SABCS Interview Series

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OBTN, March 2010, Volume 4, Issue 3

The January issue of OBTN featured highlights from the 32nd Annual San Antonio Breast Cancer Symposium (SABCS). We wrap up our SABCS coverage this month with interviews on denosumab with Alison Stopeck, MD, associate professor of medicine at the University of Arizona and director of the Clinical Breast Cancer Program at the Arizona Cancer Center; oral bisphosphonates with Rowan T.Chlebowski, MD, PhD, professor and chief of the Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center; and adjuvant chemotherapy�induced alopecia with Hugues Bourgeois, MD, Centre Jean Bernard in Lemans, France.

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The San Antonio Breast Cancer Symposium (SABCS) is held in Texas each year and brings together experts from all over the globe who present the latest research on breast disease. It is held jointly by the Cancer Therapy & Research Center at University of Texas Health Science Center in San Antonio and the American Association for Cancer Research. The 32nd annual SABCS meeting was held December 9-13, 2009, and was the largest to date. Next year’s SABCS will be held December 8-12, 2010.

Alison Stopeck, MD

Breast cancer commonly metastasizes to the bone, where it can cause a number of complications, such as fractures, spinal cord compression, hypercalcemia, and pain. The prognosis for women with breast cancer whose disease has spread to the bone has greatly improved as a result of advances in medical and surgical treatments. The most common treatment used for bone metastases today is a bisphosphonate, a drug originally developed as a therapy for osteoporosis.

Denosumab (Prolia), a monoclonal antibody, is being studied in breast and other cancers for its ability to reduce bone damage and has already been approved to treat postmenopausal women with osteoporosis and some men with prostate cancer. We discussed denosumab and the Denosumab 136 study with Alison Stopeck, MD, associate professor of medicine at the University of Arizona and director of the Clinical Breast Cancer Program at the Arizona Cancer Center.

OBTN: Can you describe the trial protocol for the Denosumab 136 study?

STOPECK: The 136 study was an international, phase III, randomized, double-blind study comparing denosumab with Zometa [zoledronic acid] in the treatment of bone metastases in patients with advanced breast cancer. This is the first phase III head-to-head trial versus Zometa in advanced breast cancer. Patients enrolled in the study were randomized in a 1:1 ratio to receive either 120 mg of denosumab subcutaneously every 4 weeks or Zometa administered intravenously at a dose of 4 mg in a 15-minute infusion every 4 weeks as per the label instructions.

What were the primary and secondary endpoints of the trial?

The primary endpoint was to evaluate if denosumab is noninferior to Zometa with respect to the time to first, on-study skeletal-related event (SRE) in patients with advanced breast cancer and bone metastases. Key secondary endpoints were to evaluate if denosumab was superior to Zometa with respect to the first on-study SRE, as well as the first-and-subsequent on-study SREs, and to assess the safety and tolerability of denosumab compared with Zometa.

Did the women in the study have a specific histological subtype of advanced breast cancer?

The participants in the study were women and men with histologically or cytologically confirmed breast adenocarcinoma. Patients with all subtypes of breast cancer were eligible. They had current or prior radiographic evidence of at least one bone metastases and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2.

Is there a relationship between type of breast cancer and risk of bone metastases?

Bone metastases are the most common site of metastatic disease in breast cancer. Tumors that are estrogen receptor—positive seem to have the highest propensity to metastasize to bone, but all subtypes of breast cancer commonly metastasize to bone

How do you measure the success of drugs for bone metastases?

In clinical trials testing new medications for bone metastases, treatment success is measured by whether bone complications, or SREs, caused by the tumor are reduced or delayed. Pain relief is also an important endpoint.

Did denosumab meet its endpoints in this study?

Denosumab met both primary and secondary endpoints and demonstrated superiority over Zometa. All results were statistically significant. Importantly, patients on denosumab also had better pain control and fewer serious adverse events or toxicities.

What is the mechanism of action of denosumab in preventing SREs?

When cancer metastasizes to the bone, it triggers a vicious cycle of bone destruction and tumor growth. Denosumab is the first fully human monoclonal antibody that specifically targets RANK Ligand, the essential regulator of osteoclasts (the cells that break down bone), thereby reducing bone absorption, inhibiting tumor growth, and specifically interrupting this vicious cycle.

