Premenopausal women with luminal A tumors may be able to skip chemo

SAN ANTONIO – Adjuvant chemotherapy does not improve outcomes in premenopausal women with luminal A breast cancer, suggests a prospective-retrospective study using samples from the 77B randomized trial of the Danish Breast Cancer Cooperative Group (DBCG).

Researchers led by Dr. Torsten O. Nielsen, professor of pathology at the University of British Columbia, Vancouver, performed immunohistochemical intrinsic subtyping on tissue microarrays from 709 participants in the trial, which began in 1977.

The women in the trial had high-risk features – positive axillary lymph nodes or tumors greater than 5 cm – and were treated with mastectomy, axillary node dissection, and radiation therapy, but no endocrine therapy. They were randomized to cyclophosphamide-based chemotherapy or no chemotherapy.

Results of the new study, reported in a session and press briefing at the San Antonio Breast Cancer Symposium, showed that patients with luminal A tumors did not see any improvement in 10-year invasive disease–free survival from chemotherapy versus no chemotherapy. In contrast, patients with other subtypes had a halving of the risk of events.

“Women with luminal A breast cancers derive no benefit from chemotherapy – even premenopausal, node positive, and no endocrine therapy,” Dr. Nielsen said. “You might expect that this would be a particularly difficult set of patients [in which to find a group that was] lacking benefit from chemotherapy. Nonetheless, we did find that group.”

It is unclear whether the findings are robust enough to change practice, he said. “The community has to decide if it is enough evidence. Technically, this is level 2 evidence. If you feel that there is another trial that’s very well matched and [has] similar results, you might consider it level 1 evidence.”

Press briefing moderator Dr. Virginia Kaklamani, professor of medicine, University of Texas, San Antonio, noted that the recently closed RxPONDER trial used OncoType DX to randomize low-risk women to chemotherapy versus no chemotherapy and should shed more light on this issue in the contemporary treatment era.

“But this data kind of confirms what we believe, that you probably don’t need chemotherapy for those patients. So this is another step, and for me, it gives me a little more confidence in my premenopausal women – because I was pretty confident in my postmenopausal women – but in my premenopausal women, to not push chemotherapy,” she said.

“This is clearly part of a body of evidence that’s building up and may be one of the themes of the conference here, that we can probably back off on the aggressiveness of our treatments and still achieve the same results,” Dr. Nielsen agreed, noting there have been similar trends in surgery and radiation therapy. “And this is where we want to be in cancer research. We cure a lot of women with breast cancer now.”

Still, the final decision rests with the patient and physician, he acknowledged. When asked about the likely reluctance of some premenopausal women with luminal A tumors to forgo chemotherapy, he replied, “It’s a woman’s choice, I think. Most oncologists would support that, although they would provide the evidence that you were probably being overtreated.”

In the session where the data were presented, attendee Dr. Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy asked, “Did you look at the prognostic role of amenorrhea in this specific subgroup of patients? I think you should do that in the context of the luminal A patients who received adjuvant chemotherapy.”

Dr. Nielsen agreed that this information is important. If that analysis has not already been done by DBCG, “it’s something we can do as an exploratory study,” he said.

Attendee Dr. Steven Vogl, an oncologist at Montefiore Medical Center in New York, noted that a positive trial with a negative subgroup finding, as in this case, presents a quandary for oncologists. Also, the study had relatively few patients with luminal A disease who did not get chemotherapy, and the cyclophosphamide likely did confer some benefit by inducing amenorrhea.

“So I will go home saying, ‘Small numbers, old study. I don’t know what it means,’ ” he said. “Convince me I should do something about it.”

“This is the best we can do because we are looking at old studies that are randomized,” Dr. Nielsen replied, noting that the trial’s no-chemotherapy arms were closed early because of lack of benefit. “We prespecified quite a stringent statistical test with the interaction test, which is hard to meet, and it did achieve that because there absolutely was no sign of benefit in those patients.”

The issue of whether adjuvant chemotherapy provides benefit in early breast cancer was settled back in the 1980s, he noted when introducing the study. “Since that time, it’s been unethical to randomize women in those settings to no chemotherapy. Most of the studies have been different types of chemotherapies as choices.”

