University Times

Breast cancer researcher Nancy E. Davidson detailed recent progress and ongoing research in her Oct. 1 talk, “Breast Cancer in the Molecular Era.”

Davidson, the new director of the University of Pittsburgh Cancer Institute (UPCI) and UPMC Cancer Centers, was the featured speaker at the annual reception welcoming new women faculty, hosted by the Provost’s Advisory Committee on Women’s Concerns and Pitt’s women’s studies program.

The former director of the Johns Hopkins Kimmel Cancer Center’s breast cancer program in Baltimore and professor of oncology at Johns Hopkins School of Medicine, Davidson began her new position March 1,  following the retirement of UPCI founding director Ronald B. Herberman.

Cancer researchers have some numbers to be proud of, Nancy Davidson said, citing more than 10 million cancer survivors in the United States and nearly 25 million worldwide. “These are real results.”

In the case of breast cancer, the two-fold impact of earlier diagnosis, thanks to screening mammograms, and the development of appropriate drug therapy has helped. “It’s only the combination of the two interventions that has led to the decrease in mortality we’re enjoying today,” she said, noting that statistical modeling suggests that without both interventions, breast cancer numbers would continue to rise.

Researchers from the Early Breast Cancer Trials Collaborative Group documented these advances through the results of 200 clinical trials involving more than 150,000 women over more than 20 years. These results have aided the development of today’s standards of care for breast cancer patients.

Surgical interventions have been minimized, moving from mastectomy to lumpectomy and greater selectivity in sampling lymph nodes for testing. And the mindset behind using the maximum therapy a patient could tolerate has given way to new thinking: using the minimum effective dose.

Clinicians are moving toward a more personalized form of medicine. “We want to be in a position where we can give the right treatment to the right person at the right time,” Davidson said. The goal is to maximize efficacy while minimizing side effects and cost —- not just financial costs but the total costs to the patient and family, she said.

Davidson said developments in translational science (the “bench to bedside” research aimed at practical clinical use) have helped in several aspects of treating breast cancer — in estimating cancer risk, gauging the prognosis for those diagnosed with cancer and in finding the treatment that may produce the best response for a particular type of cancer.

Well-known risk factors for breast cancer — being female, advancing age, exposure to estrogen, family history and outside factors such as hormone replacement therapy, alcohol consumption and other exposures — are relatively nonspecific, Davidson admitted. “If you put them together and try to counsel an individual woman about her risks, they’re not always very helpful, and in many cases there’s not much you can do about such things.”

However, one area in which biology has had an impact is in women with hereditary forms of breast cancer and ovarian cancer, she said.

While most breast cancer occurs in women with no family history, 5-10 percent — representing some 200,000 diagnoses per year in the United States — are hereditary forms, and researchers believe that mutations in the BRCA 1 and BRCA 2 tumor suppressor genes contribute to about 50 percent of those hereditary breast cancers, Davidson said.

Women who carry such mutations have a 50-85 percent chance of developing breast cancer during their lifetime, as compared to a risk of about 12 percent for those without the mutation. In addition, the chance of getting two breast cancers or ovarian cancer also is increased significantly in such women. Mutations in BRCA 2 raise the risk for breast and ovarian cancer and also predispose men to breast cancer, she said, adding that researchers also are looking at possible connections to pancreatic and other cancers.

Studies have demonstrated that women who carry BRCA mutations can reduce their risk of developing breast cancer by prophylactic surgery and can reduce their risk of developing ovarian cancer by preventive removal of the ovaries. If they choose not to have preventive surgery, additional screening tools such as magnetic resonance imaging in conjunction with mammography is an option, Davidson said.

“Over a 15-year period of time, we’ve gone from identifying these two genetic loci to being able to test for them in the clinic,” she said, arguing for routine testing for higher-risk individuals. “That’s because we believe we can give people useful information and we can empower them to make decisions about changes they might make to take advantage of this knowledge.

“This is the tip of the iceberg,” she said. “We know this is going to pervade a lot of how we think about our health in the future.”

Advances also are evident in predicting responses to certain types of therapies. Such information can help patients understand their prognosis, “and more importantly how we can counsel them on what they can do about it.”

