Lasofoxifene Is Potential New Option for Breast Cancer Risk - National Cancer Institute

Lasofoxifene Is Potential New Option for Breast Cancer Risk Reduction




Adapted from the NCI Cancer Bulletin, vol. 7/no. 22, November 16, 2010 (see the current issue).

An investigational agent in the same family of drugs as tamoxifen [Tamoxifen Citrate - National Cancer Institute] and raloxifene [Raloxifene Hydrochloride - National Cancer Institute] may be as or more effective in reducing breast cancer [Breast Cancer Home Page - National Cancer Institute] risk in some women, according to the findings of a large clinical trial. The drug, lasofoxifene, also appears to have important benefits for both bone and heart health and, with one exception, appears to lack the rare but potentially serious side effects associated with tamoxifen and raloxifene. The results were published online November 4, 2010, in the Journal of the National Cancer Institute.

The findings come from a randomized clinical trial called PEARL, in which more than 8,500 postmenopausal women with osteoporosis were randomly assigned to take a placebo or one of two different doses of lasofoxifene (0.25 mg or 0.5 mg) daily for 5 years. Initial results, based on 3 years of follow-up, showed a reduced risk of estrogen receptor (ER)-positive breast cancer in women who received the higher dose of lasofoxifene compared with the placebo.

The new, more mature results, which provide 5 years of participant follow-up, show the overall risk of breast cancer was reduced by 79 percent, and the risk of invasive ER-positive breast cancer was reduced by 83 percent in women who took 0.5 mg of lasofoxifene compared with women who took the placebo.

There was some risk reduction seen with the lower dose of lasofoxifene, but it was not statistically significant, reported Andrea LaCroix, Ph.D., of the Fred Hutchinson Cancer Research Center and her colleagues. Women who took the higher lasofoxifene dose also had statistically significant reductions in the risk of vertebral and nonvertebral fractures, cardiac events, and strokes. The only notable side effect was an increased risk of blood clots.

The researchers also conducted a nested case-control study that included all 49 cases of breast cancer in the trial and 156 women from the trial’s placebo arm. Women with higher levels of the hormone estradiol at study entry, they found, seemed to gain a greater cancer prevention benefit from lasofoxifene, but the difference was only statistically significant for total breast cancer incidence, not ER-positive breast cancer.

“We need more complete information about the long-term effects of lasofoxifene on both beneficial and unfavorable outcomes,” cautioned Victor Vogel, M.D., of the Geisinger Medical Center in an accompanying editorial. Although women in the trial were, on average, significantly younger than participants in the STAR trial, which affirmed the breast cancer risk reduction benefits of both tamoxifen and raloxifene, they were also at lower overall risk of breast cancer (based on their Gail model scores).

Nevertheless, given the “dramatic” risk reduction seen with lasofoxifene in the PEARL trial, Dr. Vogel called the findings “encouraging.” Lasofoxifene is still an investigational agent. In May, Pfizer, which manufactures the drug, withdrew its application to the FDA to market the drug for the treatment of osteoporosis. According to a company spokesperson, Pfizer is investigating several options for the drug, including selling it to another company.
Lasofoxifene Is Potential New Option for Breast Cancer Risk - National Cancer Institute





J Natl Cancer Inst. 2010 Nov 17;102(22):1706-15. Epub 2010 Nov 4.
Breast cancer incidence in the randomized PEARL trial of lasofoxifene in postmenopausal osteoporotic women.

LaCroix AZ, Powles T, Osborne CK, Wolter K, Thompson JR, Thompson DD, Allred DC, Armstrong R, Cummings SR, Eastell R, Ensrud KE, Goss P, Lee A, Neven P, Reid DM, Curto M, Vukicevic S; PEARL Investigators.

Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA. alacroix@whi.org

Comment in:

* J Natl Cancer Inst. 2010 Nov 17;102(22):1683-5.

Abstract

BACKGROUND: Currently available selective estrogen receptor modulators reduce the risk of breast cancer, but they are not widely used. In the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) trial, lasofoxifene was shown to reduce the risk of estrogen receptor-positive (ER+) breast cancer, nonvertebral and vertebral fractures, coronary artery disease, and stroke, but the effects on total breast cancer (invasive and ductal carcinoma in situ, ER+ and estrogen receptor-negative [ER-]) and ER+ invasive breast cancer are unknown.

