Medications deemed essential to breast cancer prevention

Medication can play an essential role in breast cancer prevention, Holly J. Pederson, MD, director of medical breast services at the Cleveland Clinic, said during the NAMS Annual Meeting.

“My objectives... are to identify women who will benefit most from risk-reducing medications, to recognize the importance of comorbid conditions and the timing of therapy and to develop strategies for improved uptake and adherence,” said Pederson, who also is an associate professor of medicine at the Case Comprehensive Cancer Center in Cleveland.

Only about 4% of the 16% of women who are eligible for preventive medication take it, Pederson said, and the reasons for the poor uptake include patients’ fears of side effects and physicians’ lack of time, experience or comfort with risk assessment and prescriptions.

Holly J. Pederson

“Even in trials where they’ve used computerized decision support tools to encourage uptake, the uptake has been extremely poor — less than 2% in most studies,” she said.

But uptake often is higher among patients with atypical hyperplasia and lobular carcinoma in situ (LCIS), she said. Also, studies involving specialized high-risk counseling at breast centers have seen uptake rates ranging from 11% to 58%.

Available treatments

Tamoxifen can be used in the premenopausal and postmenopausal settings, whereas raloxifene also can be used in the postmenopausal setting, Pederson said. The National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) have recommended exemestane and anastrozole for the postmenopausal setting as well.

Premenopausal and postmenopausal women in the NSABP P-1 trial who took tamoxifen experienced a 50% reduction in both invasive and noninvasive breast cancer compared with a placebo. Specifically, women with atypical hyperplasia saw an 86% risk reduction, and women with LCIS experienced a 56% risk reduction.

During the IBIS 1 trial, tamoxifen and anastrozole protected premenopausal and postmenopausal women up to 15 years after they stopped taking the medication. Tamoxifen and raloxifene saw essentially equivalent results among postmenopausal women at 5 years in the STAR P-2 trial, although raloxifene yielded a 38% risk reduction overall in long-term follow-up.

Exemestane conferred a 65% risk reduction over a 3-year period compared with placebo for postmenopausal women in the MAP3 trial. Anastrozole yielded a 53% risk reduction compared with a placebo for postmenopausal women over a 5-year period in the IBIS 2 trial.

Pederson emphasized the results of a 2019 study involving patients with breast neoplasia, atypical hyperplasia, and both lobular and ductal carcinoma who experienced a 50% risk reduction after taking 5 mg doses of tamoxifen for 3 years.

Healthy premenopausal women in the NSABP P-1 trial saw “absolutely no increased risk of serious side effects,” Pederson said. “That’s incredibly important to reinforce with your patients.”

Tamoxifen offers postmenopausal women an approximately 1% risk for blood clot, a 1% to 3% risk for uterine cancer and a slight increased risk for cataracts. It also may cause vaginal discharge, not vaginal dryness. Raloxifene has an approximately 1% risk for blood clot, but no increased risk for endometrial cancer.

Pederson also said that doctors should be able to manage other side effects such as hot flashes, night flashes, arthralgias and vaginal dryness. She also stressed that “acknowledgement and management can improve compliance” with treatment.

Absolute contraindications for tamoxifen and raloxifene include a history of deep vein thrombosis or pulmonary embolisms, thrombotic stroke, retinal vein thrombosis, transient ischemic attack and known clotting predispositions. Pregnancy, breastfeeding and concurrent warfarin or estrogen therapy are disqualifiers as well.

Relative contraindications for tamoxifen and raloxifene include age older than 60 years, obesity and smoking, all of which increase risks for blood clotting, and unreliable birth control methods since tamoxifen is teratogenic.

Benefits of genetic testing

Genetic testing has a significant role in determining who should receive treatment as well. For example, women with ATM and CHEK2 are nearly exclusively estrogen receptor positive (ER+) and should consider treatment.

Meanwhile, women with BRCA1 are prone to triple negative breast cancer, particularly if they are aged younger than 50 years, though women with BRCA1 aged older than 50 years who develop breast cancer are more likely to be ER+.

“So, in BRCA1 patients over the age of 50, it’s not unreasonable to consider chemo prevention,” Pederson said.

CDH1 predisposes patients to invasive lobular cancer, Pederson continued, and women with PALB2 and BRCA2 should be considered for preventive treatment as well. Doctors should hesitate to prescribe preventive treatment with women who have RAD51C and RAD51D, although BARD1 is a possible indicator among families who are ER+, Pederson said.

Further, there are more than 300 single nucleotide polymorphisms that may confer very small levels of risk individually but significantly affect risk in summation, Pederson said.

In addition to genetic testing, doctors can use the Gail and Tyrer-Cuzick risk models to help decide who should take preventive medication.

“I think that’s really how we’re going to initially incorporate that into our practices,” Pederson said, noting that a combination of the Tyrer-Cuzick risk model and polygenic risk score (PRS) offered a much higher degree of discriminatory accuracy than either component alone in a study published earlier this year.

Additionally, a 2020 study from the Mayo Clinic asked if the PRS influenced the willingness of women who were gene-negative to take preventive medication.

“Some women’s risk estimation went down, and other women’s risk estimation went up,” she said. “As expected, in the ones who had a decreased risk estimate based on the addition of the PRS, they were less likely to take preventive medications, and conversely, in those who had a higher risk with the addition of the PRS, they were more likely to take preventive medication,” she said. “I think this is an important direction that we’re going to be taking.”

‘So, who whould we target?’

Pederson called patient selection “key” to preventive strategies.

When the estimated 5-year risk is 3% or greater, the United States Preventive Services Task Force said, the benefits of preventive medication likely outweigh the risks. ASCO’s threshold is 5% per the 10-year Tyrer-Cuzick estimate in terms of patients most likely to benefit.

According to the NCCN, patients with atypical hyperplasia have a 30% risk for developing breast cancer over the next 25 years, whereas LCIS confers a risk of approximately 2% per year, so preventive medication should be encouraged among these patients unless contraindicated.

“Encourage motivated patients to try the medication for 90 days. Tell them you’re not committing to 5 years but try it for 90 days. Many patients tolerate it much better than they think that they will,” Pederson said.

“Send them with a written prescription if they’re on the fence. Provide them not only with a simple patient handout, but the trial papers, and consider starting at that lower dose and then increasing slowly,” she continued.

Comorbid conditions should be included with breast cancer risks in shared decision-making conversations as well, Pederson said. Since it uses their own genomic data, a PRS may help women accept and adhere to treatment.

“So, who should we target?” Pederson asked. “Patients with atypical hyperplasia and LCIS. Those with a Gail 5-year risk of 3% or greater, a Tyrer-Cuzick risk of 5% or greater, or patients with genetic mutations predisposing to ER+ tumors – BRCA2, BRCA1 over 50, CHEK2, ATM, CDHA and PALB2.”

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