Tamoxifen: TAM-01 Long Term Follow-up with Andrea De Censi SABCS 2022

Tamoxifen: TAM-01 Long Term Follow-up with Andrea De Censi SABCS 2022

What is TAM-01 long term follow-up data? Tamoxifen is a selective estrogen receptor modulator (SERMs). Which has been used firstly in the metastatic setting in women with advanced breast cancer, and then moved to the adjuvant setting where it show a survival advantage in estrogen receptor positive disease. The dose that was selected is 20 milligrams every day.

And it is associated; it is a well tolerated drug, but has some serious adverse events, namely endometrial cancer, venous thromboembolic events, and most importantly, in the provincial setting, menopausal symptoms such as hot flashes, pain during intercourse, and other gynecological side effects of Tamoxifen. So it is a good, very good drug, very cheap, very importantly nowadays, and it has also been used for prevention of high risk women (breast cancer risk) with a very significant reduction of breast cancer incidents.

But the uptake of this indication has been quite low because of the fear of adverse events (Eg aromatase inhibitors, hormone receptors).

Will the Tamoxifen Trial Help Prevent Breast Cancer?

We reason that the dose selection was a little bit empirical and thought that there was the necessity for biomarker trials to determine the minimal effective dose, a concept that is very important for drug development, but which is rarely met in the development of the drugs (not over the counter or brand names) by pharmaceutical companies.

So we did several trials, biomarker trials looking at inferior doses such as 10 milligram per day, 5 milligram per day, or even 20 milligram per week. And this biomarker studies showed us that 5 milligram per day was non-inferior to the standard dose of 20 milligram per day in decreasing breast cancer proliferation measured by MKI67 in a press surgical study of 4 weeks, and so we selected this lower dose of 5 milligram per day for a trial in women with high risk (risk of breast cancer) lesions. That is women with ductal carcinoma in situ, lobular carcinoma in situ, or a typical ductile hyperplasia. These are high risk lesions where the risk of developing an invasive breast cancer is tenfold the general population.

Primary Endpoint of the Tamoxifen Clinical Trial?

So in Tam01, which is a phase 3 trial, we invited women age 75 or younger who had  surgically removed DCIS (ductal carcinoma in situ) or LCIS (lobular carcinoma in situ) or ADH (atypical ductal hyperplasia) to receive 3 years of Tamoxifen, 5 milligram per day or placebo. And then we follow these women for up to 10 years. The primary end was the incidence of invasive breast cancer or DCIS (ductal carcinoma in situ). 500 women were randomized into the study from 14 centers in Italy.

5 Key Takeaways of Tamoxifen Treatment In Patients with DCIS, LCIS, and ADH

1. Italian, multicenter, phase III trial: controlled, parallel group comparison, randomized (1:1), double-blind, tamoxifen 5 mg/d versus placebo for three years. Under 75-year-old patients newly diagnosed with noninvasive breast cancer were examined. After treatment, long-term studies require a 10-year follow-up.

2. 14 breast neoplastic events (invasive) breast cancer or DCIS (ductal carcinoma in situ)) occurred in the tamoxifen arm (11.6 per 1,000 person-years) compared to 28 in the placebo arm (23.9 per 1,000; HR, 0.48; 95% CI, 0.26 to 0.80; log-rank P =.02)(it did not include eye problems).

3. There were twelve serious adverse events in the tamoxifen arm and sixteen in the placebo arm, including one deep vein thrombosis, one endometrial cancer in stage I, and one pulmonary embolism (rate, 0.85 per 1,000 person-years). At the five years number needed to harm was 218 (95% CI, 193 to 265), but the likelihood of helping was 10 times greater (218 v 22).

4. Menopausal symptoms, such as vasomotor symptoms, sexual discomfort, and gynecologic difficulties, have a significant impact on quality of life and tamoxifen adherence, particularly in the preventative setting; therefore, we provided validated self-administered questionnaires at each visit.

5. Limitations of the study include the lower-than-anticipated number of occurrences, which is mostly attributable to the financial limits of an academic, publicly funded trial and the early disclosure of results due to its potential to alter clinical practice. Our trial was sufficiently powered to detect valid treatment effect estimates in the absence of subgroup heterogeneity due to the extended recruiting and follow-up period and the higher-than-expected risk in the placebo arm.