METHODS: Postmenopausal women (n = 8556) aged 59-80 years with low bone density and normal mammograms were randomly assigned to two doses of lasofoxifene (0.25 and 0.5 mg) or placebo. The primary endpoints of the PEARL trial were incidence of ER+ breast cancer and nonvertebral fractures at 5 years. A nested case-control study of 49 incident breast cancer case patients and 156 unaffected control subjects from the PEARL trial was performed to evaluate treatment effects on risk of total and ER+ invasive breast cancer by baseline serum estradiol and sex hormone-binding globulin levels using logistic regression models. Cox proportional hazards models were used to evaluate risk of total breast cancer and ER+ invasive breast cancer using intention-to-treat analysis. All statistical tests were two-sided.

RESULTS: Breast cancer was confirmed in 49 women. Compared with placebo, 0.5 mg of lasofoxifene statistically significantly reduced the risk of total breast cancer by 79% (hazard ratio = 0.21; 95% confidence interval [CI] = 0.08 to 0.55) and ER+ invasive breast cancer by 83% (hazard ratio = 0.17; 95% CI = 0.05 to 0.57). The effects of 0.5 mg of lasofoxifene on total breast cancer were similar regardless of Gail score, whereas the effects were markedly stronger for women with baseline estradiol levels greater than the median (odds ratio = 0.11; 95% CI = 0.02 to 0.51) vs those with levels less than the median (odds ratio = 0.78; 95% CI = 0.16 to 3.79; P(interaction) = .04).

CONCLUSION: A 0.5-mg dose of lasofoxifene appears to reduce the risks of both total and ER+ invasive breast cancer in postmenopausal women with osteoporosis.

PMID: 21051656 [PubMed - in process]
Breast cancer incidence in the randomized PEARL tr... [J Natl Cancer Inst. 2010] - PubMed result





N Engl J Med. 2010 Feb 25;362(8):686-96.
Lasofoxifene in postmenopausal women with osteoporosis.

Cummings SR, Ensrud K, Delmas PD, LaCroix AZ, Vukicevic S, Reid DM, Goldstein S, Sriram U, Lee A, Thompson J, Armstrong RA, Thompson DD, Powles T, Zanchetta J, Kendler D, Neven P, Eastell R; PEARL Study Investigators.
Collaborators (138)
Cummings SR, Delmas P, Eastell R, Ensrud K, LaCroix A, Reid D, Sriram U, Vukicevic S, Zanchetta J, Powles T, Allred C, Goss P, Osborne K, Colgan T, Goldstein SR, Neven P, Runowicz CD, Cohen L, Sechtem U, Welty F, Johnson SR, Russell G, Cosman F, Barter P, Laird NM, Gardiol AA, Zanchetta J, Messina OD, Seeman E, Nicholson G, Hooper M, Graham JJ, Eden J, Stuckey BG, Geusens P, Boonen S, De Melo NR, Zerbini CA, Yuen CK, Brown J, Ste-Marie LG, Adachi J, Hanley DA, Josse RG, Kendler D, Olszynski WP, Castro R, Krpan D, Giljevic Z, Skreb F, Hyldstrup L, Langdahl BL, Rashed A, Maasalu K, Tammemae L, Piirisild KL, Heikkinen J, Kormano M, Valimaki MJ, Roux CC, Delmas PD, Hartard M, Doren M, Lau E, Balogh A, Horvath K, Tulassay Z, Kanakatte PM, Srinivasan B, Mehrotra RN, Patni R, Menon PS, Thomas M, Seshadri MS, Ammini AC, O'Brien M, Brandi ML, Adami S, Itabashi A, Okamoto S, Fujita N, Sawamoto A, Omata R, Han IK, Alekna V, Kazanavicius G, Jurgutis R, Balderas I, Santos J, Correa-Rotter R, Halse JI, Hoye K, Ofjord ES, Sawicki A, Marcinowska-Suchowierska E, Czerwinski E, Zosin I, Zbranca E, Codreanu C, Gzgzyan AM, Benevolenskaya LI, Dedov II, Oganov R, Smetnik V, Jordaan PJ, De Villiers TJ, Lipschitz S, Ellis G, Calaf J, Hawkins F, Mellstrom D, Kucu kdeveci A, Kirazli Y, Keen R, Reid DM, Savani N, Moffett AH Jr, Silverfield JC, Bolognese MA, McKenney JM, Rosenstock J, Greenwald MW, Lewiecki M, Miller SS, Lederman SN, Chesnut CH 3rd, Gallagher JC, Hangartner TN, Johnson KC, Ensrud K, Cauley JA, LaCroix A, Lewis CE, Broy SB, Sherman L, Barrett-Connor EL, Wallace RB, Orwoll ES.

