‘Baby TAM’ effective, tolerable for breast cancer prevention

SAN ANTONIO — Low-dose tamoxifen, sometimes called “baby TAM,” is gaining traction as an alternative to full-dose tamoxifen for use in breast cancer prevention. The drug can reduce incidence of breast cancer in high-risk individuals, but side effects that mimic menopause have led to low rates of uptake. Lower-dose tamoxifen aims to reduce those side effects, but there remains some uncertainty about the minimum dose required to maintain efficacy.

The TAM-01 study, first published in 2019, demonstrated that a 5-mg dose of tamoxifen led to a reduction in recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS). At the San Antonio Breast Cancer Symposium, two studies were presented that provided insight into dose efficacy and likelihood of medication adherence in women taking baby TAM.

“We all know that women who are at increased risk for breast cancer may benefit from the use of tamoxifen to help lower their risk, although historical uptake to tamoxifen in the prevention setting has been quite low,” said Lauren Cornell, MD, during a presentation. Her team investigated the impact of patient counseling on how well they understood their risk, as well as their likelihood of adherence to the medication.

The study included 41 women, and 31 completed follow-up at 1 year. “We saw that 90% of our patients reported good or complete understanding of their breast cancer risk after the consultation, emphasizing the benefit of that consult, and 73% reported that the availability of baby tamoxifen helped in their decision to consider a preventative medication,” said Dr. Cornell during her presentation. After 1 year of follow-up, 74% said that they had initiated baby tamoxifen, and 78% of those who started taking the drug were still taking it at 1 year.

Participants who continued to take baby TAM at 1 year had a higher estimated breast cancer risk (IBIS 10-year risk, 12.7% vs 7.6%; P = .027) than those who discontinued. “We saw that uptake to baby TAM after informed discussion in patients who qualify is high, especially in those patients with high risk and intraepithelial lesions or DCIS, and adherence and tolerability at 1 year follow up is improved, compared to what we would expect with traditional dosing of tamoxifen. It’s important to note that the NCCN guidelines and the ASCO clinical practice update now include low-dose tamoxifen as an option for select women, and future randomized control trials on de-escalation of tamoxifen and high-risk patients based on their risk model assessment still need to be done. Future study should also focus on markers to identify candidates best suited for low versus standard dose of tamoxifen,” said Dr. Cornell, who is an assistant professor of medicine at Mayo Clinic Florida in Jacksonville.

At another SABCS session, Per Hall, MD, PhD, discussed findings from the previously published KARISMA-2 study, which examined efficacy of various doses of tamoxifen. A total of 1440 participants, 240 in each arm, received tamoxifen doses of 20 mg, 10 mg, 5 mg, 2.5 mg, 1 mg, or placebo. During his talk, Dr. Hall pointed out that measuring outcomes would take a very large number of participants to identify small differences in breast cancer rates. Therefore, the researchers examined breast density changes as a proxy. As a noninferiority outcome, the researchers used the proportion of women in each arm who achieved the median decrease in breast density seen at 20 mg of tamoxifen, which is 10.1%.

The women underwent mammograms at baseline and again at 6 months to determine change in breast density. Among all women in the study, the proportion of patients who had a similar breast density reduction as the 20-mg dose were very similar in the 10 mg (50.0%; P = .002), 5 mg (49.3%; P < .001), and 2.5 mg (52.5%; P < .001) groups. The 1 mg group had a proportion of 39.5% (P = .138), while the placebo group had 38.9% (P = .161). However, the results were driven by premenopausal women, where the values were 63.3%, 70.7%, 74.4%, and 69.7% in the 20-mg, 10-mg, 5-mg, and 2.5-mg groups, respectively, and 32.9% at 1 mg and 29.7% on placebo. In postmenopausal women, the values were 41.9%, 36.7%, 33.3%, and 41.9% in the 20-mg, 10-mg, 5-mg, and 2.5-mg groups, with values of 44.2% in the 1-mg group and 43.8% in the placebo group.

The median density change was 18.5% in premenopausal women and 4.0% in postmenopausal women.

