When Alaura Keith was diagnosed with triple-negative breast cancer in 2013, every physician she saw suggested a different treatment.
“None of them could agree on what do to,” she said. “Triple-negative breast cancer hadn’t even been around that long.”
Triple-negative breast cancer, or TNBC, had only been “discovered” eight years earlier, when a landmark study defined the molecular subtype. Keith ended up going with very aggressive treatment: 13 rounds of a chemotherapy cocktail followed by surgery, then another 17 rounds of another chemotherapy, followed by 30 rounds of radiation and three years of maintenance therapy.
“It tore through my intestines,” said the 55-year-old fourth-grade teacher from Bonney Lake, Washington, now nearly 15 years out from her diagnosis and treatment. “I ended up in the ER with internal bleeding. It definitely took me a few years to get back to normal.”
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Triple-negative breast cancers are tough nuts to crack. In fact, the very name tells you they lack all three of the customary targets found in most breast cancers: estrogen receptors, progesterone receptors and the growth-promoting HER2 protein, common vulnerabilities for which there are treatments.
“Triple-negative breast cancer remains one of the hardest subtypes to treat,” said Fred Hutch Cancer Center’s Lynn Symonds, MD, clinical co-director of the Breast Oncology Program. “It is still very reliant on chemotherapy because we don’t have a lot of targeted therapies; we don't have a lot of options. There’s just a huge unmet need in that space.”
Likewise, ovarian cancer remains a leading cause of gynecologic cancer death, since warning signs are subtle and there’s no preventive screening. Women are usually diagnosed late, when the cancer is harder to treat; ovarian cancer also tends to develop resistance to chemotherapy.
As a result, the survival rate for these two cancers lags behind those of many others. Metastatic or stage 4 TNBC has a five-year survival rate of only 12 to 15%, while those with advanced or metastatic ovarian cancer have a five-year survival rate of around 31%.
“It’s an area where we need big discoveries and big, big impact,” Symonds said.
Now, thanks to the work of Symonds and her mentor and fellow breast cancer oncologist Jennifer Specht, MD, along with Fred Hutch gynecologic oncologists and clinical researchers Kalyan Banda, MD, Isabel Rodriguez, MD and Elizabeth Swisher, MD, a big discovery may soon make a “big, big impact” on patients dealing with these two intractable cancers.
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First, an important note regarding ovarian cancer: it’s usually not.
“Ovarian cancer is not one entity but really a group of cancers under one umbrella,” said Swisher, deputy director of the Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium and holder of the Torkelson Family Endowed Chair. “We now know that the most common type of what we call ovarian cancer actually starts in the fallopian tubes, so calling it ovarian cancer is a misnomer.”
Swisher said there are types that actually do start in the ovaries “but the most common cancer type comes from the fallopian tubes. We should probably call it tubo-ovarian cancer to encompass all the cancer types.”
Does it matter where a cancer starts? Absolutely, Swisher said.
“If you’re looking in the wrong place, you’re not going to identify the cancer early,” she said. “Understanding the biology of the cancer is really important if you want to figure out how to prevent it. And these changes in our understanding are leading to new ways to do early detection and prevention.”
Treatment for ovarian cancers has traditionally been surgery and chemotherapy, not necessarily in that order. But the development and approval of a class of drugs known as PARP inhibitors, beginning with olaparib (sold as Lynparza) for metastatic ovarian cancer in 2014, opened up a new treatment pathway.
“The clinical development of PARP inhibitors was done first and foremost in ovarian cancer,” said Swisher, who’s acted as principal investigator on several PARP inhibitor trials. “PARP inhibitors were discovered to be specifically lethal in cancers that had mutations in BRCA1 and BRCA2. And ovarian has the highest fraction of cases with those mutations. It made it the perfect cancer type to develop this therapy.”
The problem is only around 20% of women with tubo-ovarian cancer have inherited tumor-specific mutations in one of these two genes, Swisher said.
“Our goal for the last 10 to 15 years has been to identify which patients will have the best response to PARP inhibitors,” she said.
An equally important goal: finding additional cancers that might benefit from this treatment.
That’s where HRD and triple-negative breast cancer, or TNBC, come in.
Inside every one of our cells is something called a homologous recombination repair mechanism, a bit of biological machinery that works like a DNA spellchecker.
“Every time your cell makes a copy of itself, it has to copy all that DNA,” Symonds explained. “And to make sure that there aren’t any mistakes, your cells have a spell check. When that spell check machinery is damaged or off, it can lead to mistakes in how our DNA gets copied that can basically lead to cancer.”
Normally, our cells detect DNA “typos” and pause replication and cell division. But when that machinery is damaged, cells with mutations are not corrected or stopped. They just keep on reproducing, which in turn causes even more mistakes.
“There are a lot of different genes involved with this DNA repair machinery but currently, the only genes that have a treatment associated with them are the BRCA1 and BRCA2 genes, which are part of this pathway,” Symonds said. “If you have a mutation in those genes, you may qualify for a targeted therapy called a PARP inhibitor.”
But BRCA1 and BRCA2 mutations are only one piece of this puzzle, she said.
Multiple other genes also make up the so-called spellcheck system, which when it’s functioning normally is called homologous repair proficient, or HRP. When the spellcheck system malfunctions, it’s called homologous recombination repair deficiency, or HRD. HRD is a defining feature of BRCA1 and BRCA2 mutations.
