Breast Cancer

CHICAGO – The mTOR inhibitor everolimus appears to be effective at overcoming trastuzumab resistance in patients with advanced HER2-positive breast cancer, based on findings from the BOLERO-3 trial.

The 572 patients studied all had locally advanced or metastatic HER2-positive breast cancer that had progressed despite trastuzumab therapy.

The main trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that when everolimus (Afinitor) was added to trastuzumab and vinorelbine, it reduced the risk of progression or death by 22% compared with placebo, a difference amounting to about a 1-month benefit.

As expected, patients receiving everolimus had higher rates of certain grade 3/4 adverse events, such as stomatitis, but the two groups did not differ with respect to quality of life. Overall survival results are not yet mature.

"This is the first phase III study showing the benefit of mTOR [mammalian target of rapamycin] pathway inhibition in HER2-positive breast cancer. Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy," commented first author Dr. Ruth O’Regan, director of translational breast cancer research at the Winship Cancer Institute of Emory University in Atlanta. "The combination of everolimus with vinorelbine and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer."

"The ongoing BOLERO-1 trial will evaluate the addition of everolimus to chemotherapy and trastuzumab in the first-line setting," she added.

Session attendee Dr. Jose Baselga, physician-in-chief of Memorial Hospital at the Memorial Sloan-Kettering Cancer Center in New York, said, "In looking at the data, the first reaction I have is that you have two groups: the ER [estrogen receptor]-positives and the ER-negatives. And I’m just wondering whether this theme of mTOR and ER, this cross-talk, is so important, that whether even in the HER2-positives, we need to address the issue of ER blockade at the same time, because if the study had been only in the ER-negatives, this would have been a massively positive trial."

"It is possible that when you inhibit mTOR, in that situation, that perhaps we do need to also inhibit ER," Dr. O’Regan agreed. "It’s a fairly large trial, and the [progression-free survival] lines cross completely in the hormone receptor–positive group. So that’s a very good question. I think maybe it’s worthwhile looking at HER2, mTOR, estrogen receptor blockade in another trial."

Dr. Steven Vogl, a medical oncologist in the Bronx, N.Y., asked whether BOLERO-1 is powered to look at ER-positive and ER-negative patients individually. "Your benefit was small and probably confined to only the ER-negative patients. It would be nice to know how big the benefit is in those patients and to have a second trial showing us that we need to give everolimus to these patients only if they are ER negative."

Dr. O’Regan said she did not know whether BOLERO-1 was adequately powered to answer that question. "I doubt it is, in reality, but I think we will get some interesting data. If we find the same thing in that study, that will be something certainly we can take forward," she said.

Dr. Alan Astrow, of the Maimonides Medical Center in Brooklyn, N.Y., who also attended the session, noted that the new data suggest that everolimus now presents a third treatment option in this patient population, in addition to pertuzumab (Perjeta) and TDM-1 (Kadcyla). "So what are your thoughts about further development of this drug now that we have other drugs available?" he asked.

"At this point, it would probably be third-line after those agents in the metastatic setting," Dr. O’Regan replied. "The question is, where do you put it in regard to lapatinib? And are we going to have to start looking at ER-negative versus ER-positive differences – would you put this combination up higher in the ER-negative, HER2-positive group? There are a lot of questions that we just don’t know the answer to right now."

Session comoderator Dr. Rebecca Alexander Dent, an oncologist with Duke-NUS in Singapore, the University of Toronto, and the Sunnybrook Odette Cancer Center in Toronto, said, "Obviously, the doses [of everolimus] that have been used in trials are somewhat different. Can you comment on what kind of impact that might make or how we should move forward with that?"

Dr. O’Regan said the 5-mg dose used was based on phase I data, whereas other trials, such as BOLERO-1, are using a 10-mg dose. "Obviously, we don’t know if we had used a higher dose if we would have had a greater progression-free survival difference, but it would definitely increase the toxicity," she said; the optimal dose may depend on whether it is given with chemotherapy.

The patients in the BOLERO-3 trial were randomized evenly to daily everolimus versus daily placebo, each added to weekly trastuzumab (Herceptin) and vinorelbine.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive, HER2-positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

A fourth of patients had previously received lapatinib (Tykerb). The large majority had received one or two prior lines of therapy for metastatic disease.

Median progression-free survival was 1.22 months longer with everolimus (7.00 vs 5.78 months; hazard ratio, 0.78; P = .0067).

The overall rate of response did not differ significantly between the everolimus and placebo groups (41% vs. 37%).

The everolimus arm had higher rates than the placebo group for grade 3/4 stomatitis (13% vs. 1%), fatigue (12% vs. 4%), and hematologic adverse events. But the groups were statistically indistinguishable with respect to the time to definitive deterioration of global health status.

The rate of death was 36% with everolimus and 41% with placebo, a nonsignificant difference, although longer follow-up is needed for definitive overall survival data.

The trial was sponsored by Novartis, the maker of Afinitor. Dr. O’Regan disclosed that she is a consultant to Novartis, and receives research funding from Genentech, the maker of Kadcyla and Perjeta, and Novartis.

CHICAGO – The mTOR inhibitor everolimus appears to be effective at overcoming trastuzumab resistance in patients with advanced HER2-positive breast cancer, based on findings from the BOLERO-3 trial.

The 572 patients studied all had locally advanced or metastatic HER2-positive breast cancer that had progressed despite trastuzumab therapy.

The main trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that when everolimus (Afinitor) was added to trastuzumab and vinorelbine, it reduced the risk of progression or death by 22% compared with placebo, a difference amounting to about a 1-month benefit.

As expected, patients receiving everolimus had higher rates of certain grade 3/4 adverse events, such as stomatitis, but the two groups did not differ with respect to quality of life. Overall survival results are not yet mature.

"This is the first phase III study showing the benefit of mTOR [mammalian target of rapamycin] pathway inhibition in HER2-positive breast cancer. Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy," commented first author Dr. Ruth O’Regan, director of translational breast cancer research at the Winship Cancer Institute of Emory University in Atlanta. "The combination of everolimus with vinorelbine and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer."

"The ongoing BOLERO-1 trial will evaluate the addition of everolimus to chemotherapy and trastuzumab in the first-line setting," she added.

Session attendee Dr. Jose Baselga, physician-in-chief of Memorial Hospital at the Memorial Sloan-Kettering Cancer Center in New York, said, "In looking at the data, the first reaction I have is that you have two groups: the ER [estrogen receptor]-positives and the ER-negatives. And I’m just wondering whether this theme of mTOR and ER, this cross-talk, is so important, that whether even in the HER2-positives, we need to address the issue of ER blockade at the same time, because if the study had been only in the ER-negatives, this would have been a massively positive trial."

"It is possible that when you inhibit mTOR, in that situation, that perhaps we do need to also inhibit ER," Dr. O’Regan agreed. "It’s a fairly large trial, and the [progression-free survival] lines cross completely in the hormone receptor–positive group. So that’s a very good question. I think maybe it’s worthwhile looking at HER2, mTOR, estrogen receptor blockade in another trial."

Dr. Steven Vogl, a medical oncologist in the Bronx, N.Y., asked whether BOLERO-1 is powered to look at ER-positive and ER-negative patients individually. "Your benefit was small and probably confined to only the ER-negative patients. It would be nice to know how big the benefit is in those patients and to have a second trial showing us that we need to give everolimus to these patients only if they are ER negative."

Dr. O’Regan said she did not know whether BOLERO-1 was adequately powered to answer that question. "I doubt it is, in reality, but I think we will get some interesting data. If we find the same thing in that study, that will be something certainly we can take forward," she said.

Dr. Alan Astrow, of the Maimonides Medical Center in Brooklyn, N.Y., who also attended the session, noted that the new data suggest that everolimus now presents a third treatment option in this patient population, in addition to pertuzumab (Perjeta) and TDM-1 (Kadcyla). "So what are your thoughts about further development of this drug now that we have other drugs available?" he asked.

"At this point, it would probably be third-line after those agents in the metastatic setting," Dr. O’Regan replied. "The question is, where do you put it in regard to lapatinib? And are we going to have to start looking at ER-negative versus ER-positive differences – would you put this combination up higher in the ER-negative, HER2-positive group? There are a lot of questions that we just don’t know the answer to right now."

Session comoderator Dr. Rebecca Alexander Dent, an oncologist with Duke-NUS in Singapore, the University of Toronto, and the Sunnybrook Odette Cancer Center in Toronto, said, "Obviously, the doses [of everolimus] that have been used in trials are somewhat different. Can you comment on what kind of impact that might make or how we should move forward with that?"

Dr. O’Regan said the 5-mg dose used was based on phase I data, whereas other trials, such as BOLERO-1, are using a 10-mg dose. "Obviously, we don’t know if we had used a higher dose if we would have had a greater progression-free survival difference, but it would definitely increase the toxicity," she said; the optimal dose may depend on whether it is given with chemotherapy.

The patients in the BOLERO-3 trial were randomized evenly to daily everolimus versus daily placebo, each added to weekly trastuzumab (Herceptin) and vinorelbine.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive, HER2-positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

A fourth of patients had previously received lapatinib (Tykerb). The large majority had received one or two prior lines of therapy for metastatic disease.

Median progression-free survival was 1.22 months longer with everolimus (7.00 vs 5.78 months; hazard ratio, 0.78; P = .0067).

The overall rate of response did not differ significantly between the everolimus and placebo groups (41% vs. 37%).

The everolimus arm had higher rates than the placebo group for grade 3/4 stomatitis (13% vs. 1%), fatigue (12% vs. 4%), and hematologic adverse events. But the groups were statistically indistinguishable with respect to the time to definitive deterioration of global health status.

The rate of death was 36% with everolimus and 41% with placebo, a nonsignificant difference, although longer follow-up is needed for definitive overall survival data.

The trial was sponsored by Novartis, the maker of Afinitor. Dr. O’Regan disclosed that she is a consultant to Novartis, and receives research funding from Genentech, the maker of Kadcyla and Perjeta, and Novartis.