What are some of the most common SREs in breast cancer patients and how effective was denosumab at preventing them compared with zoledronic acid?

The most common SREs in patients with breast cancer include fractures or broken bones and radiation to the bone to manage pain or prevent fracture. Denosumab was 18% more effective than Zometa in delaying the time to the first on-study SRE and 23% more effective in delaying the time to the first and subsequent SREs.

Denosumab was also 26% more effective at specifically preventing those SREs related to radiation to bone. This is an objective measure consistent with the patients’ questionnaire results, [and] demonstrat[es] that denosumab controlled bone pain more effectively than Zometa.

Were there any other benefits seen with denosumab compared with zoledronic acid?

Denosumab presented some potential tolerability advantages for many patients, including a lower incidence of renal toxicity and acute phase reactions, combined with the convenience of a monthly subcutaneous injection.

Do SREs affect mortality for advanced breast cancer patients?

Skeletal complications from bone metastases are a significant health concern for patients with advanced breast cancer, as they lead to severe morbidity, pain, and diminished quality of life. Patients with bone metastases from breast cancer can live many productive years with modern anticancer therapies…controlling bone pain and preventing SREs is extremely important for their health and maintenance of lifestyle. There are studies that suggest patients with metastatic breast cancer who develop SREs have an increased mortality as well. Thus, controlling or preventing SREs is important for several reasons.

Why are patients with breast cancer more likely to experience SREs than patients with many other types of cancer?

Bone is the most common site for breast cancer metastases, and patients with metastatic breast cancer often survive much longer than other patients with metastatic cancer from a solid tumor. Their increased life expectancy gives the tumor more time to metastasize to bone, where increased osteoclastic activity provides a microenvironment conducive to tumor cells adhesion, growth, and metastases.

Based on these results, do you anticipate the FDA approving denosumab for women with advanced breast cancer, after declining to approve it last year?

This trial evaluated advanced breast cancer patients with bone metastases, which is an entirely different patient population than the earlier stage patients who are at risk for bone loss due to their hormone ablation therapy. The 136 trial also uses an entirely different dose of denosumab.

I think these results are compelling for several reasons and should lead to FDA approval. First, denosumab was more effective than the current standard of care, Zometa. Second, denosumab was less toxic to patients—especially the large number of patients who may have mild or moderate renal insufficiency or the growing number of metastatic breast cancer patients we are not treating with renal-toxic chemotherapy. Third, the drug offers patients improved convenience as it does not require laboratory monitoring or intravenous access and can be administered literally in seconds as a subcutaneous injection. This will save patients hours waiting in clinics for their lab results or the need for intravenous access devices. Fourth, this is not another “me too” drug. Denosumab has a completely different mechanism of action to bisphosphonates and thus offers a real advance in our treatment and understanding of bone metastases and bone biology.

Would you say this is a pivotal trial for the investigation of denosumab?

Absolutely. This data will be filed with the FDA and hopefully lead to its rapid approval for our patients with bone metastases.

At the 2008 SABCS, researchers reported that zoledronic acid might have anticancer properties. Does denosumab also appear to have antitumor effects?

This is unclear and needs to be tested in clinical trials. Denosumab’s mechanism of action would support antitumor effects similar—and perhaps in some tumors even superior—to Zometa, but again, this needs to be tested clinically in well-designed and executed clinical trials. Zometa’s role as an anticancer therapy is also controversial, and we are awaiting the results of several large clinical trials to verify this hypothesis.

Osteonecrosis of the jaw is frequently mentioned as a possible adverse effect of bisphosphonates, but some researchers think the correlation is not all that strong. Do you think there is a strong correlation between osteonecrosis of the jaw (ONJ) and use of bisphosphonates?

Yes, I believe that all drugs that profoundly effect osteoclast activity can contribute to the development of ONJ. I also think that we are learning more about the risk factors that predispose patients to ONJ, including poor dental hygiene, dental extractions, and dental appliances, which allows us to follow patients with these risk factors more closely for early signs of ONJ and stop osteoclast-inhibiting therapy with either a bisphosphonate or denosumab more quickly.