Previously, doctors would look at such factors as tumor size and whether lymph nodes were involved, whether certain estrogen or progesterone receptor proteins and HER2 proteins were present to help patients gauge their prognosis and select therapies. Now a cancer can be categorized further according to its “molecular portrait” of the genes it expresses.

“You can use computational methods to try to sort these cancers into various kinds of categories that are different from what we might have thought before,” she said. “It appears increasingly these kinds of characterizations, these portraits, are related to how somebody will do with their breast cancer.”

One example comes from the study of women with the particular type of breast cancer that does not involve the lymph nodes and expresses estrogen receptor. Research showed that treatment with tamoxifen and chemotherapy increased survival rates in these women.

The problem, Davidson said, “With tamoxifen alone, only 15 percent of those women were going to have relapsed in the first place, so we’ve given an awful lot of chemotherapy to a lot of women without a clear idea of what we’ve accomplished for the group of women as a whole.”

To fine tune their recommendations, researchers set out to differentiate among women who seemingly had the same type of breast cancer. They developed a test that yields a “recurrence score” related to the expression of 16 different genes that have an impact on the possible recurrence of cancer.

In women with a low recurrence score, they found that 96 percent did well and had no recurrence  10  years  after  treatment with tamoxifen alone, while 95 percent had no recurrence after treatment with tamoxifen and chemotherapy. Those with intermediate risk scores showed similar results: 90 percent did well with tamoxifen alone compared with 89 percent treated with tamoxifen and chemotherapy. However, for patients with high scores, there was a marked difference: 60 percent of those treated with tamoxifen had no recurrence 10 years later, compared to 88 percent of those who had both tamoxifen and chemotherapy.

“What we learned is that the use of chemotherapy added little for the women [in low score groups], but had a major impact on the women [with the high scores],” she said. “That’s allowed us to think how to fine tune and really tailor our recommendations about chemotherapy,” Davidson said, noting there is a large clinical trial underway to further refine what’s behind these results. In that study, those with low scores will be assigned tamoxifen, those with high scores will get tamoxifen plus chemotherapy. Those with scores in between will be randomized between the two options. “This is going to lead to the next incremental benefit in understanding the way we treat breast cancer,” Davidson said.

She noted that researchers aren’t focusing solely on the genetics of tumors, but also on the people within whom a cancer arises.

“Here the whole area of pharmacogenetics is exploding,” she said, pointing out that small variations in a person’s DNA sequence known as single nucleotide polymorphisms (or SNPs) can impact health outcomes in certain individuals or affect the effectiveness of some drugs.

For instance, with regard to breast cancer treatment, it’s known that tamoxifen’s effectiveness can be impacted by the enzyme known as CYP2D6. People who have variations in that enzyme or who take certain drugs that inhibit it — some antidepressants, for instance — may see less of a benefit from tamoxifen. Davidson said it’s not certain whether testing for such SNPs should be done routinely, but researchers are paying attention.

The field is using gains in knowledge to move from treating breast cancer to preventing it.

“We have been extraordinarily lucky that we have understood a lot about what makes a breast cancer tick” and have learned how to take advantage of estrogen receptor signaling pathways within the cancer cell to attack the cancer — decreasing the hormone or destroying the receptor, for example, she said.

Among the therapies that have been developed as a result of understanding these biological pathways are aromatase inhibitors, Davidson said. These oral anti-cancer drugs that inhibit the conversion of androgens from the adrenal glands to estrogen can be an effective treatment for post-menopausal women.

Clinical trials are underway to study how to integrate aromatase inhibitors into current therapies: Should they be used with or instead of tamoxifen, together or in a sequence, and for how long?

The paradigm for estrogen receptor targeting has been applied to other signaling pathways, such as the EGFR epidermal growth factor receptor (also known as the HER or Erb family).

Researchers are particularly interested in the HER2 gene, Davidson said. “In 20 years we’ve gone from understanding that about 20-30 percent of breast cancers over-express this protein, and they usually do it because of extra copies of the gene in the nucleus. We have been able to target the protein with an antibody called trastuzumab, and [found] that treatment with just this antibody all by itself leads to regression of this HER2-positive breast cancer in about 30 percent of women.”