CHICAGO – The mTOR inhibitor everolimus appears to be effective at overcoming trastuzumab resistance in patients with advanced HER2-positive breast cancer, based on findings from the BOLERO-3 trial.

The 572 patients studied all had locally advanced or metastatic HER2-positive breast cancer that had progressed despite trastuzumab therapy.

The main trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that when everolimus (Afinitor) was added to trastuzumab and vinorelbine, it reduced the risk of progression or death by 22% compared with placebo, a difference amounting to about a 1-month benefit.

As expected, patients receiving everolimus had higher rates of certain grade 3/4 adverse events, such as stomatitis, but the two groups did not differ with respect to quality of life. Overall survival results are not yet mature.

"This is the first phase III study showing the benefit of mTOR [mammalian target of rapamycin] pathway inhibition in HER2-positive breast cancer. Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy," commented first author Dr. Ruth O’Regan, director of translational breast cancer research at the Winship Cancer Institute of Emory University in Atlanta. "The combination of everolimus with vinorelbine and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer."

"The ongoing BOLERO-1 trial will evaluate the addition of everolimus to chemotherapy and trastuzumab in the first-line setting," she added.

Session attendee Dr. Jose Baselga, physician-in-chief of Memorial Hospital at the Memorial Sloan-Kettering Cancer Center in New York, said, "In looking at the data, the first reaction I have is that you have two groups: the ER [estrogen receptor]-positives and the ER-negatives. And I’m just wondering whether this theme of mTOR and ER, this cross-talk, is so important, that whether even in the HER2-positives, we need to address the issue of ER blockade at the same time, because if the study had been only in the ER-negatives, this would have been a massively positive trial."

"It is possible that when you inhibit mTOR, in that situation, that perhaps we do need to also inhibit ER," Dr. O’Regan agreed. "It’s a fairly large trial, and the [progression-free survival] lines cross completely in the hormone receptor–positive group. So that’s a very good question. I think maybe it’s worthwhile looking at HER2, mTOR, estrogen receptor blockade in another trial."

Dr. Steven Vogl, a medical oncologist in the Bronx, N.Y., asked whether BOLERO-1 is powered to look at ER-positive and ER-negative patients individually. "Your benefit was small and probably confined to only the ER-negative patients. It would be nice to know how big the benefit is in those patients and to have a second trial showing us that we need to give everolimus to these patients only if they are ER negative."

Dr. O’Regan said she did not know whether BOLERO-1 was adequately powered to answer that question. "I doubt it is, in reality, but I think we will get some interesting data. If we find the same thing in that study, that will be something certainly we can take forward," she said.

Dr. Alan Astrow, of the Maimonides Medical Center in Brooklyn, N.Y., who also attended the session, noted that the new data suggest that everolimus now presents a third treatment option in this patient population, in addition to pertuzumab (Perjeta) and TDM-1 (Kadcyla). "So what are your thoughts about further development of this drug now that we have other drugs available?" he asked.

"At this point, it would probably be third-line after those agents in the metastatic setting," Dr. O’Regan replied. "The question is, where do you put it in regard to lapatinib? And are we going to have to start looking at ER-negative versus ER-positive differences – would you put this combination up higher in the ER-negative, HER2-positive group? There are a lot of questions that we just don’t know the answer to right now."

Session comoderator Dr. Rebecca Alexander Dent, an oncologist with Duke-NUS in Singapore, the University of Toronto, and the Sunnybrook Odette Cancer Center in Toronto, said, "Obviously, the doses [of everolimus] that have been used in trials are somewhat different. Can you comment on what kind of impact that might make or how we should move forward with that?"

Dr. O’Regan said the 5-mg dose used was based on phase I data, whereas other trials, such as BOLERO-1, are using a 10-mg dose. "Obviously, we don’t know if we had used a higher dose if we would have had a greater progression-free survival difference, but it would definitely increase the toxicity," she said; the optimal dose may depend on whether it is given with chemotherapy.

The patients in the BOLERO-3 trial were randomized evenly to daily everolimus versus daily placebo, each added to weekly trastuzumab (Herceptin) and vinorelbine.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive, HER2-positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

A fourth of patients had previously received lapatinib (Tykerb). The large majority had received one or two prior lines of therapy for metastatic disease.

Median progression-free survival was 1.22 months longer with everolimus (7.00 vs 5.78 months; hazard ratio, 0.78; P = .0067).

The overall rate of response did not differ significantly between the everolimus and placebo groups (41% vs. 37%).

The everolimus arm had higher rates than the placebo group for grade 3/4 stomatitis (13% vs. 1%), fatigue (12% vs. 4%), and hematologic adverse events. But the groups were statistically indistinguishable with respect to the time to definitive deterioration of global health status.

The rate of death was 36% with everolimus and 41% with placebo, a nonsignificant difference, although longer follow-up is needed for definitive overall survival data.

The trial was sponsored by Novartis, the maker of Afinitor. Dr. O’Regan disclosed that she is a consultant to Novartis, and receives research funding from Genentech, the maker of Kadcyla and Perjeta, and Novartis.

CHICAGO – The multigene PAM50 assay identifies postmenopausal women with node-positive early breast cancer who have a low risk of distant metastases and may be able to skip adjuvant chemotherapy.

The 543 women studied had one to three positive nodes and low- or intermediate-grade tumors; all received adjuvant endocrine therapy but no chemotherapy in a pair of randomized trials: the ABCSG-8 (Austrian Breast Cancer Study Group 8) trial and the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial.

Results showed that three PAM50 parameters – the risk of recurrence (ROR) score, ROR risk group, and intrinsic subtype – significantly added to clinicopathologic factors in predicting the 10-year risk of metastases.

"A significant proportion of early breast cancer patients with only one positive node has a limited long-term risk of metastases, as well as at least some patients with two or three positive nodes," first author Dr. Michael Gnant commented in presenting the findings at the annual meeting of the American Society of Clinical Oncology.

In particular, among patients with only one positive node, those falling into the ROR low-risk group (41% of the one-node subset) and those having the luminal A intrinsic subtype (71% of the one-node subset) had 10-year risks of metastases that were less than 9%.

"Based on their low risk of metastases, these patients could – and I would personally add should – be spared the side effects of adjuvant chemotherapy despite having node-positive early breast cancer," maintained Dr. Gnant, who is a professor of surgery at the Medical University of Vienna, Austria.

"In the adjuvant treatment of hormone receptor–positive breast cancer, we every day face the dilemma of undertreatment versus overtreatment. Assessing an individual patient’s risk of metastasis as accurately as possible is an important goal in early breast cancer, and it directly impacts on treatment decisions," he added. "Still, risk assessment is mainly based on clinicopathological variables, of which nodal status is considered to be most important. As a consequence, most node-positive patients with hormone receptor–positive breast cancer globally still receive adjuvant chemotherapy."

In the study, the researchers assessed the added prognostic value derived from NanoString Technologies’ PAM50, a 50-gene assay designed to identify intrinsic subtypes of breast cancer. The subtypes are combined with a proliferation score and tumor size to yield the ROR score, and scores are used to classify patients into ROR-based risk groups.

The clinical usefulness of the PAM50 assay and other similar molecular assays, such as Genomic Health’s Oncotype DX and Agendia’s MammaPrint, has not been defined in node-positive patients, he noted.

The node-positive patients studied were drawn from the ABCSG-8 and ATAC trials. The former trial assigned women either to tamoxifen for 5 years or to 2 years of tamoxifen followed by 3 years of the aromatase inhibitor anastrozole (Arimidex); the latter assigned patients to 5 years of adjuvant anastrozole alone, tamoxifen alone, or the (subsequently discontinued) combination.

For each patient, the investigators analyzed tumor tissue to determine the PAM50 ROR score, ROR risk group, and intrinsic subtype. In addition, they derived the clinical treatment score, which is an overall integrated measure of clinicopathologic factors.

The median follow-up was 11 years, according to Dr. Gnant. As the ROR score increased from 0 to 100, so did the 10-year risk of metastases.

When added to the clinical treatment score alone, the ROR score significantly improved on the prediction of metastasis (chi-square for the difference in likelihood ratios, 32.45; P less than .0001).

The ROR risk groups also stratified patients well. The risk of metastases was about 30% in the high-risk group, 14% in the intermediate-risk group, and 8% in the low-risk group.

When added to the clinical treatment score, the luminal subtype significantly improved on prediction of metastasis (chi-square for the difference in likelihood ratios, 20.48; P less than .0001).

The estimated 10-year risk of metastasis was 11% in the luminal A group and 31% in the luminal B group.

In a combined analysis, the risk of metastases was less than 10% in several subsets of patients: those with one or two positive nodes in the ROR low-risk group (6.6% and 7.2% risks, respectively) and those with one positive node having the luminal A subtype (8.4% risk).

Finally, each factor – ROR score, ROR risk group, and intrinsic subtype – significantly improved on the prediction of risk above and beyond clinicopathologic factors in patients with one positive node, two positive nodes, and two or three positive nodes individually.

One session attendee asked, "Was there any opportunity to look at the interaction [of PAM50 parameters] with therapy?"

"Given the rather limited overall difference between anastrozole and tamoxifen both in the ATAC trial and in the sequencing study, ABCSG-8 – tamoxifen versus tamoxifen followed by anastrozole – I don’t think that we can reasonably comment on the interaction between these scores and treatment," Dr. Gnant replied.

Another attendee, Dr. Carlos Arteaga of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., asked, "Until we all start doing these genomic tests, can you tell us whether the Ki-67 had equal power in your study? It’s a simple test, and we are all using 14% as a cutoff for luminal A and B [intrinsic subtypes]. How did that pan out in this cohort?

"We are trying to have central review for Ki-67 and bring it into the multivariate model. Hopefully, later this year we will be able to answer that question," Dr. Gnant replied.

