With current technology, it is relatively cheap and easy to sequence the DNA of just about anyone or anything. The technology, which first gained acclaim in academic research institutions, has been used to decipher the mistakes and changes in DNA that drive cancer, and has led to dozens of companies that offer sequencing directly to patients.
Despite the ease, the ability to interpret sequencing results is still comparatively new science. Terms like genome, exome, germline and somatic are not entirely familiar to all doctors, let alone patients. The ability to decipher the data gene sequencing produces to determine what are important to the care of cancer patients are a complex science all its own.
If a shopper went to a large department store and asked for a pink dress, she might be presented with hundreds of dresses, but most of them would likely be the wrong size, style or perhaps even an undesirable shade of pink for the shopper. She would need to sort through them and pick out only the ones that suit her, and perhaps she would not find any that she liked.
Oversimplified, yes, but this scenario illustrates the problem with the broad use of gene sequencing. The technology is limited by the reader’s ability to sort through it and pull out data points that will make a difference in patient care. Gene sequencing of a tumor may reveal many alterations to the DNA, but it takes an expert understanding of cancer genetics to know if any of those alterations influence a patient’s cancer.
“Tumor sequencing makes a lot of information available, but how do we use it?” says sequencing and cancer genetics expert Josh Lauring. “Many doctors are not up to speed on the science and how the genetics impact the tumor and targeted therapies, and how they all interact. It’s complex.”
The clinical usefulness of alterations is also limited by currently available drugs. Identifying a genetic mistake that helps a cancer grow or spread is important to cancer research, but without a drug that can target the mistake, it has no affect on the current standard of care. By the same token, a mutation in a known cancer gene with an associated drug may not necessarily be driving the growth of the cancer. Using the drug to target this passenger mutation—the term given to gene mutations that are just along for the ride but are not actually influencing the behavior of the cancer—does nothing to abate the cancer and can actually be harmful.
Leading breast cancer genetics expert Ben Park witnessed this firsthand when a young breast cancer patient opted to forgo standard therapy with a proven track record of success to enroll in a clinical trial at another hospital solely based on one of these company-produced gene sequencing reports. Park, a member of the world-renowned team that became the first to decipher the genetic blueprint of breast and other cancers, discovered true cancer-promoting mutations in the gene that was identified in the report and recognized that the type of mutation that the patient had was not driving her cancer. “This clinical trial was not going to help her, but there were a half-dozen standard therapies we knew were likely to work against her cancer,” Park says.
This patient nearly died as a result of an ill-advised interpretation of her sequenced tumor. “That case really showed me the danger of patients and oncologists acting on these reports without having the full knowledge to really evaluate all of the information.” says Park. “Patients were chasing invalidated targets, and I recognized we needed a molecular tumor board to vet these sequencing reports.”
In 2013, soon after Park shared this patient’s experience with Kimmel Cancer Center colleagues, the GAITWAY Tumor Board was born. GAITWAY stands for Genetic Alteration In Tumors With Actionable Yields. Park ran GAITWAY until 2015, when he turned the reins over to Lauring.
Lauring leads a board made up of about a dozen experts, including oncologists, genetics experts, molecular pathologists, genetic counselors and a patient advocate. They meet weekly to review cancer gene sequencing reports to determine if they contain any actionable targets—gene alterations that have corresponding drugs that work against them.
Lauring receives sequencing reports from other Johns Hopkins colleagues, community physicians, and Johns Hopkins partners and affiliates, such as the Allegheny Health Network and Johns Hopkins Singapore, and takes them before the GAITWAY board for review and interpretation. He is among an elite group of clinicians charged with staying abreast of the ever-changing list of cancer gene targets and targeted therapies—drugs that target specific gene alterations. Under his leadership, GAITWAY findings have been published in scientific journals, and it has become a national model for how to navigate modern gene sequencing technology and integrate it into precision cancer medicine—the term for therapies that are based on the unique molecular characteristics of each patient’s cancer.
“Others can do this, but not everyone does it well,” says Breast and Ovarian Cancer Program Co-Director Vered Stearns. “Our GAITWAY board finds things others miss.”
They bring some clarity to a not-so-well-understood technology. Lauring has reviewed reports that identify a gene target, only to find that the mutation is not even in the tumor. On another occasion, GAITWAY expertise led to a completely different diagnosis for a patient—an observation that changed the treatment.
A report on a lung cancer patient came before the GAITWAY board, and Lauring recognized a gene rearrangement identified in the sequencing report occurred in a type of cancer called NUT midline carcinoma. It is a rare cancer, occurring in the trachea and chest, that many doctors have never heard of. Most of the time, the cancer is mistaken for and treated like squamous cell lung cancer. Lung cancer drugs do not work against this aggressive cancer, so Lauring’s depth of expertise in cancer genetics was critical to guiding this patient to the best treatment. Because Lauring was able to tie the genetic alteration to the rare and aggressive cancer, the GAITWAY board could guide this patient to a clinical trial of emerging targeted therapies for this cancer type.