In contrast, participants in the 77B trial were randomized to two adjuvant chemotherapy arms (cyclophosphamide alone or cyclophosphamide, methotrexate, and fluorouracil) and two nonchemotherapy arms (levamisole or no agent). Main findings showed that chemotherapy improved 10-year invasive disease–free survival (Cancer. 2010;116:2081-9).

According to results of the subtyping, which Dr. Nielsen and colleagues performed in a central lab, 26% of the tumors were of luminal A subtype, meaning they were estrogen receptor positive and HER2 negative, had a low proliferation index (13% or fewer cells staining for Ki67), and had high progesterone receptor expression (more than 20% of cells staining) (J Clin Oncol. 2013;31:203-9).

These patients did not derive significant benefit from chemotherapy. In contrast, patients with other subtypes (luminal B, HER2E, or triple negative) had a marked benefit (hazard ratio, 0.50; 95% CI, 0.38-0.66; P less than .001).

The heterogeneity in treatment impact between luminal A and non–luminal A subtypes was statistically significant (interaction test P = .048). Analyses also showed a similar trend for the endpoint of 25-year overall survival.

Discussing study caveats, Dr. Nielsen acknowledged that immunohistochemistry scoring can be subjective. “Currently, we are trying to get the original [tissue] blocks. Isolating RNA for gene profile analysis is another way to identify the subtypes,” he explained.

SAN ANTONIO – Adjuvant chemotherapy does not improve outcomes in premenopausal women with luminal A breast cancer, suggests a prospective-retrospective study using samples from the 77B randomized trial of the Danish Breast Cancer Cooperative Group (DBCG).

Researchers led by Dr. Torsten O. Nielsen, professor of pathology at the University of British Columbia, Vancouver, performed immunohistochemical intrinsic subtyping on tissue microarrays from 709 participants in the trial, which began in 1977.

The women in the trial had high-risk features – positive axillary lymph nodes or tumors greater than 5 cm – and were treated with mastectomy, axillary node dissection, and radiation therapy, but no endocrine therapy. They were randomized to cyclophosphamide-based chemotherapy or no chemotherapy.

Results of the new study, reported in a session and press briefing at the San Antonio Breast Cancer Symposium, showed that patients with luminal A tumors did not see any improvement in 10-year invasive disease–free survival from chemotherapy versus no chemotherapy. In contrast, patients with other subtypes had a halving of the risk of events.

“Women with luminal A breast cancers derive no benefit from chemotherapy – even premenopausal, node positive, and no endocrine therapy,” Dr. Nielsen said. “You might expect that this would be a particularly difficult set of patients [in which to find a group that was] lacking benefit from chemotherapy. Nonetheless, we did find that group.”

It is unclear whether the findings are robust enough to change practice, he said. “The community has to decide if it is enough evidence. Technically, this is level 2 evidence. If you feel that there is another trial that’s very well matched and [has] similar results, you might consider it level 1 evidence.”

Press briefing moderator Dr. Virginia Kaklamani, professor of medicine, University of Texas, San Antonio, noted that the recently closed RxPONDER trial used OncoType DX to randomize low-risk women to chemotherapy versus no chemotherapy and should shed more light on this issue in the contemporary treatment era.

“But this data kind of confirms what we believe, that you probably don’t need chemotherapy for those patients. So this is another step, and for me, it gives me a little more confidence in my premenopausal women – because I was pretty confident in my postmenopausal women – but in my premenopausal women, to not push chemotherapy,” she said.

“This is clearly part of a body of evidence that’s building up and may be one of the themes of the conference here, that we can probably back off on the aggressiveness of our treatments and still achieve the same results,” Dr. Nielsen agreed, noting there have been similar trends in surgery and radiation therapy. “And this is where we want to be in cancer research. We cure a lot of women with breast cancer now.”

Still, the final decision rests with the patient and physician, he acknowledged. When asked about the likely reluctance of some premenopausal women with luminal A tumors to forgo chemotherapy, he replied, “It’s a woman’s choice, I think. Most oncologists would support that, although they would provide the evidence that you were probably being overtreated.”

