The Search Magazine Article November 01, 2017

Curing breast cancer: When, how, and what’s next?

Progress to date: positive trends

A diagnosis of breast cancer is always devastating, but advances in research are pushing incidence and mortality trends in the right direction.

The U.S. Centers for Disease Control report that from 2003 to 2012 (the most recent year for which data are available), the incidence rate of breast cancer in women remained level. Most encouraging, the number of deaths from breast cancer actually decreased by 1.9 percent per year, amounting to a nearly 20 percent reduction over that decade.

In fact, says Edison Liu, M.D.Conducts research focused on the functional genomics of breast cancer through an exploration of the entire genomic space.Edison Liu, M.D., a breast cancer researcher and president and CEO of The Jackson Laboratory, “If current trends continue, theoretically there would be no breast cancer mortalities by 2045. And though this remains aspirational and may not be able to be achieved, the direction is clear: We are winning.” 

What were the medical breakthroughs behind the improvement in prognosis for women with breast cancer? Liu credits “decades of “creative innovation,” with each generation of scientists building on findings of the previous generation.

An important early insight was that cancer is not a single disease with a single cause, and that the location of a tumor has less bearing on disease progression or mortality than its mechanisms. Better profiling of breast tumors was the first step in developing more targeted and effective treatments.

The next big cancer breakthroughs, in the 1960s, were combination chemotherapy (administering multiple drugs simultaneously) and adjuvant therapy, chemotherapy following surgical removal of a tumor, to eliminate any pockets of residual disease. Liu notes that adjuvant therapy was actually pioneered in breast cancer, by researchers working in the Istituto Nazionale Tumori di Milano in Italy.

Before adjuvant therapy, Liu says, “The standard protocol for breast cancer was draconian surgery followed by draconian radiation.” And while a small number of cases still call for such drastic treatment, “Adjuvant therapy eliminated the terrible side effects of radical mastectomy followed by disfiguring radiation that actually hurt the patient’s health.”

Hormone therapy joined the oncologist’s toolkit in the 1970s. The hormones estrogen and progesterone promote the growth of some breast cancers. The cells of these so-called hormone-dependent breast cancers contain proteins called hormone receptors that become activated when hormones bind to them, causing changes in certain genes and stimulating cell growth. Hormone therapy to block the body’s hormone production is aimed at slowing or stopping the growth of hormone-sensitive tumors.

Breast cancer cell division
Dividing breast cancer cells

In 1998, the FDA approved trastuzumab, better known under the brand name Herceptin, to treat breast cancers that are HER2-receptor positive. A gene called HER2 makes HER2 proteins, receptors on breast cells that normally control how a healthy breast cell grows, divides and repairs itself. In about 25 percent of breast cancers, the HER2 gene goes into production overdrive, spurring uncontrolled growth and division of breast cells. Trastuzamab works by binding to the HER2 receptor and slowing down cell duplication.

In 1994 and 1995, researchers identified genetic mutations in genes, designated BRCA1 and BRCA2, that turned out to be the most common cause of hereditary breast cancer. In normal cells, these genes help make proteins that repair damaged DNA, but mutated versions can lead to abnormal cell growth and cancer. Since then close to a dozen other genes have been identified that are associated with elevated risk for breast cancer.

The impact of fundamental science on breast cancer outcome is clear, Liu says, “but equally important is the contribution of early diagnosis through mammographic screening. Catching cancer before it metastasizes save lives as does adherence to optimal clinical procedures in the delivery of care.” Now, he adds, with genetic screening to identify individuals at high risk for breast cancer, targeted and intensive preventive measures can further reduce cancer mortality.

“All these may sound incremental,” Liu comments, “but you add them all up, it becomes akin to building a dam, brick by brick. And pretty soon you've got a pretty effective dam.” Now, he says, the biggest challenge is improving the survival of patients with triple-negative breast cancer — those cancers that are not estrogen-receptor positive, progesterone-receptor positive or HER2 positive.

New strategies for tackling triple-negative breast cancers

Triple-negative breast cancers account for about 15 percent of all breast cancers, and according Liu, “is today the worst breast cancer to have: the fastest-growing, the most metastatic.” A study of 50,000 women with breast cancer showed five-year survival rates for patients with a triple-negative breast cancer diagnosis at 77 percent, compared to 93 percent for women with other types of breast cancer.

Liu and his lab focus on triple-negative breast cancer. Last year the Liu lab announced the discovery of a molecular “fingerprint” that is characteristic of triple-negative breast cancer as well as other deadly cancers of women, including serous ovarian cancer and endometrial carcinomas.

This configuration, which they call a “tandem duplicator phenotype,” is the result of mutations that cause faulty DNA replication during cell division. Duplications of short stretches of copied DNA are inserted in the genome next to the segments from which they were copied. These tandem duplication sequences disrupt genes at and near their insertion points and double the production of genes that happen to be copied, uninterrupted, in the middle. 

Perhaps most significantly, Liu and his team showed that triple-negative breast cancer and other cancers with the tandem duplicator phenotype respond to a specific chemotherapy, cisplatin, The researchers observed strong responses in both cell culture and in patient-derived tumors implanted in mice, with some of the tandem duplicator tumors displaying complete response (more than 80% tumor shrinkage). None of the tumors without the trait showed any response to cisplatin. The findings, Liu says, “provide the possibility for characterizing approximately 40% of these tumors by a genome-based tandem duplicator score and treating them with the best drug possible, providing more precision and effectiveness than previously.” 

Francesca Menghi, Breast Cancer Research, The Jackson Laboratory for Genomic Medicine
JAX cancer researcher Frencesca Menghi. Photo by Tiffany Laufer.