“Our goal is to get patients to the best therapy for them,” says Lauring. “The expertise the GAITWAY board brings to the table is particularly important in the case of rare cancers and new or rare mutations.”
In another case, Lauring and board were reviewing a prostate cancer case. The report listed the patient as MSI-negative. The term refers to a Kimmel Cancer Center discovery that uses mutations in genes termed mismatch repair to identify patients likely to respond to immunotherapy. Patients with mismatch repair alterations typically have many mutations in their tumors, and the GAITWAY board noted that this patient’s tumor had that telltale sign and ordered additional pathology on the tumor. The additional testing revealed the cancer was actually MSI-positive, making the patient eligible for an immunotherapy clinical trial.
“No test is perfect, and each company has issues with what it misses or doesn’t include in its reports,” says Lauring. The GAITWAY board does not simply take the reports on their face value but instead uses its broad expertise to flag and explore inconsistencies that might change treatment recommendations or provide more options to patients.
“Our job is to figure out if there is a gene in a report that we know we can target effectively with an available, FDA-approved drug now or through an open clinical trial,” says Lauring. Genetic counselors on the GAITWAY board, led by Dana Petry, help determine when genetic counseling or additional testing for inherited gene mutations should be recommended, and the patient advocate serves as a voice for all cancer patients.
As important as finding genes that can be targeted with therapy is being able to determine that a report contains no actionable targets, Lauring says. “If the evidence is weak, we need to be able to say that too.”
The GAITWAY board has reviewed 300 cases since forming in 2013. One hundred of the cases were brought to the board in 2017, demonstrating the growth in demand for the group’s specialized expertise. Still, Lauring knows they can’t review every case, but they are trying to be proactive working with companies to alert them to common mistakes and specific actionable targets they should look for and seek expert guidance.
What does this mean for breast cancer patients?
Stearns recognized that breast cancer patients wanted tumor sequencing, and it is her goal to learn how it can help patients now but also to advance the science to see how they can increase its benefit in the future.
The wide availability but often uncertain utility of cancer gene sequencing is particularly relevant to breast cancer experts and patients. Genes that drive cancer are not specific to a certain cancer type but often occur across cancers with varied frequency. Some cancers, such as lung cancer, have more known actionable targets. Breast cancer, while out in front in terms of precision medicine, with biomarkers like HER2 and estrogen receptor status long guiding therapy, has very few gene mutations associated with targeted treatments.
“One thing cancer genetics has taught us is that no two cancers are alike,” says Lauring. “Breast cancer does not yet have many actionable genetic targets, but it has so many approved standard treatments. A patient could go through 10 treatments before we would start to worry about running out of options and would recommend sequencing a tumor to see if it will point to something that directs us to a clinical trial.” That scenario may come up sooner for patients with triple-negative breast cancer, or other cancers, like pancreatic cancer, where there are fewer treatment options. “Right now, the main utility is for women with recurrent, metastatic breast cancer,” he says.
Lauring and Park say there is really no reason for an early-stage, surgically treatable cancer to be sequenced. “There are so many good standard therapies. We don’t want to mess around with curable disease,” says Park. “But, in metastatic patients whose cancers continue to grow on standard therapies, we know another chemotherapy is not going to make a difference. These are the patients we need to sequence and look for molecular targets.”
With many companies selling this service and using different platforms to sequence genes in cancers, it is a little bit like the Wild West now. Research is leading to more and more drugs being studied and approved for genetic alterations. One day, this may be routine cancer medicine, but currently there are more questions than answers. As a result, where and how the test is reviewed absolutely make a difference. The GAITWAY Tumor Board helps ensure that the excitement over the promise of sequencing technology does not overshadow the reality of what it can currently deliver.
Park points out that Kimmel Cancer Center experts are in a unique position to traverse this uncharted territory, as its experts were the first to map the genetic causes of cancers and are the undisputed leaders in this area of research. “The thing that bothered me the most was that too many doctors were ordering genetic testing at the wrong time,” says Park. “If you have a treatment you know is going to work, why order the testing? Timing is important. Who evaluates the report is too.”
“I’m not discouraging these tests, but it’s important for patients to have realistic expectations and make sure to get the recommendation of knowledgeable experts,” says Lauring. “This is complex stuff.”
Currently, breast cancer has just a few known actionable mutations that could be identified through sequencing, Lauring says.
