A woman checking her breast for the presence of concerning lumps.
Nancy Cappello was proactive. When she turned 36, she had a baseline mammogram, a standard medical recommendation in the late 1980s and early 1990s as a comparison tool for future screenings. At 40, Cappello started getting them annually.
Her breast surgeon estimated the cancer had been festering for four to five years under the radar of her annual mammograms.
Six weeks after her 11th-consecutive normal mammogram, she was diagnosed with Stage IIIc breast cancer.
A doctor felt a lump while doing a breast exam during her annual physical and a subsequent ultrasound detected cancer that had spread to 13 lymph nodes. That's when Cappello, then 51, learned she had dense breast tissue, making mammography less likely to detect tumors in her breasts.
She also discovered through her own research that she was among the 40 to 50 percent of women with dense breast tissue — almost half the female population — but medical protocol did not require physicians to inform women of their dense tissue status. If she had known, she said, she would have gotten an ultrasound every year in addition to a mammogram that could have detected the cancer much earlier. Cappello said her breast surgeon estimated the cancer had been festering for four to five years under the radar of her annual mammograms.
Although ultrasound as a cancer screening tool has been available for decades, technological advances are helping doctors find more invasive cancers in women with dense breasts, in turn giving women who know their tissue status the opportunity for earlier detection and treatment.
"We know that the gold standard for breast cancer screening is mammography, but in women with dense breast tissue, up to one third of breast cancers can be missed with this modality alone."
Dr. Georgia Giakoumis Spear, chief of the department of breast imaging at NorthShore University HealthSystem in suburban Chicago and assistant professor of radiology at the University of Chicago, has been a leader in developing standards for the use of new ultrasound technology. She is leading a study to develop more specific national guidelines around the use of Automated Whole Breast Tissue Ultrasound (ABUS), a non-invasive procedure in which sound waves are used to scan breast tissue while a patient lies on her back with her arm over her head.
Approved by the Food and Drug Administration in 2012, ABUS provides higher quality 3D images and faster delivery to provide more accurate results than past ultrasound technology. The scan does not involve radiation, and a practitioner can complete the process in 15 to 20 minutes, from patient preparation to image creation. NorthShore has been using ABUS since 2015, Dr. Spear said, and the technology can improve breast cancer detection in women with dense breasts by up to 55 percent.
"We know that the gold standard for breast cancer screening is mammography, but in women with dense breast tissue, up to one third of breast cancers can be missed with this modality alone," Spear says. "And when we supplement screening with ultrasound in this population of women, we have found a large number of cancers by ultrasound that are not visible on the mammogram."
Mammography should still be used as the first step for breast cancer detection, but if an initial mammogram shows that a patient has dense breast tissue, studies encourage discussion of additional screening with ultrasound.
On a mammogram, dense tissue appears white. So do cancerous masses, making them easy to miss.
A radiologist determines tissue density, according to the American College of Radiology's Breast Imaging Reporting and Data System (BI-RADS). "A" and "B" breast density categories designate ratios of mostly fatty, or non-dense tissues, while the "C" and "D" categories designate heterogeneously dense and extremely dense tissue, respectively. Such patients would be classified as having dense tissue. Younger women, women with lower levels of body fat and women undergoing hormone therapy are more likely to have C and D breast density.
On a mammogram, dense tissue appears white. So do cancerous masses, making them easy to miss. Fatty tissue, in comparison, appears black, making tumors easier to spot.
The FDA stated among its policy goals for 2018 that it's placing an improved focus on recognizing technological advances to help "ensure women get the most relevant, up-to-date information about their breast density, which is now recognized as a risk factor for breast cancer." An article in the March 2018 Journal of the American College of Radiology recommended supplemental screening for women with higher-than-average breast cancer risk, placing women with dense breast tissue in that category.
To be sure, some in the medical community are reluctant to push for ultrasounds, saying that a mammogram might be enough even if the woman has dense breast tissue. A patient is advised to discuss the option of ultrasound with her physician and they can decide from there.
Access to such information became political for Cappello after her diagnosis in 2004. She said that as she underwent six surgeries, a mastectomy, chemotherapy, radiation and hormone therapy, she asked doctors why they weren't required to inform women of their dense breast tissue status. Her dissatisfaction with their responses led to the formation of Are You Dense, Inc., an advocacy group aimed to inform women of their medical options while working to pass legislation mandating that women know their tissue status. Other legislation has focused on mandating insurance coverage for breast ultrasounds.
Nancy Cappello.
(Courtesy)
Cappello's work led Connecticut to become the first state to pass an information law in 2009, and 35 states now have similar requirements. Depending on the state, the law could mandate that certain language or information about breast density be included in the patient's mammogram results, or require physicians to tell women about dense tissue if their breast density falls in the BI-RADS categories C and D. Other states might require that patients be given general information about breast density and advice to discuss their options with a physician. (Note: There is a chart on Cappello's website that shows what laws exist – or don't – in each state.)
Through her site and social media, she's connected with other women who've lobbied for laws in their states, including Dr. Spear, who recently testified before legislative committees in Illinois as they considered companion bills. The Illinois legislation is expected to be signed into law this summer.
"There should be no excuses," Cappello says. "Women should have this information. There should be no concealing or hiding of her status."
As gene therapies and small molecule drugs are being studied in clinical trials, companies increasingly see the value in hiring patients to help explain the potential benefits.