Dr. Gnant disclosed ties to several companies including Sanofi-Aventis, Novartis, and Roche, as well as NanoString Technologies, the maker of the PAM50 assay.

CHICAGO – The multigene PAM50 assay identifies postmenopausal women with node-positive early breast cancer who have a low risk of distant metastases and may be able to skip adjuvant chemotherapy.

The 543 women studied had one to three positive nodes and low- or intermediate-grade tumors; all received adjuvant endocrine therapy but no chemotherapy in a pair of randomized trials: the ABCSG-8 (Austrian Breast Cancer Study Group 8) trial and the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial.

Results showed that three PAM50 parameters – the risk of recurrence (ROR) score, ROR risk group, and intrinsic subtype – significantly added to clinicopathologic factors in predicting the 10-year risk of metastases.

"A significant proportion of early breast cancer patients with only one positive node has a limited long-term risk of metastases, as well as at least some patients with two or three positive nodes," first author Dr. Michael Gnant commented in presenting the findings at the annual meeting of the American Society of Clinical Oncology.

In particular, among patients with only one positive node, those falling into the ROR low-risk group (41% of the one-node subset) and those having the luminal A intrinsic subtype (71% of the one-node subset) had 10-year risks of metastases that were less than 9%.

"Based on their low risk of metastases, these patients could – and I would personally add should – be spared the side effects of adjuvant chemotherapy despite having node-positive early breast cancer," maintained Dr. Gnant, who is a professor of surgery at the Medical University of Vienna, Austria.

"In the adjuvant treatment of hormone receptor–positive breast cancer, we every day face the dilemma of undertreatment versus overtreatment. Assessing an individual patient’s risk of metastasis as accurately as possible is an important goal in early breast cancer, and it directly impacts on treatment decisions," he added. "Still, risk assessment is mainly based on clinicopathological variables, of which nodal status is considered to be most important. As a consequence, most node-positive patients with hormone receptor–positive breast cancer globally still receive adjuvant chemotherapy."

In the study, the researchers assessed the added prognostic value derived from NanoString Technologies’ PAM50, a 50-gene assay designed to identify intrinsic subtypes of breast cancer. The subtypes are combined with a proliferation score and tumor size to yield the ROR score, and scores are used to classify patients into ROR-based risk groups.

The clinical usefulness of the PAM50 assay and other similar molecular assays, such as Genomic Health’s Oncotype DX and Agendia’s MammaPrint, has not been defined in node-positive patients, he noted.

The node-positive patients studied were drawn from the ABCSG-8 and ATAC trials. The former trial assigned women either to tamoxifen for 5 years or to 2 years of tamoxifen followed by 3 years of the aromatase inhibitor anastrozole (Arimidex); the latter assigned patients to 5 years of adjuvant anastrozole alone, tamoxifen alone, or the (subsequently discontinued) combination.

For each patient, the investigators analyzed tumor tissue to determine the PAM50 ROR score, ROR risk group, and intrinsic subtype. In addition, they derived the clinical treatment score, which is an overall integrated measure of clinicopathologic factors.

The median follow-up was 11 years, according to Dr. Gnant. As the ROR score increased from 0 to 100, so did the 10-year risk of metastases.

When added to the clinical treatment score alone, the ROR score significantly improved on the prediction of metastasis (chi-square for the difference in likelihood ratios, 32.45; P less than .0001).

The ROR risk groups also stratified patients well. The risk of metastases was about 30% in the high-risk group, 14% in the intermediate-risk group, and 8% in the low-risk group.

When added to the clinical treatment score, the luminal subtype significantly improved on prediction of metastasis (chi-square for the difference in likelihood ratios, 20.48; P less than .0001).

The estimated 10-year risk of metastasis was 11% in the luminal A group and 31% in the luminal B group.

In a combined analysis, the risk of metastases was less than 10% in several subsets of patients: those with one or two positive nodes in the ROR low-risk group (6.6% and 7.2% risks, respectively) and those with one positive node having the luminal A subtype (8.4% risk).

Finally, each factor – ROR score, ROR risk group, and intrinsic subtype – significantly improved on the prediction of risk above and beyond clinicopathologic factors in patients with one positive node, two positive nodes, and two or three positive nodes individually.

One session attendee asked, "Was there any opportunity to look at the interaction [of PAM50 parameters] with therapy?"

"Given the rather limited overall difference between anastrozole and tamoxifen both in the ATAC trial and in the sequencing study, ABCSG-8 – tamoxifen versus tamoxifen followed by anastrozole – I don’t think that we can reasonably comment on the interaction between these scores and treatment," Dr. Gnant replied.

Another attendee, Dr. Carlos Arteaga of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., asked, "Until we all start doing these genomic tests, can you tell us whether the Ki-67 had equal power in your study? It’s a simple test, and we are all using 14% as a cutoff for luminal A and B [intrinsic subtypes]. How did that pan out in this cohort?

"We are trying to have central review for Ki-67 and bring it into the multivariate model. Hopefully, later this year we will be able to answer that question," Dr. Gnant replied.

Dr. Gnant disclosed ties to several companies including Sanofi-Aventis, Novartis, and Roche, as well as NanoString Technologies, the maker of the PAM50 assay.

CHICAGO – The multigene PAM50 assay identifies postmenopausal women with node-positive early breast cancer who have a low risk of distant metastases and may be able to skip adjuvant chemotherapy.

The 543 women studied had one to three positive nodes and low- or intermediate-grade tumors; all received adjuvant endocrine therapy but no chemotherapy in a pair of randomized trials: the ABCSG-8 (Austrian Breast Cancer Study Group 8) trial and the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial.

Results showed that three PAM50 parameters – the risk of recurrence (ROR) score, ROR risk group, and intrinsic subtype – significantly added to clinicopathologic factors in predicting the 10-year risk of metastases.

"A significant proportion of early breast cancer patients with only one positive node has a limited long-term risk of metastases, as well as at least some patients with two or three positive nodes," first author Dr. Michael Gnant commented in presenting the findings at the annual meeting of the American Society of Clinical Oncology.

In particular, among patients with only one positive node, those falling into the ROR low-risk group (41% of the one-node subset) and those having the luminal A intrinsic subtype (71% of the one-node subset) had 10-year risks of metastases that were less than 9%.

"Based on their low risk of metastases, these patients could – and I would personally add should – be spared the side effects of adjuvant chemotherapy despite having node-positive early breast cancer," maintained Dr. Gnant, who is a professor of surgery at the Medical University of Vienna, Austria.

"In the adjuvant treatment of hormone receptor–positive breast cancer, we every day face the dilemma of undertreatment versus overtreatment. Assessing an individual patient’s risk of metastasis as accurately as possible is an important goal in early breast cancer, and it directly impacts on treatment decisions," he added. "Still, risk assessment is mainly based on clinicopathological variables, of which nodal status is considered to be most important. As a consequence, most node-positive patients with hormone receptor–positive breast cancer globally still receive adjuvant chemotherapy."

In the study, the researchers assessed the added prognostic value derived from NanoString Technologies’ PAM50, a 50-gene assay designed to identify intrinsic subtypes of breast cancer. The subtypes are combined with a proliferation score and tumor size to yield the ROR score, and scores are used to classify patients into ROR-based risk groups.

The clinical usefulness of the PAM50 assay and other similar molecular assays, such as Genomic Health’s Oncotype DX and Agendia’s MammaPrint, has not been defined in node-positive patients, he noted.

The node-positive patients studied were drawn from the ABCSG-8 and ATAC trials. The former trial assigned women either to tamoxifen for 5 years or to 2 years of tamoxifen followed by 3 years of the aromatase inhibitor anastrozole (Arimidex); the latter assigned patients to 5 years of adjuvant anastrozole alone, tamoxifen alone, or the (subsequently discontinued) combination.

For each patient, the investigators analyzed tumor tissue to determine the PAM50 ROR score, ROR risk group, and intrinsic subtype. In addition, they derived the clinical treatment score, which is an overall integrated measure of clinicopathologic factors.

The median follow-up was 11 years, according to Dr. Gnant. As the ROR score increased from 0 to 100, so did the 10-year risk of metastases.

When added to the clinical treatment score alone, the ROR score significantly improved on the prediction of metastasis (chi-square for the difference in likelihood ratios, 32.45; P less than .0001).

The ROR risk groups also stratified patients well. The risk of metastases was about 30% in the high-risk group, 14% in the intermediate-risk group, and 8% in the low-risk group.

When added to the clinical treatment score, the luminal subtype significantly improved on prediction of metastasis (chi-square for the difference in likelihood ratios, 20.48; P less than .0001).

The estimated 10-year risk of metastasis was 11% in the luminal A group and 31% in the luminal B group.

In a combined analysis, the risk of metastases was less than 10% in several subsets of patients: those with one or two positive nodes in the ROR low-risk group (6.6% and 7.2% risks, respectively) and those with one positive node having the luminal A subtype (8.4% risk).

Finally, each factor – ROR score, ROR risk group, and intrinsic subtype – significantly improved on the prediction of risk above and beyond clinicopathologic factors in patients with one positive node, two positive nodes, and two or three positive nodes individually.

One session attendee asked, "Was there any opportunity to look at the interaction [of PAM50 parameters] with therapy?"

"Given the rather limited overall difference between anastrozole and tamoxifen both in the ATAC trial and in the sequencing study, ABCSG-8 – tamoxifen versus tamoxifen followed by anastrozole – I don’t think that we can reasonably comment on the interaction between these scores and treatment," Dr. Gnant replied.

Another attendee, Dr. Carlos Arteaga of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., asked, "Until we all start doing these genomic tests, can you tell us whether the Ki-67 had equal power in your study? It’s a simple test, and we are all using 14% as a cutoff for luminal A and B [intrinsic subtypes]. How did that pan out in this cohort?

"We are trying to have central review for Ki-67 and bring it into the multivariate model. Hopefully, later this year we will be able to answer that question," Dr. Gnant replied.

