SAN ANTONIO – Good old tamoxifen, there’s life in the old girl yet: A 3-year course of low-dose tamoxifen – one-fourth of the standard dose – reduced the risk of breast intraepithelial neoplasia (IEN) recurrence by half, compared with placebo.
And although the patient numbers were relatively small, tamoxifen at 5 mg/day also reduced the risk of contralateral breast cancer by 75%, results of the TAM01 study showed.
Among 500 patients with either atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), or lobular carcinoma in situ (LCIS) randomized either to tamoxifen 5 mg/day for 3 years or placebo, there were 28 cases of either invasive breast cancer or recurrent DCIS in patients after a median follow-up of 5.1 years for patients assigned to placebo, compared with 14 events for patients assigned to tamoxifen, translating into a hazard ratio of 0.48 (P = .024), reported Andrea De Censi, MD, from Ospidali Galliera in Genoa, Italy, at the San Antonio Breast Cancer Symposium.
“We think our results have external validity because of the pragmatic nature of the study and the easy accessibility of the drug, and so they are generalizable,” he said, adding that “our findings are applicable in clinical practice from tomorrow [on].”
Despite concerns about the known carcinogenic and cardiovascular side effects of tamoxifen, there were no significant differences in either the rate of endometrial cancer or of deep vein thrombosis (DVT)/pulmonary embolism between the groups, and there was only a borderline increase in hot flashes among patients randomized to tamoxifen.
IEN accounts for approximately 15%-25% of all breast neoplasms. Although tamoxifen has a long track record of efficacy in prevention of recurrence, its side effects, including increased risk of endometrial cancer and thrombotic events as well as menopausal-type symptoms, have dissuaded some clinicians from prescribing it and scared some patients away from taking it.
Dr. De Censi and his colleagues conducted a phase 3 trial comparing tamoxifen 5 mg daily with placebo in 500 women with hormone-sensitive breast IEN following surgery. Women with grade 3 disease, positive margins, or comedo/necrosis DCIS received radiotherapy.
The patients were followed every 6 months, and had annual mammograms for at least 5 years after randomization.
As noted before, after 5.1 years median follow-up the primary endpoint of invasive breast cancer or DCIS had occurred in 28 patients on placebo versus 14 on tamoxifen, for an HR of 0.48. The respective incidences of contralateral breast cancer were 12 and 3, translating into a HR for tamoxifen at 0.24 (P = .018).
There were no statistically significant differences in serious adverse events between groups, including endometrial cancer (one in the tamoxifen group vs. one in the placebo group), DVT/PE (one in each group), other neoplasms (four vs. six cases, respectively), coronary heart disease (two cases each), other nonfatal events (three vs. five), or deaths (one vs. two).
“If we compare these findings with the NSABP-P1 prevention trial with a dose of 20 mg per day we would expect 2.7 endometrial cancers on tamoxifen, and 2.4 DVT or pulmonary emboli,” Dr. De Censi said in a briefing prior to his presentation of the data in a general session.
Patient-reported daily hot flashes occurred slightly but significantly more often with tamoxifen (P = .05). But when the frequency of reported hot flashes was multiplied by the intensity, the difference between the arms was not significant.
There were no significant differences between the groups for the patient-reported outcomes of vaginal dryness or pain at intercourse, or of musculoskeletal pain/arthralgia. Treatment adherence over 3 years did not differ between the groups.
Dr. De Censi noted that because 5 mg tablets of tamoxifen are not currently available, investigators recommend either cutting 10 mg tablets in half or taking the 10-mg dose every other day.
Virginia Kaklamani, MD, leader of the breast cancer program at the University of Texas, San Antonio, who moderated the briefing, commented that the study provides valuable information about the dosing of this time-tested drug.
“When you look at drug development, in many cases we rush these drugs out and we don’t pay attention to the dose that’s needed – we pay attention to the dose that’s not very toxic, and so many of the drugs that we use we end up using them at higher doses than we need to use them,” she said.
“A drug doesn’t work if you don’t take it, and so if you can find ways to take the drug, like in giving it at lower doses, then these women are going to benefit,” Dr. Kaklamani added.
She said that based on these data she would “definitely” give patients with ADH and LCIS lower doses of tamoxifen, and while she wants to see more data on DCIS patients with further follow-up, “if I have a DCIS patient who’s not tolerating tamoxifen at the 20 mg dose, I’d be extremely happy lowering to 5 mg.”
Sandhya Pruthi, MD, from the Mayo Clinic in Rochester, Minnesota, who was not involved in the study, said in an interview that, while she was impressed by both the reduction in risk and the favorable side effect profile, the patient sample was too small to draw firm conclusions.
“Could I go back to the clinic and tell all my patients who are taking 20 mg of tamoxifen that you can now cut your dose in half to 10 mg or even to the 5-mg dose based on this trial? That would I think be a little premature,” she said.
“Where I would like to go with this is that we do a larger trial – a randomized, controlled trial,” Dr. Pruthi added.
The TAM01 study was supported by the Italian Ministry of Health, Italian Association for Cancer Research, and the Italian League Against Cancer. Dr. De Censi and his coauthors reported having no direct conflicts of interest. Dr. Kaklamani and Dr. Pruthi reported no relevant conflicts of interest.
SOURCE: De Censi A et al. SABCS 2018, Abstract GS3-01.