In the session where the data were presented, attendee Dr. Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy asked, “Did you look at the prognostic role of amenorrhea in this specific subgroup of patients? I think you should do that in the context of the luminal A patients who received adjuvant chemotherapy.”

Dr. Nielsen agreed that this information is important. If that analysis has not already been done by DBCG, “it’s something we can do as an exploratory study,” he said.

Attendee Dr. Steven Vogl, an oncologist at Montefiore Medical Center in New York, noted that a positive trial with a negative subgroup finding, as in this case, presents a quandary for oncologists. Also, the study had relatively few patients with luminal A disease who did not get chemotherapy, and the cyclophosphamide likely did confer some benefit by inducing amenorrhea.

“So I will go home saying, ‘Small numbers, old study. I don’t know what it means,’ ” he said. “Convince me I should do something about it.”

“This is the best we can do because we are looking at old studies that are randomized,” Dr. Nielsen replied, noting that the trial’s no-chemotherapy arms were closed early because of lack of benefit. “We prespecified quite a stringent statistical test with the interaction test, which is hard to meet, and it did achieve that because there absolutely was no sign of benefit in those patients.”

The issue of whether adjuvant chemotherapy provides benefit in early breast cancer was settled back in the 1980s, he noted when introducing the study. “Since that time, it’s been unethical to randomize women in those settings to no chemotherapy. Most of the studies have been different types of chemotherapies as choices.”

In contrast, participants in the 77B trial were randomized to two adjuvant chemotherapy arms (cyclophosphamide alone or cyclophosphamide, methotrexate, and fluorouracil) and two nonchemotherapy arms (levamisole or no agent). Main findings showed that chemotherapy improved 10-year invasive disease–free survival (Cancer. 2010;116:2081-9).

According to results of the subtyping, which Dr. Nielsen and colleagues performed in a central lab, 26% of the tumors were of luminal A subtype, meaning they were estrogen receptor positive and HER2 negative, had a low proliferation index (13% or fewer cells staining for Ki67), and had high progesterone receptor expression (more than 20% of cells staining) (J Clin Oncol. 2013;31:203-9).

These patients did not derive significant benefit from chemotherapy. In contrast, patients with other subtypes (luminal B, HER2E, or triple negative) had a marked benefit (hazard ratio, 0.50; 95% CI, 0.38-0.66; P less than .001).

The heterogeneity in treatment impact between luminal A and non–luminal A subtypes was statistically significant (interaction test P = .048). Analyses also showed a similar trend for the endpoint of 25-year overall survival.

Discussing study caveats, Dr. Nielsen acknowledged that immunohistochemistry scoring can be subjective. “Currently, we are trying to get the original [tissue] blocks. Isolating RNA for gene profile analysis is another way to identify the subtypes,” he explained.

SAN ANTONIO – Adjuvant chemotherapy does not improve outcomes in premenopausal women with luminal A breast cancer, suggests a prospective-retrospective study using samples from the 77B randomized trial of the Danish Breast Cancer Cooperative Group (DBCG).

Researchers led by Dr. Torsten O. Nielsen, professor of pathology at the University of British Columbia, Vancouver, performed immunohistochemical intrinsic subtyping on tissue microarrays from 709 participants in the trial, which began in 1977.

The women in the trial had high-risk features – positive axillary lymph nodes or tumors greater than 5 cm – and were treated with mastectomy, axillary node dissection, and radiation therapy, but no endocrine therapy. They were randomized to cyclophosphamide-based chemotherapy or no chemotherapy.

Results of the new study, reported in a session and press briefing at the San Antonio Breast Cancer Symposium, showed that patients with luminal A tumors did not see any improvement in 10-year invasive disease–free survival from chemotherapy versus no chemotherapy. In contrast, patients with other subtypes had a halving of the risk of events.

“Women with luminal A breast cancers derive no benefit from chemotherapy – even premenopausal, node positive, and no endocrine therapy,” Dr. Nielsen said. “You might expect that this would be a particularly difficult set of patients [in which to find a group that was] lacking benefit from chemotherapy. Nonetheless, we did find that group.”