We are also finding that in some of these patients—possibly because we are more aware of this rare, but significant complication—that with stopping the agents, we are seeing reversibility of ONJ. More research in this area is needed to advise physicians on how best to treat, prevent, and follow patients with ONJ. We also need to know whether it is possible to reinitiate osteoclast-inhibiting therapy in patients once they have developed ONJ.

What were common adverse effects seen with denosumab and how do they compare with those associated with zoledronic acid?

Overall, the incidence of adverse events (96% with denosumab and 97% with Zometa) and serious adverse events (44% with denosumab and 46% with Zometa) was consistent with what has previously been reported for these two agents and mostly due to [the patients’] anticancer therapies or disease progression.

Adverse events associated with acute phase reactions during the first 3 days of the study were reported in 10.4% of the denosumab arm and 27.3% of the Zometa arm. Adverse events potentially associated with renal toxicity occurred in 4.9% of patients treated with denosumab, compared to 8.5% of patients treated with Zometa. ONJ was seen infre- quently in both treatment groups—20 patients [2%] receiving denosumab developed ONJ, compared with 14 patients [1.4%] receiving Zometa.

Rates of new primary malignancies were similar between treatment arms, occurring in 5 patients [0.5%] receiving denosumab and 5 [0.5%] receiving Zometa. Time to disease progression and overall survival were identical between the two study arms.

How should clinicians be monitoring patients with advanced breast cancer for bone health and the effectiveness of bisphosphonates or denosumab, if it is being used?

I think clinicians need to be more aware of their patient’s dental hygiene and perform oral exams and ROS [reactive oxygen species] routinely. Good dental hygiene and regular dental cleanings would be a good recommendation for any patient about to start either bisphosphonate or denosumab therapy.

In patients who develop SREs while on intravenous bisphosphonates, I think it would be reasonable to monitor urine NTx levels and, if elevated, consider changing to more effective antitumor therapy or denosumab if available.

Are you conducting any additional studies with denosumab?

Yes, I am hoping to be involved in the adjuvant denosumab study that will examine whether denosumab can prevent bone metastases or have antitumor effects in early stage breast cancer patients.

What is your take-away message for our readers?

This study, combined with the two other identically designed large phase III trials comparing denosumab to Zometa for the prevention of SREs in patients with bone metastases from prostate cancer or other solid tumors plus myeloma, clearly show a consistent result…denosumab is more effective at preventing SREs and controlling pain with less renal toxicity and acute-phase reactions.

This is an exciting drug that will offer our patients a more convenient, more effective, and less toxic therapy for the treatment of their bone metastases. All my patients on the trial have crossed over to denosumab treatment and have been very pleased with their results on this therapy. They love the convenience of the subcutaneous injection and not having the achiness, bone pains, and flu-like symptoms for up to a week after their Zometa treatment.

We need to further mine these trials for the data on ONJ, as this data was captured in a blinded manner and adjudicated by a separate committee comprised of dentists and oral surgeons. We can learn much about ONJ, its risk factors, and reversibility from these trials that will help clinicians and patients in the future avoid this complication of therapy.

Rowan T. Chlebowski, MD, PhD

While emerging clinical trial data support treating breast cancer with intravenous bisphosphonates, oral bisphosphonate use in breast cancer treatment has not been fully explored. At SABCS, Rowan T. Chlebowski, MD, PhD, professor and chief of the Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center, presented the study, “Oral Bisphosphonate and Breast Cancer: Prospective Results from the Women’s Health Initiative.” According to the study’s conclusion, oral bisphosphonates may have direct inhibiting effects on breast cancer. We discussed the research with Dr Chlebowski.

OBTN: What was the protocol of the study?

CHLEBOWSKI: Emerging evidence from adjuvant breast cancer clinical trials suggested that intravenous bisphosphonates could reduce breast cancer recurrence risk. This led us to question whether oral bisphosphonates commonly used to treat and prevent osteoporosis may influence breast cancer incidence. To address this question we examined breast cancer incidence in a cohort of 154,768 postmenopausal women participating [in the] Women’s Health Initiative. We compared breast cancer incidence in women using oral bisphosphonates at entry (90% on alendronate, 10% on etidronate) to those not using bisphosphonates. As bisphosphonate users had lower bone mineral density than nonusers and lower bone mineral density is associated with lower breast cancer risk, we adjusted for this potential difference using a hip fracture risk score which strongly correlated with bone mineral density.