The antibody therapy can be combined with chemotherapy to increase survival in cases of advanced breast cancer, and halve the recurrence rate in early cases of this form of breast cancer.

“Over a 20-year period of time going from a molecule, a gene, down to a therapy we use routinely in early-stage breast cancer is a pretty major accomplishment,” she said.

Other small molecule inhibitors that might do the same thing are under development for breast and other cancers.

Researchers also are looking at old drugs in new ways, Davidson said. “We’re very excited in our field about the possibility of using bone-targeted drugs to treat breast cancer.”

Bones are a common site for breast cancer to return and bone-strengthening agents such as Fosamax can be used to decrease problems related to bone metastasis, she said. “And, we have laboratory work to suggest that maybe these bone strengthening agents actually have some anti-breast cancer effects.”

However, several small studies have shown divergent results. Larger clinical trials are underway to find whether these agents have anti-breast cancer effects in addition to their pro-bone strength effects, Davidson said.

Another area of ongoing study is in DNA repair pathways, Davidson said. “Every day our cells are bombarded by noxious things and our genes, our DNA, gets damaged. One of the key things is we have to do is repair that damage.” In a person with BRCA mutations, the BRCA repair pathway is damaged and the tumor cells must rely on other repair pathways, such as one known as PARP.

That’s made PARP inhibitors a target of research. “That’s led to the possibility that one might actually use inhibitors of this pathway to block all DNA repair in this cancer cell, and as a consequence of this, this cancer cell would have no choice but to go on to cell death,” she said.

PARP inhibitors have been found effective in decreasing growth in those cells that have BRCA deficiency and they are not so effective in those cells that have normal repair, Davidson said, adding that many PARP inhibitor drugs are under development. “In the last couple of months we’ve been very excited because it looks like these are coming to fruition,” she said.

In one early phase trial, a new drug called olaparib was given to 60 patients with advanced cancers of all kinds and found to cause only mild side effects. The drug’s anti-tumor activity was found to be limited to people whose tumors carried BRCA mutations.

“This is a human proof of a principle of work that was done in the laboratory,” she said. “It hit the target — it did what you would expect from all the laboratory studies that had been done.”

Recent evidence also is showing that PARP inhibitors may be helpful against the hard-to-treat cancers known as “triple negative” (those that don’t make estrogen receptor, don’t make progesterone receptor and don’t make the HER2 gene).

In a recent clinical trial that assigned women with triple-negative breast cancers either to a combination chemotherapy or combination chemotherapy with a PARP inhibitor, Davidson said, “The use of this biologic in addition to chemotherapy led to a doubling of survival in those patients. This is an indication that these drugs will find a wider use and that some of our science can in fact drive their development.”

Such science is being developed close to home, Davidson said, noting that two UPCI scientists, Shannon Puhalla and Merrill Egorin,  have been awarded federal stimulus funding to look at the use of a PARP inhibitor against breast  or ovarian cancers and those with BRCA mutant cancers.

While there is much progress for researchers to brag about, still there is much to do, Davidson said.

There are challenges the academic community must face as it moves ahead to apply the concepts of personalized medicine, she said.

“We are going to have to be very smart about our clinical trials. We can’t do 10,000 women in clinical trials anymore because it’s not going to be a wise way to proceed. So we need to think about how can do this in a very efficient way to spare resources in all senses of the word — particularly patient resources, the patients who volunteer to go into these trials.”

Patients’ multiple tissue and blood samples are going to be needed for long-term study, she said. “These things are not going to be cheap. Having adequate resources is going to be extremely important. These things are increasingly burdened by bureaucracy,” she said, emphasizing the importance of trying to minimize that bureaucracy.

“Another thing that really concerns me is scientific literacy. As a country, we don’t have the kind of literacy in the science field and the math field that we would like to have and it’s important for us to make sure this is part of our society.”

Davidson also urged her colleagues to fight against extreme mindsets at both ends of the spectrum: “Those people who say, ‘Breast cancer — we’ve got it licked, don’t worry about it,’ — or the reverse, the people who say, ‘Cancer — no progress whatsoever,’ and just throw their hands up in horror.

“I think it’s incredibly important to avoid both of these extremes as we go forward.”

—Kimberly K. Barlow