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Researchers at Novato’s Buck Institute wanted to better understand what factors cause some women to have lower breast tissue density, a predictor for those with the lowest risk of breast cancer.

The study is just one example of the research underway in the North Bay to advance the fight against breast cancer. The work is being conducted in labs at the Buck Institute’s 250,000-square-foot complex and in local hospital settings where researchers test new drugs and other innovations in clinical trials.

“There’s a lot that still needs to be done,” said Dr. Christopher Benz, a founding faculty member of the Buck Institute who has been involved in both research and in treating breast cancer patients for nearly four decades.

The research often comes with a hefty price tag. One of the most ambitious trials underway in the North Bay involves Sutter Health, which in July joined a $1 billion effort to develop blood tests that can better detect cancer. Sutter is taking part in the STRIVE Study, which seeks to enroll 120,000 U.S. women in an effort to find breast cancer in its earliest stages, employing a blood test similar to that used to find genetic abnormalities in human fetuses.

“Can the test catch it before the mammogram does?” said Dr. Steven Cummings, an internal medicine specialist and the principal investigator in the STRIVE trial at Sutter. If successful, he said, “the test could affect breast cancer screening for all women.”

Overall, cancer researchers received roughly $6 billion last year in federal funds, according to the National Institutes of Health. That includes more than $700 million for breast cancer studies.

In addition, drug companies and other businesses are financing a variety of research trials, including more than 1,000 underway to test immunotherapy products, the New York Times reported this summer. The aim of the trials is to win approval by the Food and Drug Administration and make a drug or treatment available in standard care.

The research today often involves understanding complex mechanisms and interactions at the molecular level, as scientists seek to develop targeted therapies that would be less toxic than traditional chemotherapy.

In this effort, said Benz, breast cancer research “has kind of led the way.”

One of the first key discoveries was that the hormone estrogen promotes growth in certain breast tumors. The drug tamoxifen, first developed in the 1960s as a possible contraceptive, has long been shown to inhibit cancer growth by competing with estrogen to attach to certain “receptors,” protein molecules that receive chemical signals in breast cancer cells.

Benz, who joined the institute in 2000 after nearly two decades as a researcher at UC San Francisco, said another “poster child” for targeted cancer therapy involved the discovery of HER2, or human epidermal growth factor receptor 2, a gene that promotes growth in certain tumors. As a result of that finding, Bay Area biotech company Genentech developed Herceptin, which works by attaching itself to the HER2 receptors on the surface of breast cancer cells and blocking them from receiving growth signals.

The first women patients received Herceptin in the early 1990s. While at UCSF, Benz’s work included helping oversee the university’s clinical trials for the drug.

As a result of these discoveries, he said, every breast cancer patient today is tested to determine if their tumors are affected by estrogen or HER2. “That directs how they’re treated,” Benz said, even if their particular cancers don’t fall into either category.

However, neither tamoxifen nor Herceptin stops cancer in every treatment, so scientists are seeking to learn how to better target such cancers. Benz and his research team are working on separate studies exploring new inhibitors for both the estrogen and HER2 positive-type cancers.

“We’re trying to whittle away at these resistant pathways,” he said.

Benz and a half-dozen team members are part of the 188 employees at the Buck Institute, which sits on a hill high above Highway 101 with expansive views of the Petaluma River and San Pablo Bay. The institute has a $38 million annual budget, with nearly half its funding from government grants and about $6 million from the Buck Trust.

The institute is devoted to studying the connection between aging and chronic disease. As women age, Benz said, they have a greater risk of developing the most common form of breast cancer, called hormone positive because it responds to the hormones estrogen or progesterone.

Benz and colleagues made news in 2014 for their participation in the Cancer Genome Atlas, a government-funded effort to classify cancer tumors by their molecular makeup rather than the organ or tissue where they were found. The Buck Institute was one of 20 research institutions around the country that took part in the atlas, which included new findings on the genetic makeup of different forms of breast cancer.

In their recent study on breast tissue density, the Buck researchers found that women who have a certain genetic makeup and who underwent a complication in pregnancy called preeclampsia had lower breast density and a much lower risk of developing hormone-positive breast cancer. Specifically, such women have a 74 percent decrease in risk of hormone positive breast cancer. The risk decreases to 90 percent for those who suffered preeclampsia before age 30.