Dr. Gnant disclosed ties to several companies including Sanofi-Aventis, Novartis, and Roche, as well as NanoString Technologies, the maker of the PAM50 assay.

Tamoxifen for the prevention of breast cancer should be discussed with women aged 35 years or older who are at increased risk for the disease, according to an updated clinical practice guideline from the American Society of Clinical Oncology.

The use of raloxifene and exemestane should be discussed with postmenopausal women who are at increased risk for the disease, according to the update – the third since the guideline, entitled "Use of Pharmacologic Interventions for Breast Cancer Risk Reduction," was first published in 1999, and the first since 2009 (J. Clin. Onco. 2009;27:3235-58).

The new update includes stronger wording regarding discussion about the selective estrogen-receptor modulators tamoxifen and raloxifene, compared with the 2009 version, which stated that tamoxifen and raloxifene "may be offered" to women at increased risk.

"The committee felt that a stronger statement recommending the use of tamoxifen and raloxifene was needed given the weight of evidence from phase III randomized trials demonstrating a reduction in breast cancer risk for both tamoxifen and raloxifene," Update Committee cochair, Dr. Kala Visvanathan of Johns Hopkins Medical Institutions, Baltimore, and the other committee members reported (J. Clin. Oncol. 2013 July 8 [doi 10.1200/JCO.2013.49.3122]).

The guideline recommendations, which were published online on July 8 in the Journal of Clinical Oncology, and which are limited to pharmacologic interventions, specifically call for discussing with patients the options of:

• Oral tamoxifen treatment at a dose of 20 mg daily for 5 years to reduce the risk of estrogen receptor- (ER) positive invasive breast cancer in both pre- and postmenopausal women aged at least 35 years who are at increased risk of breast cancer or who have lobular carcinoma in situ (LCIS). Increased risk is defined as a 5-year projected absolute risk of 1.66% or greater according to the National Cancer Institute Breast Cancer Risk Assessment Tool or an equivalent measure. This "strong, evidence-based recommendation" is based on data from multiple randomized, controlled trials showing that the risk reduction benefit of this treatment continues for at least 10 years in these patients.

• Oral raloxifene treatment at a dose of 60 mg daily for 5 years to reduce the risk of ER-positive invasive breast cancer in postmenopausal women aged at least 35 years who are at increased risk or who have LCIS. This "strong, evidence-based recommendation" also is based on data from multiple randomized, controlled trials.

• Oral exemestane at a dose of 25 mg daily for 5 years as an alternative to tamoxifen or raloxifene to reduce the risk of ER-positive invasive breast cancer in postmenopausal women aged at least 35 years who are at increased risk of breast cancer or who have LCIS. This "moderate, evidence-based recommendation" is based on encouraging evidence from a single randomized, controlled trial of the aromatase inhibitor, which is approved for the treatment of breast cancer but not for breast cancer prevention.

Tamoxifen and raloxifene are not recommended for use in women with a history of deep vein thrombosis, pulmonary embolus, stroke, or transient ischemic attack, nor are they recommended during prolonged immobilization. Tamoxifen is not recommended in women who are pregnant or who may become pregnant or in women who are nursing, and it should not be used in combination with hormone therapy. Exemestane should not be used in premenopausal women, according to the guideline.

"Discussions with patient and health care providers should include both the risks and benefits of each agent under consideration," the committee said.

The guideline update is based on a systematic review of more than 700 potential randomized controlled trials and meta-analyses published between June 2007 and June 2012. Ultimately, 19 articles on six different chemoprevention agents met the selection criteria of the committee, which was convened by the ASCO Clinical Practice Guidelines Committee. Members were experts – with special expertise in breast cancer – from clinical medicine, public health, clinical research, health services, and related areas such as biostatistics and epidemiology. A patient representative also was appointed to the committee.

In addition to the changes regarding the discussion of tamoxifen and raloxifene, the updated guideline also eliminates a recommendation from the 2009 version calling for a baseline gynecologic examination before initiation of treatment and annually thereafter, and removes mention of treatment with fenretinide, which the committee determined is "no longer relevant for breast cancer chemoprevention."

The committee also addressed ongoing challenges with respect to minimizing health disparities, which the committee said "are an important consideration in reducing breast cancer risk."

"Members of racial and ethnic minorities, in general, tend to be diagnosed with cancer at more advanced stages and have worse outcomes ... Awareness of these disparities in quality of care and access to care should be considered in the context of this clinical practice guideline. Health care providers should strive to deliver the highest level of cancer care to all patients," the guideline states.

As for future directions, the committee stressed a need for addressing "the many unresolved issues related to the poor uptake of breast cancer chemoprevention agents in women who are at increased risk of breast cancer."

An estimated 2 million or more women could benefit from breast cancer chemoprevention, yet the agents recommended in this guideline are used infrequently for breast cancer risk reduction, the committee said, noting a need for the design of effective tools and approaches to educate providers and identify women at increased risk, and for efficacious interventions and greater understanding of the disparities and barriers that exist regarding use of chemoprevention strategies.

"Not every woman should use these preventive agents, but we believe women who are at increased risk for breast cancer should be given the option, because in some cases the magnitude of the risk reduction is large. For some women, these therapies can reduce the risk of breast cancer by up to 50%," Dr. Visvanathan said in a press statement.

A data supplement with tables and figures, and clinical tools and resources to help clinicians implement this guideline is available at ASCO’s website.

Dr. Visvanathan reported having no disclosures. Other Update Committee members reported serving as consultants and/or receiving honoraria or research funding from Novartis, Pfizer, Bayer, Champions Biotechnology, and/or AstraZeneca. One author also reported owning Novartis stock.

Tamoxifen for the prevention of breast cancer should be discussed with women aged 35 years or older who are at increased risk for the disease, according to an updated clinical practice guideline from the American Society of Clinical Oncology.

The use of raloxifene and exemestane should be discussed with postmenopausal women who are at increased risk for the disease, according to the update – the third since the guideline, entitled "Use of Pharmacologic Interventions for Breast Cancer Risk Reduction," was first published in 1999, and the first since 2009 (J. Clin. Onco. 2009;27:3235-58).

The new update includes stronger wording regarding discussion about the selective estrogen-receptor modulators tamoxifen and raloxifene, compared with the 2009 version, which stated that tamoxifen and raloxifene "may be offered" to women at increased risk.

"The committee felt that a stronger statement recommending the use of tamoxifen and raloxifene was needed given the weight of evidence from phase III randomized trials demonstrating a reduction in breast cancer risk for both tamoxifen and raloxifene," Update Committee cochair, Dr. Kala Visvanathan of Johns Hopkins Medical Institutions, Baltimore, and the other committee members reported (J. Clin. Oncol. 2013 July 8 [doi 10.1200/JCO.2013.49.3122]).

The guideline recommendations, which were published online on July 8 in the Journal of Clinical Oncology, and which are limited to pharmacologic interventions, specifically call for discussing with patients the options of:

• Oral tamoxifen treatment at a dose of 20 mg daily for 5 years to reduce the risk of estrogen receptor- (ER) positive invasive breast cancer in both pre- and postmenopausal women aged at least 35 years who are at increased risk of breast cancer or who have lobular carcinoma in situ (LCIS). Increased risk is defined as a 5-year projected absolute risk of 1.66% or greater according to the National Cancer Institute Breast Cancer Risk Assessment Tool or an equivalent measure. This "strong, evidence-based recommendation" is based on data from multiple randomized, controlled trials showing that the risk reduction benefit of this treatment continues for at least 10 years in these patients.

• Oral raloxifene treatment at a dose of 60 mg daily for 5 years to reduce the risk of ER-positive invasive breast cancer in postmenopausal women aged at least 35 years who are at increased risk or who have LCIS. This "strong, evidence-based recommendation" also is based on data from multiple randomized, controlled trials.

• Oral exemestane at a dose of 25 mg daily for 5 years as an alternative to tamoxifen or raloxifene to reduce the risk of ER-positive invasive breast cancer in postmenopausal women aged at least 35 years who are at increased risk of breast cancer or who have LCIS. This "moderate, evidence-based recommendation" is based on encouraging evidence from a single randomized, controlled trial of the aromatase inhibitor, which is approved for the treatment of breast cancer but not for breast cancer prevention.

Tamoxifen and raloxifene are not recommended for use in women with a history of deep vein thrombosis, pulmonary embolus, stroke, or transient ischemic attack, nor are they recommended during prolonged immobilization. Tamoxifen is not recommended in women who are pregnant or who may become pregnant or in women who are nursing, and it should not be used in combination with hormone therapy. Exemestane should not be used in premenopausal women, according to the guideline.

"Discussions with patient and health care providers should include both the risks and benefits of each agent under consideration," the committee said.

The guideline update is based on a systematic review of more than 700 potential randomized controlled trials and meta-analyses published between June 2007 and June 2012. Ultimately, 19 articles on six different chemoprevention agents met the selection criteria of the committee, which was convened by the ASCO Clinical Practice Guidelines Committee. Members were experts – with special expertise in breast cancer – from clinical medicine, public health, clinical research, health services, and related areas such as biostatistics and epidemiology. A patient representative also was appointed to the committee.

In addition to the changes regarding the discussion of tamoxifen and raloxifene, the updated guideline also eliminates a recommendation from the 2009 version calling for a baseline gynecologic examination before initiation of treatment and annually thereafter, and removes mention of treatment with fenretinide, which the committee determined is "no longer relevant for breast cancer chemoprevention."

The committee also addressed ongoing challenges with respect to minimizing health disparities, which the committee said "are an important consideration in reducing breast cancer risk."

"Members of racial and ethnic minorities, in general, tend to be diagnosed with cancer at more advanced stages and have worse outcomes ... Awareness of these disparities in quality of care and access to care should be considered in the context of this clinical practice guideline. Health care providers should strive to deliver the highest level of cancer care to all patients," the guideline states.

As for future directions, the committee stressed a need for addressing "the many unresolved issues related to the poor uptake of breast cancer chemoprevention agents in women who are at increased risk of breast cancer."