When an advanced breast cancer comes before the board, HER2 mutations are among the gene mutations the GAITWAY board looks for. HER2 mutations are different from the much more common HER2 amplification, a breast cancer biomarker that can be obtained without gene sequencing and is important to guiding doctors to standard therapies. “In HER2 amplification, the gene gets duplicated again and again, and this leads to a lot of HER2 protein,” says Lauring. Drugs like trastuzumab, familiar to most patients by its trade name Herceptin, work well against cancers with HER2 amplification, known as HER2-positive breast cancers.
Now, however, there is evidence that certain patients with lobular breast cancer or triple-negative breast cancer, a HER2-negative and treatment-resistant form of breast cancer, may also benefit from treatment with trastuzumab. Patients whose cancers have mutations—not amplification—of the HER2 gene might see a response to the drug. “We don’t know for certain yet if they will all benefit from HER2 therapies, but there are data that suggest that some of them will,” says Lauring. For a triple-negative breast cancer patient with a HER2 mutation who is not benefiting from standard treatments, the GAITWAY board could suggest a clinical trial that is studying the benefit of trastuzumab in triple-negative breast cancer and variety of other cancers with HER2 mutations. Breast cancer clinical research.er Roisin Connolly is leading these trials at the Kimmel Cancer Center.
HER2 mutations are rare, occurring in only about 2 percent of breast cancers, compared to HER2 amplifications, which occur in about 20 percent of breast cancers. However, in certain types of breast cancer, such as lobular and triple negative, Lauring says they may be at play in about 5 to 10 percent of cases.
In women with BRCA gene mutations, drugs known as PARP inhibitors may be able to prevent cancer cells from repairing damage caused by chemotherapy and improve the effectiveness of standard treatments. This was the case for Pam Fitzgerald, a metastatic metaplastic breast cancer patient of Park’s. (See article on page 6.) She was not a candidate for a clinical trial of PARP inhibitors, so the GAITWAY board recommended off-label use of the drug, and it helped keep Fitzgerald’s rapidly growing cancer in check for more than a year. Recently, her cancer has begun to grow again, and Park ordered new tumor sequencing to see if the cancer has acquired any new mutations that could be targeted with a drug.
Some gene mutations, known as acquired-resistance mutations, result from chemotherapy and targeted therapies as cancer cells exploit new cellular mechanisms to maintain their survival. Tumors that were once hormone receptor positive may shift to hormone negative. Sequencing can help identify these changes in patients with advanced cancers that stop responding to treatment. Right now, Lauring says, there are only a few new drugs that may work in patients with certain resistance mutations, but just as important, sequencing can inform doctors about therapies that are unlikely to work. For example, if a tumor has acquired a resistance mutation in the estrogen receptor, an aromatase inhibitor, which reduces the amount of estrogen available to tumors, is not likely to help. “Sequencing advancing breast cancers can help us select the right drug or avoid using the wrong one,” says Lauring.
PIK3CA mutations, discovered in breast cancers in high frequency by Park in 2004, occur in about 40 percent of breast cancers. Lauring says there is early evidence that patients who have this mutation and are not responding to standard therapies may benefit from investigational drugs that block PIK3CA. “If we confirm this finding in ongoing clinical trials, we’ll have a reason to test for this mutation, and it could change the landscape for breast cancer,” he says.
Emerging immunotherapies are also showing promise for breast cancer, and triple-negative breast cancer in particular, which usually has a larger number of mutations and, even in the absence of mismatch repair mutations, may still attract an immune response simply because of the sheer volume of mutations. “It’s still early, but this is something we can identify with tumor sequencing,” says Lauring. “We’re not there yet, but as immunotherapy evolves and as we understand more about targets, we may evaluate how mutations effect driver genes in the tumor, but also how they could alter the proteins in a way that might make the immune system recognize the cancer. Then we could begin to think about personalized vaccines and other types of immunotherapy.”
Ultimately, Park says, he wants women to be driven by knowledge and not by fear. “I see the devastation this disease causes, and we all want women to have more options,” he says. “Cancer figures out ways to get around almost everything when it becomes metastatic, and that’s where having a foot in both fields—clinical care and genetics—has helped me direct laboratory research so that we can use tumor sequencing to help even more breast cancer patients in the future.”
How does research help?
Lauring says there are two very important aspects of research. “There is the kind of research we do in the laboratory to help us better understand the biology of breast cancer, and then there is the human experiment all around us where patients are desperate and are requesting these tests,” he says. Lauring believes there is a lot to learn from both. In addition to offering the expert advice of the GAITWAY board, they are building a database that marries tumor genetics with clinical outcomes, so they can learn more about targeted therapies that work, for whom they work best and also ones that don’t work. “Genetics tell you drivers and potential targets, but there is a lot more we can learn by combining it with the patient data,” says Lauring.