What were the primary and secondary endpoints?

Invasive breast cancer was the primary endpoint and ductal carcinoma in situ [DCIS], noninvasive breast cancer, was the secondary endpoint.

What were the major findings?

After 7.8 year, mean follow-up, invasive breast cancer was 32% lower in bisphosphonate users (P <.01). The lower incidence was statistically significant for estrogen—receptor positive cancers, and while a similar trend was seen for estrogen– receptor negative cancers, the latter difference was not statistically significant. In contrast, DCIS incidence was significantly higher in bisphosphonate users.

What is the take-home message for practicing oncologists?

While these observational study findings require prospective confirmation, the results support the concept that bisphosphonates may have activity against breast cancer. The influence of bisphosphonates in current adjuvant breast cancer trials addressing outcomes including contralateral breast cancer will help clarify the clinical significance of our findings.

What do the results mean for patients?

While the results from this observational study are not definitive, women considering bisphosphonate use for bone health could consider this potential breast cancer benefit as well.

What are your plans for future study?

[An] ongoing adjuvant breast cancer trial involving bisphosphonates where contralateral breast cancer is an endpoint will provide further evidence regarding bisphosphonate effects on breast cancer. A primary prevention study evaluating bisphosphonates, perhaps together with an aromatase inhibitor, could be considered for the future.

Hugues Bourgeois, MD

In a poster presentation, Hugues Bourgeois, medical oncologist, Centre Jean Bernard in Lemans, France, and colleagues summarized data collected from 15 private institutions and public hospitals in France that shows adjuvant chemotherapy can lead to persistent alopecia or suboptimal hair regrowth. The investigators based their findings on case report forms for 82 patients (median age, 60 years) who received adjuvant treatment for breast cancer. The forms were completed by each patient’s physician between May 2008 and October 2009..

OBTN: What was the design of the study?

BOURGEOIS: It was a declarative study based on the goodwill of medical oncologists and organized by the Observatory of Medicine and Therapeutic Innovation, with Françoise Grudé (OMIT West of France).

What were the major findings from your research?

Definitive alopecia is possible with Taxotere [docetaxel].

How many patients out of the 82 reports you looked at suffered permanent hair loss?

One hundred percent, and now [there] are 100 women! Dramatic! And now, with the 36 self-questionnaires, we know that these women still have problems with eyebrows (27/36), eyelashes (20/36), and nails (14/36).

Do you know what is causing the permanent hair loss?

No—probably the destruction of the [hair] bulb.

Is the risk of permanent alopecia greater with longer use or with higher doses of docetaxel?

Yes, I think that Taxotere 100 mg/m2 is too high, but it is the recommended dosage through some clinical trials. [Other] trials have tested Taxotere at 75 mg/m2.

To your knowledge, is this a problem with other chemotherapy drugs?

Yes, but in my [experience treating patients with] breast cancer, Taxotere is the most frequent. Please choose Taxol or try cooling scalp!

Do physicians have a responsibility to warn their patients that this is a risk?

Yes, it’s an ethical and a juridical duty.

What do you tell your patients about the risks of alopecia associated with Taxotere use—do you give them other options if they are concerned?

Yes, of course. I do give them the choice [of] 4 courses of Taxotere with a [small percent chance] of permanent hair loss, or 12 weeks of Taxol with no risk of permanent hair loss. For the efficacy, it is the same.

Are you continuing your research in this area? We are collecting a quality-of-life questionnaire from these patients, and we shall present the results [at the] Milan Cancer Conference during October 2010. A clinical trial is going on to demonstrate the effectiveness of scalp cooling. We need [financing] because [Taxotere’s manufacturer] sanofi-aventis does not care about [studying] that.

Is there anything you would like to add or highlight about the study?

Globe and Mail

You will find [additional information in] the article, “Women who took chemo drug say they weren’t warned of permanent hair loss: Maker of Taxotere says risk is low and not life threatening, but women angered by a lack of choice” [http://tiny.cc/4r8tq].