An estimated 2 million or more women could benefit from breast cancer chemoprevention, yet the agents recommended in this guideline are used infrequently for breast cancer risk reduction, the committee said, noting a need for the design of effective tools and approaches to educate providers and identify women at increased risk, and for efficacious interventions and greater understanding of the disparities and barriers that exist regarding use of chemoprevention strategies.

"Not every woman should use these preventive agents, but we believe women who are at increased risk for breast cancer should be given the option, because in some cases the magnitude of the risk reduction is large. For some women, these therapies can reduce the risk of breast cancer by up to 50%," Dr. Visvanathan said in a press statement.

A data supplement with tables and figures, and clinical tools and resources to help clinicians implement this guideline is available at ASCO’s website.

Dr. Visvanathan reported having no disclosures. Other Update Committee members reported serving as consultants and/or receiving honoraria or research funding from Novartis, Pfizer, Bayer, Champions Biotechnology, and/or AstraZeneca. One author also reported owning Novartis stock.

Tamoxifen for the prevention of breast cancer should be discussed with women aged 35 years or older who are at increased risk for the disease, according to an updated clinical practice guideline from the American Society of Clinical Oncology.

The use of raloxifene and exemestane should be discussed with postmenopausal women who are at increased risk for the disease, according to the update – the third since the guideline, entitled "Use of Pharmacologic Interventions for Breast Cancer Risk Reduction," was first published in 1999, and the first since 2009 (J. Clin. Onco. 2009;27:3235-58).

The new update includes stronger wording regarding discussion about the selective estrogen-receptor modulators tamoxifen and raloxifene, compared with the 2009 version, which stated that tamoxifen and raloxifene "may be offered" to women at increased risk.

"The committee felt that a stronger statement recommending the use of tamoxifen and raloxifene was needed given the weight of evidence from phase III randomized trials demonstrating a reduction in breast cancer risk for both tamoxifen and raloxifene," Update Committee cochair, Dr. Kala Visvanathan of Johns Hopkins Medical Institutions, Baltimore, and the other committee members reported (J. Clin. Oncol. 2013 July 8 [doi 10.1200/JCO.2013.49.3122]).

The guideline recommendations, which were published online on July 8 in the Journal of Clinical Oncology, and which are limited to pharmacologic interventions, specifically call for discussing with patients the options of:

• Oral tamoxifen treatment at a dose of 20 mg daily for 5 years to reduce the risk of estrogen receptor- (ER) positive invasive breast cancer in both pre- and postmenopausal women aged at least 35 years who are at increased risk of breast cancer or who have lobular carcinoma in situ (LCIS). Increased risk is defined as a 5-year projected absolute risk of 1.66% or greater according to the National Cancer Institute Breast Cancer Risk Assessment Tool or an equivalent measure. This "strong, evidence-based recommendation" is based on data from multiple randomized, controlled trials showing that the risk reduction benefit of this treatment continues for at least 10 years in these patients.

• Oral raloxifene treatment at a dose of 60 mg daily for 5 years to reduce the risk of ER-positive invasive breast cancer in postmenopausal women aged at least 35 years who are at increased risk or who have LCIS. This "strong, evidence-based recommendation" also is based on data from multiple randomized, controlled trials.

• Oral exemestane at a dose of 25 mg daily for 5 years as an alternative to tamoxifen or raloxifene to reduce the risk of ER-positive invasive breast cancer in postmenopausal women aged at least 35 years who are at increased risk of breast cancer or who have LCIS. This "moderate, evidence-based recommendation" is based on encouraging evidence from a single randomized, controlled trial of the aromatase inhibitor, which is approved for the treatment of breast cancer but not for breast cancer prevention.

Tamoxifen and raloxifene are not recommended for use in women with a history of deep vein thrombosis, pulmonary embolus, stroke, or transient ischemic attack, nor are they recommended during prolonged immobilization. Tamoxifen is not recommended in women who are pregnant or who may become pregnant or in women who are nursing, and it should not be used in combination with hormone therapy. Exemestane should not be used in premenopausal women, according to the guideline.

"Discussions with patient and health care providers should include both the risks and benefits of each agent under consideration," the committee said.

The guideline update is based on a systematic review of more than 700 potential randomized controlled trials and meta-analyses published between June 2007 and June 2012. Ultimately, 19 articles on six different chemoprevention agents met the selection criteria of the committee, which was convened by the ASCO Clinical Practice Guidelines Committee. Members were experts – with special expertise in breast cancer – from clinical medicine, public health, clinical research, health services, and related areas such as biostatistics and epidemiology. A patient representative also was appointed to the committee.

In addition to the changes regarding the discussion of tamoxifen and raloxifene, the updated guideline also eliminates a recommendation from the 2009 version calling for a baseline gynecologic examination before initiation of treatment and annually thereafter, and removes mention of treatment with fenretinide, which the committee determined is "no longer relevant for breast cancer chemoprevention."

The committee also addressed ongoing challenges with respect to minimizing health disparities, which the committee said "are an important consideration in reducing breast cancer risk."

"Members of racial and ethnic minorities, in general, tend to be diagnosed with cancer at more advanced stages and have worse outcomes ... Awareness of these disparities in quality of care and access to care should be considered in the context of this clinical practice guideline. Health care providers should strive to deliver the highest level of cancer care to all patients," the guideline states.

As for future directions, the committee stressed a need for addressing "the many unresolved issues related to the poor uptake of breast cancer chemoprevention agents in women who are at increased risk of breast cancer."

An estimated 2 million or more women could benefit from breast cancer chemoprevention, yet the agents recommended in this guideline are used infrequently for breast cancer risk reduction, the committee said, noting a need for the design of effective tools and approaches to educate providers and identify women at increased risk, and for efficacious interventions and greater understanding of the disparities and barriers that exist regarding use of chemoprevention strategies.

"Not every woman should use these preventive agents, but we believe women who are at increased risk for breast cancer should be given the option, because in some cases the magnitude of the risk reduction is large. For some women, these therapies can reduce the risk of breast cancer by up to 50%," Dr. Visvanathan said in a press statement.

A data supplement with tables and figures, and clinical tools and resources to help clinicians implement this guideline is available at ASCO’s website.

Dr. Visvanathan reported having no disclosures. Other Update Committee members reported serving as consultants and/or receiving honoraria or research funding from Novartis, Pfizer, Bayer, Champions Biotechnology, and/or AstraZeneca. One author also reported owning Novartis stock.

Angelina Jolie caused a social and public media storm recently when she revealed that she carries a mutation in the BRCA1 gene, thus putting her at heightened risk for developing breast cancer and ovarian cancer. She also disclosed her very personal decision to have preventative bilateral mastectomy, at the age of 37, to reduce her risk of breast cancer, which she was informed was 87%.

Jolie was courageous in sharing this personal decision and bringing the conversation of genetics and one’s health to the forefront. It did spark discussion and debate on genetic testing and how to manage the risk associated with having a BRCA mutation. When a star of Jolie’s status makes such an announcement, it provides an opportunity to help educate patients and discuss their management options. It gives them the chance to decide on a risk reduction strategy that is medically sound and their own personal choice.

My clinic did see an influx of patients calling about having BRCA testing. But what was more interesting were the calls from former patients who had tested positive for a BRCA mutation – they were concerned about the actual level of risk (87%) being quoted by the media’s medical correspondents, many of whom were physicians. They were worried about whether "they are doing enough" to manage their risk, given that they had decided on a different strategy involving high-risk breast cancer screening, which consists of an annual breast MRI, an annual mammogram, a clinical breast exam every 6 months (one with a breast specialist), and a self-exam monthly.

These patients’ reactions raise an important point: Physicians need to have an ongoing conversation about the different options for managing risk – specifically, about screening vs. prevention.

While mastectomy is certainly a medically sound option, high-risk screening is, too, if the protocol is followed. There are additional ways to reduce risk, and the conversation cannot be one-sided in favor of surgery.

Many women who choose the option of high-risk breast cancer screening will opt to take tamoxifen preventively. This can reduce breast cancer risk up to 50% and, when combined with high-risk screening, is a medically sound plan. A similar reduction in breast cancer risk is achieved with prophylactic salpingo-oophorectomy, if performed premenopausally, which is necessary to manage the ovarian cancer risk associated with the BRCA genes.

Finally, making a decision on the right risk-reduction strategy to pursue relies on having an appropriate understanding of risk – so one can understand what "reducing risk by 50%" really means. The 87% breast cancer risk that made the media reports is a very high estimate based on early studies in BRCA families. Most genetics professionals would quote lower lifetime estimates (60%-70%) and use age-adjusted data that are more recent.

For example, Dr. Sining Chen and Dr. Giovanni Parmigiani have provided a nice meta-analysis to estimate BRCA1 and BRCA2 mutation carriers’ risks of developing breast cancer or ovarian cancer, broken down by decade, all the way to age 70 years (J. Clin. Oncol. 2007;25:1329-33).

In Angelina Jolie’s case, her BRCA1-associated risk from age 40 to age 70 is approximately 49%. For comparison, the risk for a BRCA2 carrier from age 40 to age 70 is approximately 38%. Granted, the risk remains elevated (average breast cancer risk is 12% lifetime), and there is risk beyond age 70. But the data provide a more informed perspective on actual risk.

This is key to having patients understand their own risk and the timing of that risk. That understanding can help them make an informed decision regarding their strategy to manage BRCA-related cancer risks.

While Jolie’s decision is sound medically, there are sound alternatives. Choosing the right plan requires an in-depth conversation with our patients to make sure they understand their risk and devise a medically sound plan that is personalized to them.

Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill., and a clinician educator at the University of Chicago. He reported having no conflicts of interest.

Angelina Jolie caused a social and public media storm recently when she revealed that she carries a mutation in the BRCA1 gene, thus putting her at heightened risk for developing breast cancer and ovarian cancer. She also disclosed her very personal decision to have preventative bilateral mastectomy, at the age of 37, to reduce her risk of breast cancer, which she was informed was 87%.