Through the GAITWAY program, they are collecting and analyzing information, including age, family history, genetic profile, diagnosis, stage of the cancer, treatments, length of response to treatments, recurrences and survival, to begin to draw conclusions. “It’s amazing how little data we have of this kind,” says Lauring. “Details about treatments received and how patients did on them do not exist.” For example, they will begin to look at how many breast cancer patients had PIK3CA mutations and how they did on a specific targeted therapy compared to patients who did not receive a targeted therapy.
The group is also collaborating on research beyond the Kimmel Cancer Center, including the National Cancer Institute’s MATCH trial and the American Society of Clinical Oncology’s TAPUR trial. MATCH stands for Molecular Analysis for Therapy of Choice and will do what GAITWAY already does, but on a larger scale, sequencing thousands of cancer patients to look specifically for changes in 143 genes to match them to specific targeted therapies. TAPUR, Targeted Agent and Profiling Utilization Registry, is ASCO’s first clinical trial and will collect data on the activity of about 10 drugs targeting specific genetic mutations across a variety of cancer types. “We’re collecting real-world data with community oncologists around the country to see if tumor sequencing is helping patients and if the therapies it points to are helping patients,” says Lauring.
At the Kimmel Cancer Center, Park and Stearns are conducting research studies to better determine if gene sequencing using noninvasive liquid biopsy samples works as well as, or potentially even better than, sequencing tumor samples. Two Avon Center of Excellence-funded research studies known as IMAGE, for Individualized Molecular Analyses Guide Efforts, compare both methods of using genetic information to help guide breast cancer therapy and to track and monitor the progress of cancer to see if a treatment is working.
The first IMAGE study compared tissue DNA to liquid biopsy DNA in 20 patients with triple-negative breast cancer. They wanted to see if liquid biopsy provided a more complete genetic profile of metastatic cancers than tissue biopsy, which is typically limited to sampling one metastatic site. Liquid biop.sy, which gathers cancer DNA from plasma circulating throughout the bloodstream, has the potential to collect tumor DNA from all metastatic sites.
“The results demonstrated that liquid biopsy is a good representation of tissue,” says Stearns. In most of the patients, they found the same mutations in blood as in tissue, but there were six patients where they could not get adequate amounts of tumor tissue to biopsy. “Liquid biopsy provides another way to obtain tumor DNA from these patients. It provides faster results, and since it is noninvasive, we can perform the test repeatedly and potentially even replace the need for tissue biopsy,” says Stearns.
The second study builds on these findings and expands the study to 200 patients and all breast cancer types. “We will be looking at tumor profiling and liquid biopsy, trying to identify targets and really understand the interplay of mutations and response to treatment,” says Stearns. They will perform a liquid biopsy on all patients and tissue biopsies when possible. They will bring the genetic profile obtained from both to the GAITWAY board, which will provide each patient and her physician with therapy recommendations based on the genomic profile in tumor and blood. They will also compare liquid biopsies taken before and after treatment to look for changes in cancer DNA.
“Right now, we have to wait three months and do an imaging scan to see if a drug is working,” says Stearns. “We want to see if we can do a liquid biopsy after a week and tell if a therapy is working. If not, we can quickly switch course. We would rather know sooner than later. We don’t want to lose three months.”
In patients with early-stage breast cancer, Park says, about 30 percent of patients who receive chemotherapy before surgery will have no visible tumor left at the time of surgery. He, Stearns and breast cancer colleague Antonio Wolff would also like to see if liquid biopsy can drill down to the molecular level to identify patients who need no additional treatment from those who may have genetic evidence of remaining cancer cells. “Maybe some patients will not need surgery,” says Park. They would compare liquid biopsy results before and after the course of chemotherapy given leading up to surgery. If they are able to detect cancer DNA through liquid biopsy before chemotherapy is started but find no visible tumor and no cancer DNA after the course of chemotherapy ends, perhaps these patients can avoid surgery.
“It would enable physicians to identify the patients who are cancer-free—and who may not need surgery after chemotherapy or chemotherapy after surgery,” says Park. “That’s the biggest unmet need in breast cancer care right now. About 30 of every 100 postsurgical breast cancer patients are at a high risk for relapse and need chemotherapy, but we can’t distinguish them from the patients who are cured, so we give postsurgical chemotherapy to all 100 of those patients because we can’t tell. If liquid biopsy is able to identify the high-risk cases in advance, many women could be spared chemotherapy.”
“All of this work looks really promising,” Park says, “and it fits in nicely with our goals of precision or individualized medicine. What we’re trying to do is get to a point where we can say, ‘You don’t need to get everything and the kitchen sink. You just need to get what your individual cancer needs so that it’s cured—not too little, not too much.’”