amount worked out from body weight.

Note the phrase "first-line maintenance." This is treatment that starts after chemotherapy has already worked, to hold the response. It is not a substitute for chemotherapy.

A BRCA change found in tumor tissue can be somatic or germline. Somatic means it arose in the cancer. Germline means you were born with it. Tumor testing alone often cannot tell them apart.

NCI says someone with a harmful BRCA change found in their tumor should consider germline testing. That is how you learn whether it was inherited. Germline testing uses blood or saliva, not tumor.

The stakes for relatives are large. NCI reports that 39% to 58% of women who inherit a harmful BRCA1 change develop ovarian cancer. For a harmful BRCA2 change, the range is 13% to 29%. General population risk is about 1.1%.

Genomic instability without a BRCA finding does not carry the same family message. That is another reason to know which route made you HRD-positive.

It does not make the cancer more aggressive or less aggressive by itself. It does not mean chemotherapy is finished. It does not guarantee a PARP inhibitor is right for you. Eligibility also turns on your response to platinum chemotherapy, your blood counts, your kidney and liver function, and whether bevacizumab is safe for you.

It also does not apply evenly across subtypes. NCI reports repair-gene variants in about 11% of low-grade serous carcinoma. In high-grade histologies the figure is 27%.

LiverTox lists the common effects of olaparib. They include anemia, fatigue, nausea, diarrhea, indigestion, belly pain, poor appetite, cough, muscle and joint pain, headache, and rash. Serious but uncommon risks are also listed. Those include pneumonitis, blood clots, myelodysplastic syndrome, acute myelogenous leukemia, acute liver injury, and harm to a fetus.

Niraparib is given at 300 mg by mouth once daily. Its list is similar, plus low platelets. It also carries risks of marked bone marrow suppression and myelodysplastic syndrome.

Both PARP tablets are taken at home, and the figures above are the labels'. Starting amounts differ from person to person, so use the prescription your own gynaecological oncology team wrote and go to your blood tests as booked.

Because of the marrow risks, blood counts are drawn on a schedule, not only when you feel unwell.

• Fever of 100.4 degrees F, or 38 degrees C, or higher. NCI treats this as urgent during cancer treatment. Call before taking a fever reducer.
• New shortness of breath or a cough that keeps worsening. These can signal pneumonitis.
• Pain, swelling, or warmth in one calf, or sudden chest pain. These suggest a clot.
• Bruising with no injury, bleeding gums, nosebleeds that will not stop, or black stools.
• Yellow eyes or skin, or urine that turns dark.

• Which assay was used, and did it report a genomic instability score or BRCA only?
• Was I HRD-positive because of BRCA, because of instability, or both?
• Has germline testing been ordered, and should my sisters or daughters be tested?
• Is maintenance being offered as olaparib alone, olaparib with bevacizumab, or niraparib?
• How long is the planned course, and what marks the stopping point?
• How often will my blood counts be checked?

The list above is the same-day tier. Two other tiers sit either side of it.

• Call 911 or go to an emergency department if you have severe difficulty breathing, chest pain or pain in the upper back, a heart that is racing, or if you pass out. The NHS puts those in the emergency group, because a clot in the leg can travel to the lung, and clots are on the label for both olaparib and niraparib. Do the same for bleeding that will not stop after a few minutes, or for a bad headache with confusion or sudden trouble seeing, which matter more when platelets are low.
• Call your care team within a day or two if you feel newly and unusually breathless on stairs or short walks, or so tired that ordinary activity has stopped. Anemia is one of the most common effects of these drugs, and it may show up between scheduled blood draws. The same applies to nausea, diarrhea or poor appetite that is starting to keep food and fluids down to a trickle.

For related reading, see BRCA Gene Mutations Explained, What Does PARP Inhibitor Mean?, and Biomarker Testing and Precision Medicine.

• FDA — FDA Approves Olaparib Plus Bevacizumab as Maintenance Treatment for Ovarian, Fallopian Tube, or Primary Peritoneal Cancers
• FDA — List of Cleared or Approved Companion Diagnostic Devices
• National Cancer Institute — BRCA Gene Changes: Cancer Risk and Genetic Testing
• National Cancer Institute — Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment (PDQ), Health Professional Version
• LiverTox (NCBI Bookshelf, NIH) — Olaparib
• LiverTox (NCBI Bookshelf, NIH) — Niraparib
• National Cancer Institute — Infection and Neutropenia during Cancer Treatment
• NCI — Bleeding and Bruising (Thrombocytopenia) and Cancer Treatment
• NHS — Pulmonary embolism