One measurement of HRD is an assay called HRDetect, developed 10 years ago by cancer genomics expert Serena Nik-Zainal, MD, PhD, at the University of Cambridge. But this assay, used to predict whether or not a patient will respond to a PARP inhibitor, only measures whether a cancer is positive or negative for HRD.
Swisher and Banda, collaborating with Nik-Zainal, combined the HRDetect assay with whole genome sequencing, or WGS, then comprehensively profiled a cohort of tubo-ovarian cancer tissue samples. They then folded in clinical data regarding the patients’ response to PARP inhibition and gained additional insights.
“HRDetect is an algorithm that combines many different mutational signatures to give you a probability score,” said Banda, who along with Swisher and others, published the study in AACR’s Clinical Cancer Research Journal in July that showed combining HRDetect with WGS “can not only sharpen prognostic predictions but also suggest therapeutic avenues.”
“We thought there would be a high and a low HRD category, but we found that 25% of patients were actually intermediate,” he said. “We’ve been treating ovarian cancer as two subtypes but now we see that it’s almost a dozen types, maybe even more. The biology is so much richer than these two bins that we’ve been sorting patients into. That’s what’s exciting here.”
Patients classified as “HRDetect-high,” he said, had significantly longer median overall survival (6.2 years vs. 4.1 years) and vastly different responses to PARP inhibitors than patients in other categories. Now, Banda is working on a novel way to identify cancers with HRD using artificial intelligence and pathology slides to predict genomic signatures.
“What do they respond to?” he said. “That’s the next question. Because only then is the information useful. There’s no point in me just defining things without being able to act on them.”
What’s also exciting is that the researchers believe these insights will help to expand treatment beyond patients with inherited BRCA1 and BRCA2 mutations.
“In addition to mutations, which are DNA changes in the gene, we’re looking at methylation, a different kind of alteration in the gene that confers the same sensitivity to PARP inhibitors,” Swisher said, adding that she worked with Rodriguez to develop the new methylation assay.
The assay, dubbed HRDefine, is “much more precise,” in that it picks up homologous repair deficiencies caused by methylation and other means.
“It doesn’t just look at a downstream characteristic of HRD but finds the cause of the HRD in cancer,” Swisher said. “You can look at a current biopsy and determine if the cancer has HRD and that will really help define who gets a PARP inhibitor or not.”
Symonds and Specht, who serves as clinical research director for the Breast Oncology Program at UW Medicine and leads the TNBC working group for the Translational Breast Cancer Research Consortium, are poised to validate the HRDefine assay for use in triple-negative breast cancer. Specht holds the Jill D. Bennett Endowed Professorship in Breast Cancer at UW Medicine.
“Rather than just looking at BRCA1 and BRCA2, HRDefine is looking at a broader group of genes in that pathway using a couple of different techniques,” Symonds said. “Our hope is that we can demonstrate that this assay detects the signal we want to detect. And then we hope to use that to expand the number of patients that might be eligible for a PARP inhibitor.”
Oral PARP inhibitors are currently only available for the fraction of triple-negative breast cancer patients with BRCA1 or BRCA2 inherited mutations.
“This means only around 5% of patients of TNBC patients qualify,” Symonds said. “But most patients with triple-negative breast cancer have HRD which means we are missing a large number of patients who would benefit from these treatments.”
Swisher, who’s studied HRD and PARP inhibitors for 15 years, said it’s all about “giving more choices to patients with triple-negative breast cancer.”
For TNBC patients like Keith, who wasn’t treated at Fred Hutch but raised funds for breast cancer research via Climb to Fight Breast Cancer, more therapy choices are a much-needed development.
“This is why I raised funds for Fred Hutch research,” she said. “Anything anybody could do would be a benefit. When I went through treatment, it was just a crapshoot. They didn’t know what was going on.”
HRDetect is only available for research purposes at the moment, Banda said. As for HRDefine, the University of Washington currently has a patent pending for it; assays do not require U.S. Food and Drug Administration approval. Symonds said the plan is to make it available in the clinic ― and to make it affordable.
But first, she and colleagues are launching a study to validate their findings “in hundreds of samples,” funded in part by Symonds’ recent Conquer Cancer, the ASCO Foundation Career Development Award. Eventually, there will be a treatment-related clinical trial for patients.
Symonds, who pursued both research and oncology specifically for moments like this, said the work is significant for a few reasons.
“We were able to take a home-grown assay developed at the University of Washington by Dr. Swisher, a recognized expert in ovarian cancer genetics who led the development of PARP inhibitors, and expand it into breast cancer patients,” she said. “It’s also a really a wonderful example of precision medicine ― bringing the right drug to the right patient at the right time.”
Their work also highlights the importance of continuing to explore and exploit cancer’s complicated biology and to correct course, as needed.
As Banda puts it: “We cannot precisely treat the cancer if we cannot precisely define the cancer.”
The study was funded in part by grants from Conquer Cancer®, the ASCO Foundation, including a Conquer Cancer Career Development Award, and other support from the Aldarra Foundation, Roger Wilcox and family, the Lopker Family Foundation and Judith Lese.
Diane Mapes is a senior editor and writer at Fred Hutch Cancer Center, who's written for NBC News, TODAY, CNN, MSN, Seattle Magazine and other publications. A breast cancer survivor and patient advocate, you can reach her at dmapes@fredhutch.org or doublewhammied.com / @double_whammied / @doublewhammied.bsky.social. Just diagnosed and need information and resources? Visit our Patient Care page.
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