San Francisco Coordinating Center, California Pacific Medical Center Research Institute, and University of California, San Francisco, San Francisco, USA. scummings@sfcc-cpmc.net

Comment in:

* N Engl J Med. 2010 Feb 25;362(8):752-4.
* N Engl J Med. 2010 Jun 10;362(23):2228; author reply 2228-9.
* Expert Opin Pharmacother. 2010 Jul;11(10):1773-5.
* Ann Intern Med. 2010 Jul 20;153(2):JC1-11.
* N Engl J Med. 2010 Jun 10;362(23):2227; author reply 2228-9.
* N Engl J Med. 2010 Jun 10;362(23):2227-8; author reply 2228-9.

Abstract

BACKGROUND: The effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain.

METHODS: In this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density T score of -2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)-positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke.

RESULTS: Lasofoxifene at a dose of 0.5 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95% CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years; hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60], respectively). Endometrial cancer occurred in three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Rates of death per 1000 person-years were 5.1 in the placebo group, 7.0 in the lower-dose lasofoxifene group, and 5.7 in the higher-dose lasofoxifene group.

CONCLUSIONS: In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. (ClinicalTrials.gov number, NCT00141323.)
2010 Massachusetts Medical Society

PMID: 20181970 [PubMed - indexed for MEDLINE]
Free Article
Lasofoxifene in postmenopausal women with osteopor... [N Engl J Med. 2010] - PubMed result







Long-term Follow-up Confirms Breast Cancer Risk Reduction with Raloxifene


Study of Tamoxifen And Raloxifene logo


The drugs raloxifene (Evista) and tamoxifen both substantially reduce the risk of breast cancer in women at high risk for the disease, but raloxifene causes fewer and less-severe side effects, according to the long-term results of a large breast cancer prevention trial presented yesterday at the American Association for Cancer Research (AACR) annual meeting in Washington, DC.

The findings, from the NCI-supported Study of Tamoxifen and Raloxifene (STAR) trial, were mostly consistent with the trial’s initial results published in 2006; findings that eventually led to FDA approval of raloxifene to reduce the risk of breast cancer in postmenopausal women at increased risk. With nearly 3 more years of follow-up data on the more than 19,000 women who participated in the study, raloxifene was modestly less effective than tamoxifen at reducing the incidence of both invasive and noninvasive breast cancer, but was markedly safer and had a substantially lower risk of rare side effects, including endometrial cancer.

The updated STAR findings and the overall data on both tamoxifen and raloxifene—both of which are in a class of drugs known as selective estrogen receptor modulators, or SERMs—for breast cancer prevention are “good news for women,” said Dr. D. Lawrence Wickerham of the National Surgical Adjuvant Breast and Bowel Project, the NCI cooperative group that led the trial. “Among postmenopausal women with increased breast cancer risk, there are now two options to reduce that risk,” he said.

“I think these data are particularly good news for the primary care community,” said Dr. Judy Garber, director of the Cancer Risk and Prevention Program at the Dana-Farber Cancer Institute, during a press briefing. Particularly given their heavy use of and comfort with raloxifene to prevent and treat osteoporosis, for which it is also approved, she said, the results should “encourage primary care physicians to discuss raloxifene [for breast cancer risk reduction] more often.”

Dr. Wickerham acknowledged that the idea of taking a drug to prevent or reduce cancer risk, often called chemoprevention, has been a tough sell. “Chemoprevention is still in its infancy,” he said. “These STAR data are an important step toward bringing chemoprevention to the same level as that seen in areas like preventive cardiology,” he continued, where drug therapy is commonly used to treat heart disease precursors such as high blood pressure and high cholesterol.

Tamoxifen has been approved for breast cancer risk reduction since 1998, following the findings from the Breast Cancer Prevention Trial (BCPT), which showed a nearly 50 percent reduction in breast cancer risk among women at increased risk who took tamoxifen for 5 years compared with those who took a placebo. But tamoxifen has never caught on as a cancer prevention agent. The drug’s low uptake has often been attributed to concerns about its potential side effects, namely increased risk of endometrial cancer and dangerous blood clots.

