Every year, I look to this meeting for the inspiration that will sustain me in my work with women who are living with metastatic breast cancer and their families. Like them, I am looking for hope. “You are our eyes and ears,” one woman wrote me in an e-mail I received during the conference. “What do you think were the biggest revelations at this year’s conference? Any disappointments? Any surprises?”

Responding to her questions fully is something that will take time, as I am still digesting the sheer volume of data, and the complexity of the science. But right now I can say that, this year, beyond a palpable sense of the progress being made in understanding the various forms of breast cancer and determining “druggable” targets for new therapies, there appears to be some real signs of hope in the emergence of truly effective, less toxic treatments.

Caution is in order, as promising new approaches often prove disappointing once they are tested in clinical trials. Just a few years ago, we thought starving a tumor’s blood supply with an angiogenesis inhibitor like bevacizumab (Avastin) was going to revolutionize cancer treatment—not just for breast cancer, but for all solid tumors. Yet, to date, in multiple large trials of Avastin—two of which were reported at this year’s San Antonio meeting—there has been no improvement in overall survival, the length of time that patients live. Equally disappointing were the results of clinical trials that looked at the tyrosine kinase inhibitors—sorafenib (Nexavar) and sunitinib (Sutent)—for treating metastatic breast cancer. (These drugs are currently used to treat other types of cancer.)

In contrast, a multiple blockade of the HER2 pathway that was achieved by combining trastuzumab (Herceptin) and lapatinib (Tykerb) did result in increased survival. In addition, researchers are hoping that combining Herceptin with another drug still in development, called pertuzumab (Omnitarg), will also increase survival.

We also learned that patients with HER2-positive metastatic breast cancer who had exhausted most of their treatment options experienced a dramatic benefit when started on a drug called T-DM1. This drug is a conjugate of Herceptin and a derivative of an effective but very toxic chemotherapy drug known as maytansine. It works by making Herceptin bind to the chemotherapy molecules in such a way that they can only be released into the cancer cell. This means the drug spares the rest of the body and has few side effects. In the study that was presented, investigators had enrolled a group of very treatment-resistant women, and they found that 45 percent of them had their tumors shrink or stop growing for a period of six months or more—a virtually unmatched achievement.

Progress also is being made in the research that is looking at how to reverse resistance to hormonal therapies. When that comes to fruition, it will be critical for women with hormone-sensitive cancer. And although not presented at this meeting, it’s been reported that drugs that inhibit PARP show great promise for women who have triple-negative breast cancer or whose tumors have a BRCA mutations. We eagerly await the results of these trials.

This kind of success in drug development and translational science gives me hope that there is more, and better, to come.

There was something else that set this San Antonio meeting apart for me: I presented a poster (this link opens to a PDF) representing the steering committee for the BRIDGE Metastatic Breast Cancer Patient Survey. Sponsored by Pfizer and fielded by Harris International, this global survey asked 1,342 women with metastatic breast cancer from 13 countries what it was like to live with this disease. Topics included available resources, support networks, attention given to metastatic breast cancer relative to early breast cancer, and the personal impact of the disease. Patients also were asked if they had ever participated in, or searched for information about, clinical trials.

I’ve been working as an advocate for many years to help women with metastatic breast cancer and their families get the support, services and recognition they deserve. So it was deeply gratifying to see this project come to fruition, and to participate equally as an advocate and presenter among scientists and clinicians in a meeting I’ve attended now for 14 years.

Musa Mayer
www.AdvancedBC.org

The newer aromatase inhibitors (AI), which include letrrozole (Femara), anastrozole (Arimidex) and exemestane (Aromasin), appear to be even more effective in reducing recurrence and death. The AIs, as they are called, work in a different way than tamoxifen does. These drugs inhibit an enzyme called aromatase, which converts androgens (male hormones) to estrogen. Unlike tamoxifen, which can be used by both pre- and postmenopausal women, the AIs can only be used by postmenopausal women.

Chemotherapy is given over an intense few months after the diagnosis of early-stage breast cancer. In contrast, anti-estrogen therapies must be taken daily for five years to be maximally effective. Newer research suggests there might even be an additional benefit if these drugs are used for up to10 years, or even longer.

Like all other drugs, anti-estrogen treatments have side effects. At least one-third of women on an AI experience chronic joint and soft-tissue pain. Other common side effects include bone loss and vaginal dryness. (These are a result of the estrogen depletion.) Tamoxifen’s side effects include vaginal discharge and hot flashes along with  a slightly increased risk of endometrial cancer, blood clots and cataracts. As a result, it’s not uncommon for women to find that they may need to take other drugs to alleviate some of these side effects.