Jolie was courageous in sharing this personal decision and bringing the conversation of genetics and one’s health to the forefront. It did spark discussion and debate on genetic testing and how to manage the risk associated with having a BRCA mutation. When a star of Jolie’s status makes such an announcement, it provides an opportunity to help educate patients and discuss their management options. It gives them the chance to decide on a risk reduction strategy that is medically sound and their own personal choice.

My clinic did see an influx of patients calling about having BRCA testing. But what was more interesting were the calls from former patients who had tested positive for a BRCA mutation – they were concerned about the actual level of risk (87%) being quoted by the media’s medical correspondents, many of whom were physicians. They were worried about whether "they are doing enough" to manage their risk, given that they had decided on a different strategy involving high-risk breast cancer screening, which consists of an annual breast MRI, an annual mammogram, a clinical breast exam every 6 months (one with a breast specialist), and a self-exam monthly.

These patients’ reactions raise an important point: Physicians need to have an ongoing conversation about the different options for managing risk – specifically, about screening vs. prevention.

While mastectomy is certainly a medically sound option, high-risk screening is, too, if the protocol is followed. There are additional ways to reduce risk, and the conversation cannot be one-sided in favor of surgery.

Many women who choose the option of high-risk breast cancer screening will opt to take tamoxifen preventively. This can reduce breast cancer risk up to 50% and, when combined with high-risk screening, is a medically sound plan. A similar reduction in breast cancer risk is achieved with prophylactic salpingo-oophorectomy, if performed premenopausally, which is necessary to manage the ovarian cancer risk associated with the BRCA genes.

Finally, making a decision on the right risk-reduction strategy to pursue relies on having an appropriate understanding of risk – so one can understand what "reducing risk by 50%" really means. The 87% breast cancer risk that made the media reports is a very high estimate based on early studies in BRCA families. Most genetics professionals would quote lower lifetime estimates (60%-70%) and use age-adjusted data that are more recent.

For example, Dr. Sining Chen and Dr. Giovanni Parmigiani have provided a nice meta-analysis to estimate BRCA1 and BRCA2 mutation carriers’ risks of developing breast cancer or ovarian cancer, broken down by decade, all the way to age 70 years (J. Clin. Oncol. 2007;25:1329-33).

In Angelina Jolie’s case, her BRCA1-associated risk from age 40 to age 70 is approximately 49%. For comparison, the risk for a BRCA2 carrier from age 40 to age 70 is approximately 38%. Granted, the risk remains elevated (average breast cancer risk is 12% lifetime), and there is risk beyond age 70. But the data provide a more informed perspective on actual risk.

This is key to having patients understand their own risk and the timing of that risk. That understanding can help them make an informed decision regarding their strategy to manage BRCA-related cancer risks.

While Jolie’s decision is sound medically, there are sound alternatives. Choosing the right plan requires an in-depth conversation with our patients to make sure they understand their risk and devise a medically sound plan that is personalized to them.

Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill., and a clinician educator at the University of Chicago. He reported having no conflicts of interest.

Angelina Jolie caused a social and public media storm recently when she revealed that she carries a mutation in the BRCA1 gene, thus putting her at heightened risk for developing breast cancer and ovarian cancer. She also disclosed her very personal decision to have preventative bilateral mastectomy, at the age of 37, to reduce her risk of breast cancer, which she was informed was 87%.

Jolie was courageous in sharing this personal decision and bringing the conversation of genetics and one’s health to the forefront. It did spark discussion and debate on genetic testing and how to manage the risk associated with having a BRCA mutation. When a star of Jolie’s status makes such an announcement, it provides an opportunity to help educate patients and discuss their management options. It gives them the chance to decide on a risk reduction strategy that is medically sound and their own personal choice.

My clinic did see an influx of patients calling about having BRCA testing. But what was more interesting were the calls from former patients who had tested positive for a BRCA mutation – they were concerned about the actual level of risk (87%) being quoted by the media’s medical correspondents, many of whom were physicians. They were worried about whether "they are doing enough" to manage their risk, given that they had decided on a different strategy involving high-risk breast cancer screening, which consists of an annual breast MRI, an annual mammogram, a clinical breast exam every 6 months (one with a breast specialist), and a self-exam monthly.

These patients’ reactions raise an important point: Physicians need to have an ongoing conversation about the different options for managing risk – specifically, about screening vs. prevention.

While mastectomy is certainly a medically sound option, high-risk screening is, too, if the protocol is followed. There are additional ways to reduce risk, and the conversation cannot be one-sided in favor of surgery.

Many women who choose the option of high-risk breast cancer screening will opt to take tamoxifen preventively. This can reduce breast cancer risk up to 50% and, when combined with high-risk screening, is a medically sound plan. A similar reduction in breast cancer risk is achieved with prophylactic salpingo-oophorectomy, if performed premenopausally, which is necessary to manage the ovarian cancer risk associated with the BRCA genes.

Finally, making a decision on the right risk-reduction strategy to pursue relies on having an appropriate understanding of risk – so one can understand what "reducing risk by 50%" really means. The 87% breast cancer risk that made the media reports is a very high estimate based on early studies in BRCA families. Most genetics professionals would quote lower lifetime estimates (60%-70%) and use age-adjusted data that are more recent.

For example, Dr. Sining Chen and Dr. Giovanni Parmigiani have provided a nice meta-analysis to estimate BRCA1 and BRCA2 mutation carriers’ risks of developing breast cancer or ovarian cancer, broken down by decade, all the way to age 70 years (J. Clin. Oncol. 2007;25:1329-33).

In Angelina Jolie’s case, her BRCA1-associated risk from age 40 to age 70 is approximately 49%. For comparison, the risk for a BRCA2 carrier from age 40 to age 70 is approximately 38%. Granted, the risk remains elevated (average breast cancer risk is 12% lifetime), and there is risk beyond age 70. But the data provide a more informed perspective on actual risk.

This is key to having patients understand their own risk and the timing of that risk. That understanding can help them make an informed decision regarding their strategy to manage BRCA-related cancer risks.

While Jolie’s decision is sound medically, there are sound alternatives. Choosing the right plan requires an in-depth conversation with our patients to make sure they understand their risk and devise a medically sound plan that is personalized to them.

Dr. Hulick is a medical geneticist at NorthShore University HealthSystem, Evanston, Ill., and a clinician educator at the University of Chicago. He reported having no conflicts of interest.

The National Cancer Institute (NCI) has defined cancer health disparities as adverse differences in incidence, prevalence, mortality, survivorship, and burden of cancer or related health conditions that exist among specific populations in the United States.¹ African Americans are more likely than members of any other racial or ethnic population to develop and die from cancer.2 African American women are more likely than are white women to die of breast cancer, although African American women have a lower incidence rate of this disease than white women.^3,4 The most conspicuous factors that contribute to the observed disparities are associated with a lack of health care coverage, low socioeconomic status, and race/ethnicity. We recently provided care to a woman who presented to the emergency room with 20-cm chest wall mass. She was found to have inoperable stage IV triple-negative breast cancer with significantly poor prognosis. We describe her presentation, diagnosis, and treatment, identify the factors that contributed to her current condition, discuss the cancer health disparities and the associated risk factors, and reiterate what physicians should know to prevent similar unfortunate and unnecessary scenarios.

*Click on the link to the left for a PDF of the full article.  

The National Cancer Institute (NCI) has defined cancer health disparities as adverse differences in incidence, prevalence, mortality, survivorship, and burden of cancer or related health conditions that exist among specific populations in the United States.¹ African Americans are more likely than members of any other racial or ethnic population to develop and die from cancer.2 African American women are more likely than are white women to die of breast cancer, although African American women have a lower incidence rate of this disease than white women.^3,4 The most conspicuous factors that contribute to the observed disparities are associated with a lack of health care coverage, low socioeconomic status, and race/ethnicity. We recently provided care to a woman who presented to the emergency room with 20-cm chest wall mass. She was found to have inoperable stage IV triple-negative breast cancer with significantly poor prognosis. We describe her presentation, diagnosis, and treatment, identify the factors that contributed to her current condition, discuss the cancer health disparities and the associated risk factors, and reiterate what physicians should know to prevent similar unfortunate and unnecessary scenarios.

*Click on the link to the left for a PDF of the full article.  

The National Cancer Institute (NCI) has defined cancer health disparities as adverse differences in incidence, prevalence, mortality, survivorship, and burden of cancer or related health conditions that exist among specific populations in the United States.¹ African Americans are more likely than members of any other racial or ethnic population to develop and die from cancer.2 African American women are more likely than are white women to die of breast cancer, although African American women have a lower incidence rate of this disease than white women.^3,4 The most conspicuous factors that contribute to the observed disparities are associated with a lack of health care coverage, low socioeconomic status, and race/ethnicity. We recently provided care to a woman who presented to the emergency room with 20-cm chest wall mass. She was found to have inoperable stage IV triple-negative breast cancer with significantly poor prognosis. We describe her presentation, diagnosis, and treatment, identify the factors that contributed to her current condition, discuss the cancer health disparities and the associated risk factors, and reiterate what physicians should know to prevent similar unfortunate and unnecessary scenarios.

*Click on the link to the left for a PDF of the full article.  

CHICAGO – Adding the mTOR inhibitor everolimus to trastuzumab and vinorelbine reduced the risk of progression by 22% in women with trastuzumab-resistant, HER2-positive breast cancer that progressed after taxane therapy.

This translated into a gain of just 1.2 months in progression-free survival compared with trastuzumab (Herceptin) and vinorelbine (Navelbine) plus placebo (7 months vs. 5.8 months; hazard ratio 0.78; P = .0067) in the phase III BOLERO-3 trial.