“We didn’t see anything in the postmenopausal women. The decrease for those on 20 milligrams and those on placebo were exactly the same. Why this is, we still don’t know because we do know that tamoxifen in the adjuvant setting could be used for postmenopausal women. It could be that 6 months is too short of a time [to see a benefit]. We don’t know,” said Dr. Hall, who is a medical epidemiologist and biostatistician at Karolinska Institutet, Stockholm, Sweden.

Severe vasomotor side effects like hot flashes, cold flashes, and night sweats were reduced by about 50% in the lower tamoxifen doses, compared with 20 mg.

Dr. Hall also pointed out that tamoxifen is a prodrug. The CYP2D6 enzyme produces a range of metabolites, with endoxifen having the strongest affinity to the estrogen receptor and being present at the highest plasma concentration. He showed a table of endoxifen plasma levels at various tamoxifen doses in women of various metabolizer status, ranging from poor to ultrafast. Among intermediate, normal, and ultrarapid metabolizers, 5- and 10-mg doses produced plasma endoxifen levels ranging from 2.4 to 6.2 ng/mL, which represents a good therapeutic window. “For intermediate and normal metabolizers, it could be that 5 mg [of tamoxifen] is enough, but I want to underline that we didn’t use breast cancer incidence or recurrence in this study, we used density change, so we should be careful when we use these results,” said Dr. Hall. His group is now conducting the KARISMA Endoxifen trial, which will test endoxifen directly at doses of 1 and 2 mg.

Dr. Cornell has no relevant financial disclosures. Dr. Hall is a member of the scientific advisory board for Atossa Therapeutics.

SAN ANTONIO — Low-dose tamoxifen, sometimes called “baby TAM,” is gaining traction as an alternative to full-dose tamoxifen for use in breast cancer prevention. The drug can reduce incidence of breast cancer in high-risk individuals, but side effects that mimic menopause have led to low rates of uptake. Lower-dose tamoxifen aims to reduce those side effects, but there remains some uncertainty about the minimum dose required to maintain efficacy.

The TAM-01 study, first published in 2019, demonstrated that a 5-mg dose of tamoxifen led to a reduction in recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS). At the San Antonio Breast Cancer Symposium, two studies were presented that provided insight into dose efficacy and likelihood of medication adherence in women taking baby TAM.

“We all know that women who are at increased risk for breast cancer may benefit from the use of tamoxifen to help lower their risk, although historical uptake to tamoxifen in the prevention setting has been quite low,” said Lauren Cornell, MD, during a presentation. Her team investigated the impact of patient counseling on how well they understood their risk, as well as their likelihood of adherence to the medication.

The study included 41 women, and 31 completed follow-up at 1 year. “We saw that 90% of our patients reported good or complete understanding of their breast cancer risk after the consultation, emphasizing the benefit of that consult, and 73% reported that the availability of baby tamoxifen helped in their decision to consider a preventative medication,” said Dr. Cornell during her presentation. After 1 year of follow-up, 74% said that they had initiated baby tamoxifen, and 78% of those who started taking the drug were still taking it at 1 year.

Participants who continued to take baby TAM at 1 year had a higher estimated breast cancer risk (IBIS 10-year risk, 12.7% vs 7.6%; P = .027) than those who discontinued. “We saw that uptake to baby TAM after informed discussion in patients who qualify is high, especially in those patients with high risk and intraepithelial lesions or DCIS, and adherence and tolerability at 1 year follow up is improved, compared to what we would expect with traditional dosing of tamoxifen. It’s important to note that the NCCN guidelines and the ASCO clinical practice update now include low-dose tamoxifen as an option for select women, and future randomized control trials on de-escalation of tamoxifen and high-risk patients based on their risk model assessment still need to be done. Future study should also focus on markers to identify candidates best suited for low versus standard dose of tamoxifen,” said Dr. Cornell, who is an assistant professor of medicine at Mayo Clinic Florida in Jacksonville.

At another SABCS session, Per Hall, MD, PhD, discussed findings from the previously published KARISMA-2 study, which examined efficacy of various doses of tamoxifen. A total of 1440 participants, 240 in each arm, received tamoxifen doses of 20 mg, 10 mg, 5 mg, 2.5 mg, 1 mg, or placebo. During his talk, Dr. Hall pointed out that measuring outcomes would take a very large number of participants to identify small differences in breast cancer rates. Therefore, the researchers examined breast density changes as a proxy. As a noninferiority outcome, the researchers used the proportion of women in each arm who achieved the median decrease in breast density seen at 20 mg of tamoxifen, which is 10.1%.