Tamoxifen is also used as breast cancer risk reduction in high-risk women. However, many high-risk women opt not to take it. Studies suggest this is because high-risk healthy women are reluctant to take a daily drug with side effects for a disease they may never get. For them, the risk-to-benefit balance just doesn’t seem to make sense.

Less understandable are findings from a study presented Dec. 11, at the San Antonio Breast Cancer Symposium by Stephen Chia, a medical oncologist at the British Columbia Cancer Research Center in Vancouver, Canada, which showed that an alarming percentage of women who have been diagnosed with invasive breast cancer are not taking the tamoxifen or aromatase inhibitor they were prescribed.

Chia and his colleagues found that nearly 40 percent of a group of 2,403 postmenopausal women prescribed adjuvant hormonal therapies were not taking them. (Actually, this was not the first study to highlight this problem. Prior studies looking at tamoxifen noncompliance found rates of 20 to 49 percent.) In the United States, one factor that must be taken into account is a woman’s inability to afford the medication, as it may not be fully covered by her insurance or she may lack insurance coverage. But this isn’t the case in Canada, where these medications are covered under a national health care plan.

Because this study used data obtained from a retrospective review of pharmaceutical records, the researchers could not ask these women why they didn’t take their daily pill. This means, we can only speculate as to the reasons they did not comply. Was the favorable benefit-to-risk ratio not well explained or understood? Were the side effects too difficult, or not properly attended to by these women’s doctors? Did better quality of life in the present come to matter more than preventing a future recurrence that might never happen? Did the scary specter of breast cancer simply begin to fade over time?  Or, were these women just plain tired of treatment and medical care?

So, we’re left with a troubling reality: Even when we do know how to help women diagnosed with breast cancer survive their disease, many of them simply choose not to avail themselves of treatment.

Something else is wrong here. The first session of this year’s meeting, like last year, focused on the results of large, costly randomized trials comparing various sequences and permutations of these anti-estrogen therapies, teasing out the vanishingly small incremental gains. Imagine if a fraction of the millions spent on these trials was invested in discovering why it is that women with breast cancer discontinue taking these drugs. Let’s ask the women themselves.

Musa Mayer
www.AdvancedBC.org

Denosumab
Three quarters of women with metastatic breast cancer develop bone metastases, which can cause pain, fractures and other miseries. In recent years, high-potency intravenous bisphosphonates, like zoledronic acid (Zometa) and pamidronate (Aredia), have made a big  difference in the quality of life of women with bone metastases by slowing the growth of their tumors, preventing fractures and reducing pain. (These drugs are close cousins to the bisphosphonates used to treat osteoporosis.)

Today we heard a presentation about denosumab, a new monoclonal antibody that targets RANKL inhibition, a mediator of osteoclast formation. Osteoclasts are cells that are involved in destroying bone so it can be replaced by new bone. A study comparing denosumab with standard Zometa treatment in women with metastatic disease found a meaningful reduction in bone fractures, pain and time before these women needed radiation to control pain. Because denosumab is a more targeted drug, there were fewer side effects in the patients who received it than in who received Zometa. Unfortunately, denosumab was not able reduce the incidence of osteonecrosis of the jaw. This particularly troublesome side effect occurred in about 2 percent of the patients who were on either drug.

Moving drugs into the breast cancer arena
Some presentations discussed drugs used  in other diseases that are now being studied as breast cancer treatments. One such drug is metformin, which is used to treat diabetes. Cancer researchers became interested in metformin after doctors reported observing a lowered incidence of breast cancer in diabetics receiving metformin compared with those not receiving this drug. Their observation led to laboratory investigations aimed at identifying possible mechanisms of action, and, now, clinical trials will soon begin investigating their effectiveness.

When hearing about promising population studies, or laboratory findings, I’ve learned through long experience not to get too excited. After all, other drugs in common use have been similarly investigated, and many, like the COX-2 inhibitors and the statins, have not withstood the careful scrutiny of clinical trials. As a result, I watch closely to see if any real benefit is seen in a phase II or III clinical trial. If and when that happens, I allow myself to get excited, as I did last summer, when researchers reported findings from a new class of drugs called PARP inhibitors that may prove to be the first targeted therapy for women with breast cancer who have a BRCA mutation or who have triple-negative disease.

New approach to HER2
We don’t always have to wait the dozen or more years that it takes for a new drug to be developed and tested to find a successful new treatment. Sometimes, combinations of already approved therapies can provide impressive results beyond those achievable with either drug alone.

It is common for women with HER2-positive metastatic disease to receive multiple lines of treatments that include the monoclonal antibody trastuzumab (Herceptin). Lapatinib (Tykerb) is a tyrosine kinase inhibitor that is approved by the U.S. Food and Drug Administration for use in combination with the oral chemotherapy drug Xeloda after Herceptin plus a chemotherapy drug has failed. Some years ago, researchers wondered if creating a “total blockade” of the HER2 pathway by using both Herceptin and Tykerb might be more effective than using lapatinib alone.

