Even though preventive chemotherapy is effective for breast cancer, uptake of these medications is low among women who have a high risk of developing breast cancer or who have benign lesions, such as atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS).
"It is definitely a national problem," said Julie Nangia, MD, medical director of Breast Oncology at the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine in Houston.
The proportion of women who decline to have chemoprevention can -- in part depending on the physician's familiarity with the medications, with reports of the percentage of patients who do chose chemoprevention ranging from 5% to 42%.
The rate of uptake tends to differ between women who are high risk for developing breast cancer, defined as a risk level above a prespecified threshold determined by a risk model, and those with benign lesions. Andrew McKay, MD, of Health Sciences Centre University of Manitoba Winnipeg in Canada, and co-authors noted that their own prospective of high-risk patients (average 5-year Gail risk of 3% and 61% with atypia) found an overall rate of uptake of 15%.
Evidence Supporting Use
The low uptake is despite the overwhelming evidence that use of 5 years of treatment with selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) is effective at preventing breast cancer. FDA-approved SERMs for chemoprevention are tamoxifen and raloxifene, and approved AIs are exemestane and anastrozole.
A of randomized controlled trials, most of which evaluated 5 years of chemoprevention, showed that taking tamoxifen or raloxifene reduced the risk of breast cancer by 38% at 10 years of follow-up and estrogen receptor-positive tumors by 51%.
The showed that treatment with exemestane compared with placebo for 5 years reduced the risk of breast cancer by 65% for postmenopausal women at high risk for breast cancer. About 2 years later, the showed that treatment with anastrozole compared with placebo for 5 years reduced the risk of breast cancer by 53% for postmenopausal women at high risk for breast cancer.
"We need more emphasis on chemoprevention," said Charles Shapiro, MD, of Icahn School of Medicine at Mount Sinai in New York City. He explained that side effects can make patients fearful, and a psychological aspect is also at play -- i.e., patients who do not have cancer tend to be less willing to risk and ensure side effects than if they had cancer.
Evidence suggests that while the patient decision-making process is complex, the concern about side effects is a major factor. For example, a of 158 high-risk women found that, when these women were asked to rate their concern about the side effects of tamoxifen on a scale of 1 to 5, with a higher score indicating greater concern, the average score given was 4.28.
Shapiro said that because of this, he believes that properly educating the patient on the side effects and explaining the evidence can help overcome their reluctance to pursue chemoprevention therapy.
Nangia and Shapiro both agree that tamoxifen and raloxifene, which have been around the longest, are the preferred chemoprevention agents compared with exemestane and anastrozole.
"Unfortunately, the aromatase inhibitors have increased side effects," said Shapiro.
He explained that tamoxifen is favored for premenopausal patients as raloxifene is not indicated for these patients, and raloxifene is preferred for postmenopausal patients to avoid the less than 1% risk of uterine cancer with tamoxifen, which is a major concern for patients.
About raloxifene, Nangia said: "It's incredibly well tolerated, [and] very few people have side effects on it."
Low-Dose Tamoxifen
Even though the only option for premenopausal patients is tamoxifen -- AIs are for postmenopausal women -- the phase III , published in 2019, showed that using a lower dose of tamoxifen can reduce not only toxicity but also the the risk of recurrence.
The trial evaluated adjuvant tamoxifen at 5 mg for 3 years compared with placebo in 500 women with hormone-sensitive or unknown breast intraepithelial neoplasia, including ADH, ductal carcinoma in situ, and LCIS.
A of patient reported outcomes from the trial showed no difference between the low-dose tamoxifen and placebo groups, although the frequency of daily hot flashes increased slightly from 1.5 times per day for placebo to 2.1 times per day for low-dose tamoxifen (P=0.05).
Nangia said that because 5 mg tamoxifen tablets are not available in the U.S. (only 10 mg and 20 mg tablets are), she prescribes 10 mg, as many others do, and has seen her patients do well on that dose. "I have a handful of patients that have side effects on the 10 mg dose," said Nangia, noting that she asks those patients to split their tablets in half.
Nangia said that for patients who receive a lower dose of tamoxifen, she has noticed "much better" tolerance and fewer people stopping treatment.
"Prevention is very different than cancer treatment because you kind of have one shot to get them to tolerate it," she said.
The exception to this, she added, are patients with a personal history of precancerous lesions, like LCIS, ADH, and ALH. Nangia said she recommends full-dose tamoxifen for women with precancerous lesions because the data are "so compelling" that chemoprevention reduces the risk of breast cancer and there are no data to suggest that a lower dose would be just as effective.
For women with atypical hyperplasia, 5 years of full-dose tamoxifen reduces the risk of breast cancer by 86%, according to the .
Disclosures
Nangia reported having consulted for Novartis and Biotheranostics and that her institution received clinical trial funding from Paxman Coolers.
Shapiro had no disclosures.