The women underwent mammograms at baseline and again at 6 months to determine change in breast density. Among all women in the study, the proportion of patients who had a similar breast density reduction as the 20-mg dose were very similar in the 10 mg (50.0%; P = .002), 5 mg (49.3%; P < .001), and 2.5 mg (52.5%; P < .001) groups. The 1 mg group had a proportion of 39.5% (P = .138), while the placebo group had 38.9% (P = .161). However, the results were driven by premenopausal women, where the values were 63.3%, 70.7%, 74.4%, and 69.7% in the 20-mg, 10-mg, 5-mg, and 2.5-mg groups, respectively, and 32.9% at 1 mg and 29.7% on placebo. In postmenopausal women, the values were 41.9%, 36.7%, 33.3%, and 41.9% in the 20-mg, 10-mg, 5-mg, and 2.5-mg groups, with values of 44.2% in the 1-mg group and 43.8% in the placebo group.

The median density change was 18.5% in premenopausal women and 4.0% in postmenopausal women.

“We didn’t see anything in the postmenopausal women. The decrease for those on 20 milligrams and those on placebo were exactly the same. Why this is, we still don’t know because we do know that tamoxifen in the adjuvant setting could be used for postmenopausal women. It could be that 6 months is too short of a time [to see a benefit]. We don’t know,” said Dr. Hall, who is a medical epidemiologist and biostatistician at Karolinska Institutet, Stockholm, Sweden.

Severe vasomotor side effects like hot flashes, cold flashes, and night sweats were reduced by about 50% in the lower tamoxifen doses, compared with 20 mg.

Dr. Hall also pointed out that tamoxifen is a prodrug. The CYP2D6 enzyme produces a range of metabolites, with endoxifen having the strongest affinity to the estrogen receptor and being present at the highest plasma concentration. He showed a table of endoxifen plasma levels at various tamoxifen doses in women of various metabolizer status, ranging from poor to ultrafast. Among intermediate, normal, and ultrarapid metabolizers, 5- and 10-mg doses produced plasma endoxifen levels ranging from 2.4 to 6.2 ng/mL, which represents a good therapeutic window. “For intermediate and normal metabolizers, it could be that 5 mg [of tamoxifen] is enough, but I want to underline that we didn’t use breast cancer incidence or recurrence in this study, we used density change, so we should be careful when we use these results,” said Dr. Hall. His group is now conducting the KARISMA Endoxifen trial, which will test endoxifen directly at doses of 1 and 2 mg.

Dr. Cornell has no relevant financial disclosures. Dr. Hall is a member of the scientific advisory board for Atossa Therapeutics.

SAN ANTONIO — Low-dose tamoxifen, sometimes called “baby TAM,” is gaining traction as an alternative to full-dose tamoxifen for use in breast cancer prevention. The drug can reduce incidence of breast cancer in high-risk individuals, but side effects that mimic menopause have led to low rates of uptake. Lower-dose tamoxifen aims to reduce those side effects, but there remains some uncertainty about the minimum dose required to maintain efficacy.

The TAM-01 study, first published in 2019, demonstrated that a 5-mg dose of tamoxifen led to a reduction in recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS). At the San Antonio Breast Cancer Symposium, two studies were presented that provided insight into dose efficacy and likelihood of medication adherence in women taking baby TAM.

“We all know that women who are at increased risk for breast cancer may benefit from the use of tamoxifen to help lower their risk, although historical uptake to tamoxifen in the prevention setting has been quite low,” said Lauren Cornell, MD, during a presentation. Her team investigated the impact of patient counseling on how well they understood their risk, as well as their likelihood of adherence to the medication.

The study included 41 women, and 31 completed follow-up at 1 year. “We saw that 90% of our patients reported good or complete understanding of their breast cancer risk after the consultation, emphasizing the benefit of that consult, and 73% reported that the availability of baby tamoxifen helped in their decision to consider a preventative medication,” said Dr. Cornell during her presentation. After 1 year of follow-up, 74% said that they had initiated baby tamoxifen, and 78% of those who started taking the drug were still taking it at 1 year.