The researchers next want to identify the mechanisms that helped these women develop “protective breast tissue” and to see if that knowledge could lead to new prevention applications for all women

To study breast tissue density, the scientists eventually used data from a long-term study involving more than 133,000 female California school teachers and administrators. But first they turned to a yearslong study conducted in their own backyard, one they helped start over a decade ago when Marin County women were alarmed to learn their community had abnormally high breast cancer rates.

The Marin Women’s Study “came out of a growing concern that rates for breast cancer in Marin County were among the highest in the state in the late 1990s and were increasing,” said Dr. Matt Willis, the county’s public health officer.

Starting in 2006, more than 13,000 Marin women took part in the study. Besides making available mammograms and offering a total of 8,000 saliva samples — still stored at the Buck Institute — the women filled out a 14-page survey with questions on diet, environment and socioeconomic factors that might help answer the mystery.

What investigators found was the cancer rates dropped “pretty dramatically” about a decade ago after medical experts warned women that certain types of hormone replacement therapy were connected to increased rates in the type of breast cancer that responds to estrogen, Willis said. Through the study, he said, researchers were able to better describe the association between the therapy and the cancer rates.

Benz, who helped to advance the local study and to host a 2002 symposium that addressed the rising cancer rates, explained that Marin County women were “early adopters” of hormone replacement therapy. Similarly, their higher level of education and access to health care prompted them to more quickly reject the therapy in large numbers once the dangers came to light.

In addition to the Buck Institute’s laboratory research, North Bay health care systems are conducting clinical trials to advance the fight against breast cancer.

Among them is Sutter Health, which began its first cancer trial in Sonoma County in 2012. Last month Sutter announced its participation in the STRIVE study, which is funded by Grail, a Menlo Park startup whose investors include Amazon, Bill Gates, Merck, Bristol-Myers Squibb and Johnson & Johnson. The 2-year-old company announced in January that it was seeking $1 billion in a second round of financing to advance the development of cancer screening blood tests.

“Grail’s mission is to detect cancer early when it can be cured,” said Dr. Anne-Renee Hartman, the company’s vice president of clinical development.

The trials will help researchers develop the test, Hartman said. A key factor came years ago in clinical trials for prenatal blood tests when researchers found genetic abnormalities in a tiny number of the pregnant women tested. The women were later found to have advanced stages of various cancers.

What’s needed now is to develop a test so sensitive that it can detect early stages of cancer in patients coming in for mammograms, Hartman said. In such circumstances, an estimated 1 percent of women are expected to already have developed breast cancer or another form of the disease.

At Kaiser Permanente, North Bay patients are taking part in about a dozen clinical trials, said Dr. Christine Kaiser, an oncologist.

Some involve chemotherapy or other drugs. But one sponsored by the National Cancer Institute seeks to learn whether encouraging healthier diets and exercise in overweight breast cancer patients can lead to better success in battling the disease.

Kaiser suggested it isn’t surprising that oncologists are big proponents of the clinical trials. “We obviously want to find better cancer treatments,” she said.

At St. Joseph’s Health, researchers took part in their first clinical trials for breast cancer four years ago. They have enrolled more than 110 patients in 23 such trials, including six still underway.

Among the ongoing trials is a study for BriaCell, a Berkeley company testing a vaccine with the potential to activate the body’s immune system in patients with advanced breast cancer. Leading the BriaVax trials is Dr. Jarrod P. Holmes, an oncologist and expert in breast cancer vaccines with Annadel Medical Group and St. Joseph Health-Sonoma County.

Kim Young, St. Joseph’s director of clinical research, said one challenge scientists seek to overcome is how to help immune systems better recognize and attack cancer cells. She likened it to a security checkpoint where “the cancer cells are really good at making disguises” and passing by unmolested.

Local patients who take part in the trials help advance research that could prolong or save lives, the health experts said. The patients also have a chance to try potentially helpful medicines or treatments that aren’t yet offered in standard care.

“They’ll have access to something that’s not available,” said Young.

You can reach Staff Writer Robert Digitale at robert.digitale@pressdemocrat.com.