It is unclear whether the findings are robust enough to change practice, he said. “The community has to decide if it is enough evidence. Technically, this is level 2 evidence. If you feel that there is another trial that’s very well matched and [has] similar results, you might consider it level 1 evidence.”

Press briefing moderator Dr. Virginia Kaklamani, professor of medicine, University of Texas, San Antonio, noted that the recently closed RxPONDER trial used OncoType DX to randomize low-risk women to chemotherapy versus no chemotherapy and should shed more light on this issue in the contemporary treatment era.

“But this data kind of confirms what we believe, that you probably don’t need chemotherapy for those patients. So this is another step, and for me, it gives me a little more confidence in my premenopausal women – because I was pretty confident in my postmenopausal women – but in my premenopausal women, to not push chemotherapy,” she said.

“This is clearly part of a body of evidence that’s building up and may be one of the themes of the conference here, that we can probably back off on the aggressiveness of our treatments and still achieve the same results,” Dr. Nielsen agreed, noting there have been similar trends in surgery and radiation therapy. “And this is where we want to be in cancer research. We cure a lot of women with breast cancer now.”

Still, the final decision rests with the patient and physician, he acknowledged. When asked about the likely reluctance of some premenopausal women with luminal A tumors to forgo chemotherapy, he replied, “It’s a woman’s choice, I think. Most oncologists would support that, although they would provide the evidence that you were probably being overtreated.”

In the session where the data were presented, attendee Dr. Angelo Di Leo, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy asked, “Did you look at the prognostic role of amenorrhea in this specific subgroup of patients? I think you should do that in the context of the luminal A patients who received adjuvant chemotherapy.”

Dr. Nielsen agreed that this information is important. If that analysis has not already been done by DBCG, “it’s something we can do as an exploratory study,” he said.

Attendee Dr. Steven Vogl, an oncologist at Montefiore Medical Center in New York, noted that a positive trial with a negative subgroup finding, as in this case, presents a quandary for oncologists. Also, the study had relatively few patients with luminal A disease who did not get chemotherapy, and the cyclophosphamide likely did confer some benefit by inducing amenorrhea.

“So I will go home saying, ‘Small numbers, old study. I don’t know what it means,’ ” he said. “Convince me I should do something about it.”

“This is the best we can do because we are looking at old studies that are randomized,” Dr. Nielsen replied, noting that the trial’s no-chemotherapy arms were closed early because of lack of benefit. “We prespecified quite a stringent statistical test with the interaction test, which is hard to meet, and it did achieve that because there absolutely was no sign of benefit in those patients.”

The issue of whether adjuvant chemotherapy provides benefit in early breast cancer was settled back in the 1980s, he noted when introducing the study. “Since that time, it’s been unethical to randomize women in those settings to no chemotherapy. Most of the studies have been different types of chemotherapies as choices.”

In contrast, participants in the 77B trial were randomized to two adjuvant chemotherapy arms (cyclophosphamide alone or cyclophosphamide, methotrexate, and fluorouracil) and two nonchemotherapy arms (levamisole or no agent). Main findings showed that chemotherapy improved 10-year invasive disease–free survival (Cancer. 2010;116:2081-9).

According to results of the subtyping, which Dr. Nielsen and colleagues performed in a central lab, 26% of the tumors were of luminal A subtype, meaning they were estrogen receptor positive and HER2 negative, had a low proliferation index (13% or fewer cells staining for Ki67), and had high progesterone receptor expression (more than 20% of cells staining) (J Clin Oncol. 2013;31:203-9).

These patients did not derive significant benefit from chemotherapy. In contrast, patients with other subtypes (luminal B, HER2E, or triple negative) had a marked benefit (hazard ratio, 0.50; 95% CI, 0.38-0.66; P less than .001).

The heterogeneity in treatment impact between luminal A and non–luminal A subtypes was statistically significant (interaction test P = .048). Analyses also showed a similar trend for the endpoint of 25-year overall survival.

Discussing study caveats, Dr. Nielsen acknowledged that immunohistochemistry scoring can be subjective. “Currently, we are trying to get the original [tissue] blocks. Isolating RNA for gene profile analysis is another way to identify the subtypes,” he explained.