Biomedical corporations and government research agencies are now incorporating patient advocacy more than ever, says Alice Lara, president and CEO of the Sudden Arrhythmia Death Syndromes Foundation in Salt Lake City, Utah. These organizations have seen the effectiveness of including patient voices to communicate and exemplify the benefits that key academic research institutions have shown in their medical studies.
“From our side of the aisle,” Lara says, “what we know as patient advocacy organizations is that educated patients do a lot better. They have a better course in their therapy and their condition, and understanding the genetics is important because all of our conditions are genetic.”
Founded in 2016, Tenaya is advancing gene therapies and small molecule drugs in clinical trials for both prevalent and rare forms of heart disease, says Ali, the CEO.
The firm's first small molecule, now in a Phase 1 clinical trial, is intended to treat heart failure with preserved ejection fraction, where the amount of blood pumped by the heart is reduced due to the heart chambers becoming weak or stiff. The condition accounts for half or more of all heart failure in the U.S., according to Ali, and is growing quickly because it's closely associated with diabetes. It’s also linked with metabolic syndrome, or a cluster of conditions including high blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol levels.
“We have a novel molecule that is first in class and, to our knowledge, best in class to tackle that, so we’re very excited about the clinical trial,” Ali says.
The first phase of the trial is being performed with healthy participants, rather than people with the disease, to establish safety and tolerability. The researchers can also look for the drug in blood samples, which could tell them whether it's reaching its target. Ali estimates that, if the company can establish safety and that it engages the right parts of the body, it will likely begin dosing patients with the disease in 2024.
Tenaya’s therapy delivers a healthy copy of the gene so that it makes a copy of the protein missing from the patients' hearts because of their mutation. The study will start with adult patients, then pivot potentially to children and even newborns, Ali says, “where there is an even greater unmet need because the disease progresses so fast that they have no options.”
Although this work still has a long way to go, Ali is excited about the potential because the gene therapy achieved positive results in the preclinical mouse trial. This animal trial demonstrated that the treatment reduced enlarged hearts, reversed electrophysiological abnormalities, and improved the functioning of the heart by increasing the ejection fraction after the single-dose of gene therapy. That measurement remained stable to the end of the animals’ lives, roughly 18 months, Ali says.
He’s also energized by the fact that heart disease has “taken a page out of the oncology playbook” by leveraging genetic research to develop more precise and targeted drugs and gene therapies.
“Now we are talking about a potential cure of a disease for which there was no cure and using a very novel concept,” says Melind Desai of the Cleveland Clinic.
Tenaya’s second program focuses on developing a gene therapy to mitigate the leading cause of hypertrophic cardiomyopathy through a specific gene called MYPBC3. The disease affects approximately 600,000 patients in the U.S. This particular genetic form, Ali explains, affects about 115,000 in the U.S. alone, so it is considered a rare disease.
“There are infants who are dying within the first weeks to months of life as a result of this mutation,” he says. “There are also adults who start having symptoms in their 20s, 30s and 40s with early morbidity and mortality.” Tenaya plans to apply before the end of this year to get the FDA’s approval to administer an investigational drug for this disease humans. If approved, the company will begin to dose patients in 2023.
“We now understand the genetics of the heart much better,” he says. “We now understand the leading genetic causes of hypertrophic myopathy, dilated cardiomyopathy and others, so that gives us the ability to take these large populations and stratify them rationally into subpopulations.”
Melind Desai, MD, who directs Cleveland Clinic’s Hypertrophic Cardiomyopathy Center, says that the goal of Tenaya’s second clinical study is to help improve the basic cardiac structure in patients with hypertrophic cardiomyopathy related to the MYPBC3 mutation.
“Now we are talking about a potential cure of a disease for which there was no cure and using a very novel concept,” he says. “So this is an exciting new frontier of therapeutic investigation for MYPBC3 gene-positive patients with a chance for a cure.
Neither of Tenaya’s two therapies address the gene mutation that has affected Borsari and her family. But Ali sees opportunity down the road to develop a gene therapy for her particular gene mutation, since it is the second leading cause of cardiomyopathy. Treating the MYH7 gene is especially challenging because it requires gene editing or silencing, instead of just replacing the gene.
Wendy Borsari was diagnosed at age 24 with a commonly inherited heart disease. She joined Tenaya as a patient advocate in 2021.
Wendy Borsari
“If you add a healthy gene it will produce healthy copies,” Ali explains, “but it won’t stop the bad effects of the mutant protein the gene produces. You can only do that by silencing the gene or editing it out, which is a different, more complicated approach.”
Euan Ashley, professor of medicine and genetics at Stanford University and founding director of its Center for Inherited Cardiovascular Disease, is confident that we will see genetic therapies for heart disease within the next decade.
“We are at this really exciting moment in time where we have diseases that have been under-recognized and undervalued now being attacked by multiple companies with really modern tools,” says Ashley, author of The Genome Odyssey. “Gene therapies are unusual in the sense that they can reverse the cause of the disease, so we have the enticing possibility of actually reversing or maybe even curing these diseases.”
Although no one is doing extensive research into a gene therapy for her particular mutation yet, Borsari remains hopeful, knowing that companies such as Tenaya are moving in that direction.
“I know that’s now on the horizon,” she says. “It’s not just some pipe dream, but will happen hopefully in my lifetime or my kids’ lifetime to help them.”