But the potential risks of tamoxifen and raloxifene have been overstated, said Dr. Gabriel Hortobagyi, chair of the Department of Breast Medical Oncology at the University of Texas M. D. Anderson Cancer Center, during the briefing. In the BCPT, for example, even though women taking tamoxifen had a significantly increased risk of developing endometrial cancer, the risk was still less than 1 percent.

Like tamoxifen, raloxifene had been shown to decrease breast cancer risk in clinical trials. Consequently, STAR was launched to test the two drugs head-to-head in postmenopausal women who are at an elevated risk of breast cancer (based on the commonly used NCI Breast Cancer Risk Assessment Tool). On average, the women in STAR had a 15 percent increased lifetime risk of breast cancer. Participants were randomly assigned to take one of the drugs every day for 5 years.

When the initial STAR findings were published, with a median follow-up of 47 months, both drugs were equally effective in reducing the risk of invasive breast cancer. But the updated results show that raloxifene’s effectiveness appears to wane over time. With a median follow-up of 81 months, raloxifene was about 76 percent as effective as tamoxifen at reducing invasive breast cancer risk. For noninvasive breast cancer, which includes conditions known as ductal carcinoma in situ and lobular carcinoma in situ, tamoxifen was initially shown to be modestly more effective than raloxifene. That finding held true with the longer follow-up, but the gap narrowed, with raloxifene proving to be about 78 percent as effective as tamoxifen.

Raloxifene’s side-effect profile remained far superior, with a 45 percent reduced risk of endometrial cancer and a 25 percent lower risk of serious blood clots compared with women who took tamoxifen.

The findings add to “the evidence that supports the long-term benefits of these drugs,” said Dr. Katrina Armstrong, co-director of the Cancer Control Program at the University of Pennsylvania Abramson Cancer Center in Philadelphia. What’s needed now, Dr. Armstrong continued, “is an active effort to understand the barriers to use [of raloxifene and tamoxifen] and the implementation of clinical decision-support tools to help providers identify women who are eligible to take them and make decisions about their use.” (See the sidebar.)

In essence, she continued, it comes down to getting health care providers, namely primary care physicians, “to be comfortable doing risk stratification and prescribing preventive medications without having a biomarker like cholesterol” to guide those decisions.

“Even 12 years after tamoxifen was approved by the FDA for breast cancer risk reduction,” said Dr. Katherine Lee, co-director of the High Risk Clinic at the Cleveland Clinic Breast Center, “[many clinicians] are still very reluctant to have that conversation” with patients about taking raloxifene or tamoxifen. “I see high-risk women every day. So they will hear about chemoprevention from me; and tamoxifen and raloxifene are your current options for risk reduction,” Dr. Lee said.

Part of the reluctance, she agreed, comes back to concerns about side effects, both on the part of the clinician and the patient. But there is also another key difference between drug therapy for blood pressure or cholesterol and drug therapy for cancer prevention, she stressed: a hard endpoint that both clinicians and patients can follow. “Doctors like to follow numbers,” said Dr. Lee, who was also an investigator on the STAR trial. “With raloxifene or tamoxifen, there are no numbers. You can’t tell whether a patient is improving upon her risk. It’s far more complex.”

—Carmen Phillips

Tools to Aid Clinician Decision Making

To help clinicians discuss breast cancer chemoprevention options with patients at the University of Pennsylvania Abramson Cancer Center, Dr. Armstrong and her colleagues are developing decision-support tools to disseminate to primary care practices. These tools will allow clinicians to take information from a patient’s health-risk appraisal, looking at factors such as family health history and reproductive risks, and link it with a decision-support tool built into the center’s electronic medical record system.

The approach is being piloted in several clinical settings and is expected to be rolled out more widely next year. The hope, said Dr. Armstrong, “is that we can get to a point where we can say that these are the women who will receive the greatest benefit from raloxifene or tamoxifen; they are way over the threshold for absolute benefit and should be offered the medication.”

If such an approach can be shown to reduce breast cancer mortality, she continued, “I think it will produce a significant impetus for health care providers to be more innovative about how we can really individualize what we do for our patients.”
NCI Cancer Bulletin for April 20, 2010 - National Cancer Institute