Kimberly Blackwell, a medical oncologist at Duke University Medical Center, in Durham, N.C.,  presented results from a trial that enrolled 296 women with HER2-positive metastatic breast cancer that tested this idea. All of the women had received on average three prior Herceptin plus chemotherapy regimens. In this trial, these “heavily pretreated” patients were randomized to receive either the combination of Herceptin and Tykerb or Tykerb alone. Blackwell reported that the addition of Herceptin to Tykerb  improved overall survival from nine months to 14.5 months—an impressive finding. (Remember, the increase of five and a half months only describes the average.)

If treatment failure ordinarily would be evidence of resistance, and a signal that it’s time to move on to another treatment, why would Herceptin continue to be beneficial? Many oncologists believed that Herceptin continued to exert continuing control over this aggressive form of breast cancer, even when treatment appeared to fail. However, until now, there was never definitive proof to support the practice of continuing Herceptin past treatment failure. This study not only confirms the continued use of Herceptin after treatment failure, but it offers patients a treatment regimen without chemotherapy—something many women undergoing continuous treatment will certainly appreciate.

Musa Mayer
AdvancedBC.org

Valerie Beral, an epidemiologist at the University of Oxford in England, opened this year’s conference with a plenary session on the causes and prevention of breast cancer. This was hardly new information, yet I found it compelling.

“Why,” Beral asked, “does breast cancer vary across the world so dramatically?” She noted that the cumulative incidence of breast cancer until age 70, by percentage of the population, is only about 1 percent in rural Africa and Asia. In contrast, in developed countries, the cumulative incidence is six- to sevenfold higher, with breast cancer affecting 6 percent of women by age 70. Furthermore, while the rates of new breast cancers have apparently stabilized in developed countries like the U.S., the rates are now rising steeply—just as they did here 30 to 40 years ago—in the crowded cities of the developing world.

If this trend continues—and there is no reason to believe it won’t before it, too, levels off—the one million cases of breast cancer diagnosed worldwide each year will double by 2040, she added. What could be responsible for these hugely escalating numbers?

The protective nature of early childbearing and breastfeeding is of course well known, as are the changing childbearing patterns that occur when women move to cities and leave rural life. In the 18th century, said Beral, Italian physician Bernardino Ramazzini referred to breast cancer as “an occupational disease of nuns,” observing that nuns in Verona suffered a sevenfold higher mortality from the disease.  “For over two centuries,” said Beral, “it was believed that a major cause of breast cancer was women not using their breasts for ‘natural purposes.’ ” Indeed, more recent research has shown that each pregnancy confers a 10 percent reduction in risk. “We are all nuns,” concluded Beral.

But the story turns out to be far more complicated than exposure to the protective hormones of early pregnancy and breastfeeding. Starting in the 1970s, according to Beral, with the rise of birth control and, later, with the tremendous rise in the use of postmenopausal hormones, a large part of the female population was being exposed to “exogenous” hormones—those not naturally occurring in the body. The revelation in 1991, from the Women’s Health Initiative study, that hormone replacement therapy (HRT) promoted breast cancer (as well as heart disease, stroke and some dementia), led to a massive drop in hormone use. This, in turn, Beral said, led to a major decrease in breast cancer incidence that was seen almost immediately in the United States, as well as in a dozen countries around the world that had similarly high rates of post-menopausal hormone use.

What does this tell us? ”Breast cancer incidence in developed countries would be more than halved if women had similar childbearing patterns to women in developing countries,” said Beral. The rest of the risk disparity between developed and developing countries can be accounted for by so-called “nutrition” factors, she said, noting that obesity, early menarche and alcohol consumption have all been associated with higher rates of breast cancer, and with breast cancer recurrence. (Later in the day we heard two studies that confirmed this association.) In fact, Beral said, statistical modeling shows that there would be 40,000 fewer breast cancer diagnoses each year in the U.S. if women were not obese and did not drink alcohol or use HRT.

Since it’s not likely that most women will be returning to villages to bear many children at a young age, Beral suggested that we need to develop a way, perhaps with a vaccine, to reduce breast cancer incidence by mimicking the protective effects of youthful, full-term pregnancy.

The advocates I spoke with were far from convinced. Having been down that risky road of hormonal protection already, we can be forgiven for our skepticism. What about other factors not discussed by Beral, like environmental risks or the endocrine disruptors we’re told act like estrogen?  There was, as there always is at this meeting, a lot to ponder.

Musa Mayer

www.AdvancedBC.org