Francesca Menghi, Ph.D.Studies critical genomic changes implicated in ovarian and breast cancers.Francesca Menghi, Ph.D., an associate research scientist in Liu’s lab who collaborated in the tandem duplicator phenotype research, wants oncologists to have a much larger array of therapies available for their triple-negative breast cancer patients.

Based on the genomic configurations and defects of specific tumors, Menghi says, and the lines of therapy of interest to the clinician-oncologists that she collaborates with, “we have compiled a list of about 20 single agents or combinations — all of which are already FDA-approved — to test for effectiveness. Our preliminary data in the lab would suggest that certain tumors with specific genomic profiles will be more responsive to certain drugs.”

Not only will the resulting study reveal which drugs and combinations work best on individual tumors, she says, “but also, when we find treatments that work well, we will go back in and figure out why, what the mechanisms are.”

These studies in the  The Liu LabResearching the fundamental genomics of breast cancer.Liu lab are possible thanks to the advent of patient-derived xenograft (PDX) trials in special mice that can host (and not reject) human tumors. Fragments of a patient’s tumor can be propagated in these mice, and researchers can use the models to explore the basic biology of any cancer.

Moreover, PDX models are ideal for testing multiple cancer drugs simultaneously, singly and in combination, and for gleaning insight into chemotherapy responses. PDX drug trials offer a clinical-trial roadmap for piloting treatments for patients with similar tumors or molecular profiles. They are also a powerful system for understanding the mechanisms of treatment resistance — one of the most serious obstacles to successful chemotherapy — and for devising strategies for overcoming that resistance.

The PDX approach has gained significant traction in the cancer research community due to its increased precision in measuring drug-response. In 2016, the NCI decided to refocus its repository of cancer models, which has long been dominated by the NCI60 panel of human cancer cell lines, to include PDX models for cancer drug screening.

JAX Professor Carol Bult, Ph.D.Bridges the digital biology divide, by integrating computation and informatics with biomedical research.Carol Bult, Ph.D., is the scientific director of the JAX PDX program. “This is about finding the right drug for a breast cancer patient as early as possible,” Bult says. “Better combination therapies mean we could turn triple-negative breast cancer from a death sentence into a chronic but manageable disease.”

For a patient facing a triple-negative breast cancer diagnosis, she says, “That would be everything.”

Next steps: Putting cancer research findings to work for patients

Maine Cancer Genomics Initiative
The Alfond Center for Cancer Care at MaineGeneral Health Center in Augusta, Maine.

Outside the Alfond Center for Cancer Care at MaineGeneral Health Center in Augusta, Maine, the building sign includes a JAX logo. This is the home of the  Maine Cancer Genomics InitiativeThe Maine Cancer Genomics Initiative (MCGI), enabled through generous financial support from the Harold Alfond Foundation, leverages the strengths of key medical and bioscience research institutions in Maine to create an alliance focused on precision cancer diagnostics and treatment.Maine Cancer Genomics Initiative (MCGI) , a bold community genomic medicine project launched in 2016 with a charitable contribution from the Harold Alfond Foundation. MCGI Medical Director Jens Rueter, M.D., says the program will “bring cancer genomics expertise into the clinical decision-making process for Maine cancer patients.”

Maine is the home of the JAX headquarters campus in Bar Harbor. The state also has one of the highest incidences of cancer in the country, Rueter notes, “and with approximately 9,000 new cancer cases each year in our state, addressing treatment in Maine is of the utmost importance.”

Clinicians from every cancer care provider in Maine now have access to the advanced genomic medicine tools in the JAX CLIA-certified/CAP-accredited laboratory including cancer-specific tests that identify new treatment options for patients.

“This is taking that big step from the ivory tower into the real world,” Rueter says. “We’re making these tests globally accessible to the cancer community so oncologists can decide when to use these tests, on which patients, at what time point.” He notes that the JAX tests will be available for patients with triple-negative breast cancer, “the most difficult-to-treat breast cancer.”

The MCGI has developed a study protocol that will measure how effectively these tests will guide decision-making. “How are oncologists using this information in making decisions, and what are the patients’ outcomes?” Rueter asks. “Do they do better than  patients that didn’t have the testing?”

Direct input from Maine oncologists is “an opportunity to listen to the community and hear what their needs are, and to work with the community to improve existing tests and processes.” And better tests, Rueter says, will mean better treatment, and better outcomes for patients.

Where are we now?

At the  Discovering precise genomic solutions for diseaseThe Jackson Laboratory for Genomic medicine is a new research center that discovers precise genomic solutions for disease.JAX Genomic Medicine campus in Farmington, Conn., Menghi reflects on how research in breast cancers, including triple-negative breast cancer, will ultimately translate into more targeted and effective treatments.  

“Every time I talk with my family or friends that don't have a scientific background,” she says, “there's one question they always ask me: Are we going to cure cancer? And it's just so frustrating because in the short term, the individual discoveries are always really small and incremental.”

To answer the question, she says she explains that the rise of sequencing technology over the past decade has enabled an entirely new approach to cancer research and treatment. “Genome sequencing will open up so much in terms of our ability to understand what drives tumor initiation, as a consequence, our ability to target it, to prevent it, to diagnose it early, to monitor it better, to diagnose relapses better, to stratify patients and to find novel treatments.

“I think that this is a time of progress, and I’m really confident about it,” Menghi says.

Liu adds, “The most gratifying aspect of this is not only that science has advanced so dramatically, but that all elements of the scientific community are coordinating their efforts into providing cures. I have been working in the field of breast cancer for 30 years, and I have seen how basic, clinical, and epidemiological sciences, when all work together, have a direct impact on patient lives.”

The rate of advancement is speeding up, Liu says. “So, perhaps 2045 as the year when breast cancer mortality ceases is not such a pipe dream.”