Watch and Share the Video Here: https://oncologytube.com/v/41483

What is the Primary Statistical Data from the Tamoxifen Trial In Breast Cancer?

So the study was powered to detect a 50% (breast cancer risk) reduction in the risk of recurrence of invasive breast cancer or DCIS (ductal carcinoma in situ). And the study was powered at 80% to have a total number of events, which was 55. So the study had 80% power to detect a  50% reduction in recurrence after 5 years based on a total number of events of 55.

Four years ago in San Antonio, we presented the 5 years data of babytam, and we showed a 52% reduction of recurrence with with babytam and a 76% reduction of contra breast cancer. Now In these days, we will present the 10 years data of babytam, which show a statistically significant 42% reduction of recurrence.

At 10 years and a seven 64% reduction of Contralateral W breast cancer. So there is still a carryover effect of beam after seven years from treatment cessation. And I think the data are very important for several. Reasons. So first of all high risk lesions can be managed with a very tolerable drug. We have no excess of serious adverse events with babytam, nor was there an increase in patient reported to their health care providers.

Except for a slight increase in hot flashes in less than a extra hot flash per day with babytam. Secondly the effect on lateral breast cancer opens the door for a primary breast cancer prevention in high risk individuals and believe that with this lower dose, we can increase the uptake of women who have a high risk of developing breast cancer, but are frightened all the toxicity of the drug and so don’t take it. And another interesting implication is that, babytambabytam has been shown to decrease mammographic density and therefore increase the sensitivity of screening mammography and possibly also reduce the risk of interval cancers (like breast cancer). So this is another potential, very exciting implication of our study.

Lastly, there is, the important request for from many women in the adjuvant setting to have a tolerable treatment and with 20 milligram per day, let’s say 30 to 40% of patients do not tolerate the treatment because of the menopausal symptoms, and with dose reduction, you can manage to continue the treatment, otherwise the women would stop.

Final Thoughts On Tamoxifen Therapy In Breast Cancer

I think that our study is one more example of a drug, one of the most popular drugs ever in oncology, which has been registered and given at a too high dose. And this is a leading team of this symposium here the knowledge that we are using drugs at two high doses, and this is because of the pressure of pharmaceutical companies to register drugs with the lack of understanding of the search of the minimal effective dose, so this is very important, and oncologist must learn how to think in terms of safety, tolerability, and because it’s not the treatment or the (breast) cancer, we are treating a whole person.

Andrea De Censi, MD – About The Author, Credentials, and Affiliations

Dr. De Censi has directed Genoa’s National Hospital E.O. Ospedali Galliera – S.C. Oncologia Medica’s Medical Oncology Unit since 2004. In 1984, Andrea De Censi earned a first-class degree in medicine and surgery from Pavia University. In 1987, he specialized in medical oncology at Genoa’s Postgraduate Medical School. He received ESMO European Certification in Medical Oncology in 2008.

Since 1998, Dr. De Censi has worked as a medical doctor and clinic researcher at the Genoa National Institute for Cancer Research, where he earned his PhD. Dr. De Censi headed Milan’s European Institute of Oncology’s Cancer Prevention and Genetics Division from 1995 to 2003.

ANVUR, an ENQA affiliate, awarded him the National Scientific Qualification as University Full Professor in 2013. Dr. De Censi reviews top cancer journals and has over 170 peer-reviewed papers with an H-index of 38.

ESMO, ASCO, and AACR members. Dr. De Censi has a Master agreement with the National Cancer Institute for phase I and phase II clinical trials since 2004.

References

1. Clinical Trials Gov – Trial of Low Dose Tamoxifen in Women With Breast Intraepithelial Neoplasia – Long Term Follow-up (TAM-01). Clinical Trials gov, September 28, 2022, Breast Cancer

2. ASCO Pubs – Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Local and Contralateral Recurrence in Breast Intraepithelial Neoplasia. ASCO Pubs, July 01, 2019, Breast Cancer