Interim overall survival data are not yet mature, but of the 220 deaths reported as of March 15, 2013, 36.3% were in the everolimus (Afinitor) arm and 41.1% were in the control arm, Dr. Ruth O’Regan said at the annual meeting of the American Society of Clinical Oncology. A final overall survival analysis will be conducted after 384 deaths in 2014.

The progression-free survival benefit is not as substantive as the 4.2-month PFS gain observed when 10 mg everolimus was added to exemestane (Aromasin) in the paradigm-shifting BOLERO-2 trial. Those patients had estrogen receptor–positive, HER2-negative, advanced breast cancer that failed treatment with letrozole (Femara) or anastrozole (Arimidex).

Based on those results, everolimus gained approval last year in the United States and Europe in combination with exemestane in this setting. Everolimus inhibits the mTOR (mammalian target of rapamycin) protein associated with resistance to trastuzumab, the mainstay for HER2-positive breast cancer treatment.

"Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy, and the combination of everolimus, vinorelbine, and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer," said Dr. O’Regan of Emory University, Atlanta.

She noted that the ongoing BOLERO-1 trial will further evaluate everolimus as a first-line therapy in patients with HER2-positive advanced breast cancer.

BOLERO-3 enrolled 572 women with locally advanced or metastatic HER2-positive disease who had all received prior taxane therapy and experienced trastuzumab resistance. Patients were randomly assigned to weekly trastuzumab 2 mg/kg and vinorelbine 25 mg/km² plus daily everolimus 5 mg or placebo until disease progression or intolerable toxicity. The 5 mg-dose was carried forward from phase I trials because of grade 3/4 neurotoxicity observed with 10-mg everolimus, Dr. O’Regan said.

About 75% of patients had visceral involvement, 55% had estrogen receptor–positive and/or progesterone receptor–positive breast cancer, and 27% had prior lapatinib (Tykerb) therapy. The median patient age was 55.

Patients given everolimus were less likely to stop treatment due to disease progression than were those in the control arm (68% vs. 78%), but more likely to do so due to adverse events (10% vs. 5%), although those numbers are small, she said.

The overall response rate (complete or partial responses) was similar at 41% in the everolimus arm and 37% in the control arm (P = .21). The clinical benefit rate (objective response or stable disease for at least 24 weeks) was 59.2% and 53.3%, again not significantly different (P = .09).

Adverse events were consistent with previous everolimus experience in breast cancer and did not impact quality of life, Dr. O’Regan said. The most common adverse events were neutropenia, anemia, stomatitis, pyrexia and decreased appetite.

In PFS subgroup analyses, the majority of groups favored the addition of everolimus, although women who received trastuzumab in the early stage setting derived more benefit, as did those with hormone receptor–negative disease or prior lapatinib, she said.

Invited discussant Dr. Kimberly Blackwell of Duke University, Durham, N.C., said BOLERO-3 demonstrates a role for mTOR inhibition in HER2-positive metastatic disease, and that the inclusion of women with prior lapatinib or in the fourth-line metastatic setting suggests that the patients were more treatment refractory than were those in EMILIA or BIG 03-05, two key trastuzumab-resistant clinical trials.

Questions remain, however, about the interpretation and clinical application of the BOLERO-3 results, such as whether the combination of vinorelbine and trastuzumab is an acceptable comparator or whether an overall survival benefit is needed in this patient population to use the combination clinically. Other questions include the optimal dose of everolimus and which patients need the addition of everolimus since some subgroups, notably those with estrogen receptor–positive cancer, liver involvement, and "probably most intriguingly, those patients who had never seen trastuzumab in the adjuvant setting," appeared to derive less benefit, she said.

Dr. O’Regan reported ties with the study sponsor, Novartis, and research funding from Genentech. Several coauthors reported ties with Novartis. Dr. Blackwell disclosed ties with Genentech and GlaxoSmithKline and research funding from Novartis, Roche/Genentech.

pwendling@frontlinemedcom.com

CHICAGO – Adding the mTOR inhibitor everolimus to trastuzumab and vinorelbine reduced the risk of progression by 22% in women with trastuzumab-resistant, HER2-positive breast cancer that progressed after taxane therapy.

This translated into a gain of just 1.2 months in progression-free survival compared with trastuzumab (Herceptin) and vinorelbine (Navelbine) plus placebo (7 months vs. 5.8 months; hazard ratio 0.78; P = .0067) in the phase III BOLERO-3 trial.

Interim overall survival data are not yet mature, but of the 220 deaths reported as of March 15, 2013, 36.3% were in the everolimus (Afinitor) arm and 41.1% were in the control arm, Dr. Ruth O’Regan said at the annual meeting of the American Society of Clinical Oncology. A final overall survival analysis will be conducted after 384 deaths in 2014.

The progression-free survival benefit is not as substantive as the 4.2-month PFS gain observed when 10 mg everolimus was added to exemestane (Aromasin) in the paradigm-shifting BOLERO-2 trial. Those patients had estrogen receptor–positive, HER2-negative, advanced breast cancer that failed treatment with letrozole (Femara) or anastrozole (Arimidex).

Based on those results, everolimus gained approval last year in the United States and Europe in combination with exemestane in this setting. Everolimus inhibits the mTOR (mammalian target of rapamycin) protein associated with resistance to trastuzumab, the mainstay for HER2-positive breast cancer treatment.

"Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy, and the combination of everolimus, vinorelbine, and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer," said Dr. O’Regan of Emory University, Atlanta.

She noted that the ongoing BOLERO-1 trial will further evaluate everolimus as a first-line therapy in patients with HER2-positive advanced breast cancer.

BOLERO-3 enrolled 572 women with locally advanced or metastatic HER2-positive disease who had all received prior taxane therapy and experienced trastuzumab resistance. Patients were randomly assigned to weekly trastuzumab 2 mg/kg and vinorelbine 25 mg/km² plus daily everolimus 5 mg or placebo until disease progression or intolerable toxicity. The 5 mg-dose was carried forward from phase I trials because of grade 3/4 neurotoxicity observed with 10-mg everolimus, Dr. O’Regan said.

About 75% of patients had visceral involvement, 55% had estrogen receptor–positive and/or progesterone receptor–positive breast cancer, and 27% had prior lapatinib (Tykerb) therapy. The median patient age was 55.

Patients given everolimus were less likely to stop treatment due to disease progression than were those in the control arm (68% vs. 78%), but more likely to do so due to adverse events (10% vs. 5%), although those numbers are small, she said.

The overall response rate (complete or partial responses) was similar at 41% in the everolimus arm and 37% in the control arm (P = .21). The clinical benefit rate (objective response or stable disease for at least 24 weeks) was 59.2% and 53.3%, again not significantly different (P = .09).

Adverse events were consistent with previous everolimus experience in breast cancer and did not impact quality of life, Dr. O’Regan said. The most common adverse events were neutropenia, anemia, stomatitis, pyrexia and decreased appetite.

In PFS subgroup analyses, the majority of groups favored the addition of everolimus, although women who received trastuzumab in the early stage setting derived more benefit, as did those with hormone receptor–negative disease or prior lapatinib, she said.

Invited discussant Dr. Kimberly Blackwell of Duke University, Durham, N.C., said BOLERO-3 demonstrates a role for mTOR inhibition in HER2-positive metastatic disease, and that the inclusion of women with prior lapatinib or in the fourth-line metastatic setting suggests that the patients were more treatment refractory than were those in EMILIA or BIG 03-05, two key trastuzumab-resistant clinical trials.

Questions remain, however, about the interpretation and clinical application of the BOLERO-3 results, such as whether the combination of vinorelbine and trastuzumab is an acceptable comparator or whether an overall survival benefit is needed in this patient population to use the combination clinically. Other questions include the optimal dose of everolimus and which patients need the addition of everolimus since some subgroups, notably those with estrogen receptor–positive cancer, liver involvement, and "probably most intriguingly, those patients who had never seen trastuzumab in the adjuvant setting," appeared to derive less benefit, she said.

Dr. O’Regan reported ties with the study sponsor, Novartis, and research funding from Genentech. Several coauthors reported ties with Novartis. Dr. Blackwell disclosed ties with Genentech and GlaxoSmithKline and research funding from Novartis, Roche/Genentech.

pwendling@frontlinemedcom.com

CHICAGO – Adding the mTOR inhibitor everolimus to trastuzumab and vinorelbine reduced the risk of progression by 22% in women with trastuzumab-resistant, HER2-positive breast cancer that progressed after taxane therapy.

This translated into a gain of just 1.2 months in progression-free survival compared with trastuzumab (Herceptin) and vinorelbine (Navelbine) plus placebo (7 months vs. 5.8 months; hazard ratio 0.78; P = .0067) in the phase III BOLERO-3 trial.

Interim overall survival data are not yet mature, but of the 220 deaths reported as of March 15, 2013, 36.3% were in the everolimus (Afinitor) arm and 41.1% were in the control arm, Dr. Ruth O’Regan said at the annual meeting of the American Society of Clinical Oncology. A final overall survival analysis will be conducted after 384 deaths in 2014.

The progression-free survival benefit is not as substantive as the 4.2-month PFS gain observed when 10 mg everolimus was added to exemestane (Aromasin) in the paradigm-shifting BOLERO-2 trial. Those patients had estrogen receptor–positive, HER2-negative, advanced breast cancer that failed treatment with letrozole (Femara) or anastrozole (Arimidex).

Based on those results, everolimus gained approval last year in the United States and Europe in combination with exemestane in this setting. Everolimus inhibits the mTOR (mammalian target of rapamycin) protein associated with resistance to trastuzumab, the mainstay for HER2-positive breast cancer treatment.

"Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy, and the combination of everolimus, vinorelbine, and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer," said Dr. O’Regan of Emory University, Atlanta.

She noted that the ongoing BOLERO-1 trial will further evaluate everolimus as a first-line therapy in patients with HER2-positive advanced breast cancer.