Participants who continued to take baby TAM at 1 year had a higher estimated breast cancer risk (IBIS 10-year risk, 12.7% vs 7.6%; P = .027) than those who discontinued. “We saw that uptake to baby TAM after informed discussion in patients who qualify is high, especially in those patients with high risk and intraepithelial lesions or DCIS, and adherence and tolerability at 1 year follow up is improved, compared to what we would expect with traditional dosing of tamoxifen. It’s important to note that the NCCN guidelines and the ASCO clinical practice update now include low-dose tamoxifen as an option for select women, and future randomized control trials on de-escalation of tamoxifen and high-risk patients based on their risk model assessment still need to be done. Future study should also focus on markers to identify candidates best suited for low versus standard dose of tamoxifen,” said Dr. Cornell, who is an assistant professor of medicine at Mayo Clinic Florida in Jacksonville.

At another SABCS session, Per Hall, MD, PhD, discussed findings from the previously published KARISMA-2 study, which examined efficacy of various doses of tamoxifen. A total of 1440 participants, 240 in each arm, received tamoxifen doses of 20 mg, 10 mg, 5 mg, 2.5 mg, 1 mg, or placebo. During his talk, Dr. Hall pointed out that measuring outcomes would take a very large number of participants to identify small differences in breast cancer rates. Therefore, the researchers examined breast density changes as a proxy. As a noninferiority outcome, the researchers used the proportion of women in each arm who achieved the median decrease in breast density seen at 20 mg of tamoxifen, which is 10.1%.

The women underwent mammograms at baseline and again at 6 months to determine change in breast density. Among all women in the study, the proportion of patients who had a similar breast density reduction as the 20-mg dose were very similar in the 10 mg (50.0%; P = .002), 5 mg (49.3%; P < .001), and 2.5 mg (52.5%; P < .001) groups. The 1 mg group had a proportion of 39.5% (P = .138), while the placebo group had 38.9% (P = .161). However, the results were driven by premenopausal women, where the values were 63.3%, 70.7%, 74.4%, and 69.7% in the 20-mg, 10-mg, 5-mg, and 2.5-mg groups, respectively, and 32.9% at 1 mg and 29.7% on placebo. In postmenopausal women, the values were 41.9%, 36.7%, 33.3%, and 41.9% in the 20-mg, 10-mg, 5-mg, and 2.5-mg groups, with values of 44.2% in the 1-mg group and 43.8% in the placebo group.

The median density change was 18.5% in premenopausal women and 4.0% in postmenopausal women.

“We didn’t see anything in the postmenopausal women. The decrease for those on 20 milligrams and those on placebo were exactly the same. Why this is, we still don’t know because we do know that tamoxifen in the adjuvant setting could be used for postmenopausal women. It could be that 6 months is too short of a time [to see a benefit]. We don’t know,” said Dr. Hall, who is a medical epidemiologist and biostatistician at Karolinska Institutet, Stockholm, Sweden.

Severe vasomotor side effects like hot flashes, cold flashes, and night sweats were reduced by about 50% in the lower tamoxifen doses, compared with 20 mg.

Dr. Hall also pointed out that tamoxifen is a prodrug. The CYP2D6 enzyme produces a range of metabolites, with endoxifen having the strongest affinity to the estrogen receptor and being present at the highest plasma concentration. He showed a table of endoxifen plasma levels at various tamoxifen doses in women of various metabolizer status, ranging from poor to ultrafast. Among intermediate, normal, and ultrarapid metabolizers, 5- and 10-mg doses produced plasma endoxifen levels ranging from 2.4 to 6.2 ng/mL, which represents a good therapeutic window. “For intermediate and normal metabolizers, it could be that 5 mg [of tamoxifen] is enough, but I want to underline that we didn’t use breast cancer incidence or recurrence in this study, we used density change, so we should be careful when we use these results,” said Dr. Hall. His group is now conducting the KARISMA Endoxifen trial, which will test endoxifen directly at doses of 1 and 2 mg.

Dr. Cornell has no relevant financial disclosures. Dr. Hall is a member of the scientific advisory board for Atossa Therapeutics.