BOLERO-3 enrolled 572 women with locally advanced or metastatic HER2-positive disease who had all received prior taxane therapy and experienced trastuzumab resistance. Patients were randomly assigned to weekly trastuzumab 2 mg/kg and vinorelbine 25 mg/km² plus daily everolimus 5 mg or placebo until disease progression or intolerable toxicity. The 5 mg-dose was carried forward from phase I trials because of grade 3/4 neurotoxicity observed with 10-mg everolimus, Dr. O’Regan said.

About 75% of patients had visceral involvement, 55% had estrogen receptor–positive and/or progesterone receptor–positive breast cancer, and 27% had prior lapatinib (Tykerb) therapy. The median patient age was 55.

Patients given everolimus were less likely to stop treatment due to disease progression than were those in the control arm (68% vs. 78%), but more likely to do so due to adverse events (10% vs. 5%), although those numbers are small, she said.

The overall response rate (complete or partial responses) was similar at 41% in the everolimus arm and 37% in the control arm (P = .21). The clinical benefit rate (objective response or stable disease for at least 24 weeks) was 59.2% and 53.3%, again not significantly different (P = .09).

Adverse events were consistent with previous everolimus experience in breast cancer and did not impact quality of life, Dr. O’Regan said. The most common adverse events were neutropenia, anemia, stomatitis, pyrexia and decreased appetite.

In PFS subgroup analyses, the majority of groups favored the addition of everolimus, although women who received trastuzumab in the early stage setting derived more benefit, as did those with hormone receptor–negative disease or prior lapatinib, she said.

Invited discussant Dr. Kimberly Blackwell of Duke University, Durham, N.C., said BOLERO-3 demonstrates a role for mTOR inhibition in HER2-positive metastatic disease, and that the inclusion of women with prior lapatinib or in the fourth-line metastatic setting suggests that the patients were more treatment refractory than were those in EMILIA or BIG 03-05, two key trastuzumab-resistant clinical trials.

Questions remain, however, about the interpretation and clinical application of the BOLERO-3 results, such as whether the combination of vinorelbine and trastuzumab is an acceptable comparator or whether an overall survival benefit is needed in this patient population to use the combination clinically. Other questions include the optimal dose of everolimus and which patients need the addition of everolimus since some subgroups, notably those with estrogen receptor–positive cancer, liver involvement, and "probably most intriguingly, those patients who had never seen trastuzumab in the adjuvant setting," appeared to derive less benefit, she said.

Dr. O’Regan reported ties with the study sponsor, Novartis, and research funding from Genentech. Several coauthors reported ties with Novartis. Dr. Blackwell disclosed ties with Genentech and GlaxoSmithKline and research funding from Novartis, Roche/Genentech.

pwendling@frontlinemedcom.com

Private companies do not have the right to patent human genes, the U.S. Supreme Court has ruled.

In a unanimous decision issued on June 13, the high court ruled that a naturally occurring DNA segment is a "product of nature" and is not eligible for a patent simply because it has been isolated. But the court also ruled that synthetically created DNA known as complementary DNA (cDNA) can be granted a patent.

In Association for Molecular Pathology et al. v. Myriad Genetics, the high court considered the validity of patents held by Utah-based Myriad Genetics for the BRCA1 and BRCA2 genes, which are associated with an increased risk of breast and ovarian cancer.

Scientists at Myriad Genetics uncovered the location and sequence of the BRCA1 and BRCA2 genes in the mid-1990s. Since then, they have held the exclusive rights to the diagnostic testing for the mutations. But critics say the monopoly on testing held by Myriad is bad for patients because the test is expensive and they have no alternative confirmatory test.

"It is undisputed that Myriad did not create or alter any of the genetic information encoded in the BRCA1 and BRCA2 genes," Justice Clarence Thomas wrote in the court’s opinion. "Myriad’s principal contribution was uncovering the precise location and genetic sequence of the BRCA1 and BRCA2 genes within chromosomes 17 and 13."

The justices concluded that simply isolating genes and the information they encode from the surrounding genetic material is insufficient for a patent. However, cDNA are not naturally occurring so tests using that technology can be patented.

The American Medical Association, which filed an amicus brief in support of invalidating the Myriad patents, praised the Court’s decision.

“Removing the patents on the building blocks of life ensures that scientific discovery and medical care based on insights into human DNA will remain freely accessible and widely disseminated, not hidden behind a vast thicket of exclusive rights,” Dr. Jeremy A. Lazarus, AMA president, said in a statement.

The American Civil Liberties Union, which joined the suit against Myriad, said the decision brings down a major barrier to patient care and medical innovation. "Because of this ruling, patients will have greater access to genetic testing and scientists can engage in research on these genes without fear of being sued," Sandra Park, senior staff attorney with the ACLU Women’s Rights Project, said in a statement.

The Supreme Court’s decision comes too late to have much of a practical impact on BRCA1 and BRCA2 testing, since Myriad’s 20-year exclusivity on the patents in dispute all expire by 2015.

mschneider@frontlinemedcom.com

On Twitter @MaryEllenNY

Private companies do not have the right to patent human genes, the U.S. Supreme Court has ruled.

In a unanimous decision issued on June 13, the high court ruled that a naturally occurring DNA segment is a "product of nature" and is not eligible for a patent simply because it has been isolated. But the court also ruled that synthetically created DNA known as complementary DNA (cDNA) can be granted a patent.

In Association for Molecular Pathology et al. v. Myriad Genetics, the high court considered the validity of patents held by Utah-based Myriad Genetics for the BRCA1 and BRCA2 genes, which are associated with an increased risk of breast and ovarian cancer.

Scientists at Myriad Genetics uncovered the location and sequence of the BRCA1 and BRCA2 genes in the mid-1990s. Since then, they have held the exclusive rights to the diagnostic testing for the mutations. But critics say the monopoly on testing held by Myriad is bad for patients because the test is expensive and they have no alternative confirmatory test.

"It is undisputed that Myriad did not create or alter any of the genetic information encoded in the BRCA1 and BRCA2 genes," Justice Clarence Thomas wrote in the court’s opinion. "Myriad’s principal contribution was uncovering the precise location and genetic sequence of the BRCA1 and BRCA2 genes within chromosomes 17 and 13."

The justices concluded that simply isolating genes and the information they encode from the surrounding genetic material is insufficient for a patent. However, cDNA are not naturally occurring so tests using that technology can be patented.

The American Medical Association, which filed an amicus brief in support of invalidating the Myriad patents, praised the Court’s decision.

“Removing the patents on the building blocks of life ensures that scientific discovery and medical care based on insights into human DNA will remain freely accessible and widely disseminated, not hidden behind a vast thicket of exclusive rights,” Dr. Jeremy A. Lazarus, AMA president, said in a statement.

The American Civil Liberties Union, which joined the suit against Myriad, said the decision brings down a major barrier to patient care and medical innovation. "Because of this ruling, patients will have greater access to genetic testing and scientists can engage in research on these genes without fear of being sued," Sandra Park, senior staff attorney with the ACLU Women’s Rights Project, said in a statement.

The Supreme Court’s decision comes too late to have much of a practical impact on BRCA1 and BRCA2 testing, since Myriad’s 20-year exclusivity on the patents in dispute all expire by 2015.

mschneider@frontlinemedcom.com

On Twitter @MaryEllenNY

Private companies do not have the right to patent human genes, the U.S. Supreme Court has ruled.

In a unanimous decision issued on June 13, the high court ruled that a naturally occurring DNA segment is a "product of nature" and is not eligible for a patent simply because it has been isolated. But the court also ruled that synthetically created DNA known as complementary DNA (cDNA) can be granted a patent.

In Association for Molecular Pathology et al. v. Myriad Genetics, the high court considered the validity of patents held by Utah-based Myriad Genetics for the BRCA1 and BRCA2 genes, which are associated with an increased risk of breast and ovarian cancer.

Scientists at Myriad Genetics uncovered the location and sequence of the BRCA1 and BRCA2 genes in the mid-1990s. Since then, they have held the exclusive rights to the diagnostic testing for the mutations. But critics say the monopoly on testing held by Myriad is bad for patients because the test is expensive and they have no alternative confirmatory test.

"It is undisputed that Myriad did not create or alter any of the genetic information encoded in the BRCA1 and BRCA2 genes," Justice Clarence Thomas wrote in the court’s opinion. "Myriad’s principal contribution was uncovering the precise location and genetic sequence of the BRCA1 and BRCA2 genes within chromosomes 17 and 13."

The justices concluded that simply isolating genes and the information they encode from the surrounding genetic material is insufficient for a patent. However, cDNA are not naturally occurring so tests using that technology can be patented.

The American Medical Association, which filed an amicus brief in support of invalidating the Myriad patents, praised the Court’s decision.

“Removing the patents on the building blocks of life ensures that scientific discovery and medical care based on insights into human DNA will remain freely accessible and widely disseminated, not hidden behind a vast thicket of exclusive rights,” Dr. Jeremy A. Lazarus, AMA president, said in a statement.

The American Civil Liberties Union, which joined the suit against Myriad, said the decision brings down a major barrier to patient care and medical innovation. "Because of this ruling, patients will have greater access to genetic testing and scientists can engage in research on these genes without fear of being sued," Sandra Park, senior staff attorney with the ACLU Women’s Rights Project, said in a statement.

The Supreme Court’s decision comes too late to have much of a practical impact on BRCA1 and BRCA2 testing, since Myriad’s 20-year exclusivity on the patents in dispute all expire by 2015.

mschneider@frontlinemedcom.com

On Twitter @MaryEllenNY

In an interview at the ASCO 2013 meeting, ASCO's chief medical officer, Dr. Richard Schilsky, discusses the negative impact federal spending cuts are having on physicians' care of cancer patients.

In an interview at the ASCO 2013 meeting, ASCO's chief medical officer, Dr. Richard Schilsky, discusses the negative impact federal spending cuts are having on physicians' care of cancer patients.

In an interview at the ASCO 2013 meeting, ASCO's chief medical officer, Dr. Richard Schilsky, discusses the negative impact federal spending cuts are having on physicians' care of cancer patients.