Breast Cancer

SAN ANTONIO – Increasing the dose intensity of adjuvant chemotherapy reduced risks of breast cancer recurrence and death by about 15% in an Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis of individual patient data from 25 randomized trials among 34,122 women. Lead author Richard Gray, MSc, professor of medical statistics in the Nuffield Department of Population Health at University of Oxford, England, discussed the findings for various dose-intensification approaches and likely impact on clinical practice in an interview at the San Antonio Breast Cancer Symposium.

[email protected]

SAN ANTONIO – Increasing the dose intensity of adjuvant chemotherapy reduced risks of breast cancer recurrence and death by about 15% in an Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis of individual patient data from 25 randomized trials among 34,122 women. Lead author Richard Gray, MSc, professor of medical statistics in the Nuffield Department of Population Health at University of Oxford, England, discussed the findings for various dose-intensification approaches and likely impact on clinical practice in an interview at the San Antonio Breast Cancer Symposium.

[email protected]

SAN ANTONIO – Increasing the dose intensity of adjuvant chemotherapy reduced risks of breast cancer recurrence and death by about 15% in an Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis of individual patient data from 25 randomized trials among 34,122 women. Lead author Richard Gray, MSc, professor of medical statistics in the Nuffield Department of Population Health at University of Oxford, England, discussed the findings for various dose-intensification approaches and likely impact on clinical practice in an interview at the San Antonio Breast Cancer Symposium.

[email protected]

SAN ANTONIO – Half of premenopausal breast cancer patients who had completed chemotherapy conceived by intercourse alone within 3 months of beginning to attempt conception, a study showed.

This single-center study provides some guidance for women and the physicians caring for them that an attempt at natural conception is worthwhile if ovarian function has returned after chemotherapy, said Nikita Sinha.

Speaking at the annual meeting of the American Society for Reproductive Medicine, Ms. Sinha, a medical student at the University of California, San Francisco, said that this is a worthwhile strategy, “even for patients with limited ovarian reserve, prior to using cryopreserved tissue.” Cytotoxicity of chemotherapy was not associated with decreased chances for conception, she said.

Ms. Sinha and her colleagues designed a prospective cohort study to follow women aged 18-44 years who had been diagnosed with breast cancer and had received a fertility preservation consult. A total of 297 women who had completed cancer treatment were contacted and asked to complete a survey that asked questions about their oncologic and reproductive history. Of these, 200 (67%) completed the survey, but 43 more patients were excluded because they had not received chemotherapy.

Of the remaining 157 women, 40 (25%) attempted to conceive. Return of ovarian function occurred in 36 of the 40 women (90%). Of these 36 women, 4 also began their attempts to conceive with assisted reproductive technology (ART) because of age, previous history of infertility, or a preimplantation genetic diagnosis of the BRCA mutation. Thus, a total of eight patients (20%) first attempted to conceive with ART.

Three-fourths of women in both groups had eggs or embryos cryopreserved before their chemotherapy. In the ART group, a total of five women (62.5%) became pregnant: One first attempted intrauterine insemination and became pregnant; two first attempted pregnancy by egg donation, and one became pregnant; and three of five women who attempted embryo transfer from cryopreserved eggs or embryos became pregnant.

Of the 32 women who first attempted to conceive by intercourse, 18 became pregnant after 3 months, and 16 women had a live birth, for a 50% live birth rate for this group. Of the remaining 14 women who did not become pregnant by intercourse, 8 went on to attempt conception by ART.

Of these eight women, intrauterine insemination was attempted by three, with two resulting pregnancies. The single patient who used letrozole became pregnant. Of the four patients who attempted frozen embryo transfer, two became pregnant, for a total of five pregnancies (62.5%).

Comparing the 18 women who became pregnant with the 14 women who did not, Ms. Sinha and her colleagues found no significant differences in age, parity, hormone receptor status, pre- or postchemotherapy antral follicle count, type of chemotherapy, or time since chemotherapy. Receiving leuprolide acetate during therapy was not a significant factor.

Of the patients who became pregnant, 2 of 28 (7%) have had a recurrence of their breast cancer; both of these patients are estrogen receptor positive, said Ms. Sinha. One of the 12 patients who didn’t become pregnant also has had a recurrence; she is estrogen receptor negative.

In this study, the winnowing process of patient selection resulted in a limited sample size, with the potential for selection bias, said Ms. Sinha. Data collection is ongoing for breast cancer patients who receive fertility preservation consultations at her facility, she said.

The women trying to conceive were, on average, 37 years old at their initial attempt at conception, and had completed chemotherapy about 4 years ago. Most patients received cytotoxic chemotherapy, and 25 (63%) had estrogen receptor–positive cancer.

Previous work had shown that up to 80% of women of reproductive age will have some ovarian function resume after treatment with gonadotoxic chemotherapy agents, said Ms. Sinha.

However, the fertility risk for cancer survivors is twofold, said Ms. Sinha. “While acute ovarian failure is a well-known risk, there remains an increased risk of early menopause despite resumption of menses, especially in younger aged women” who are cancer survivors, she said.

Ms. Sinha reported that her work was supported by the University of California, San Francisco Clinical and Translational Science Institute.

[email protected]

On Twitter @karioakes

SAN ANTONIO – Half of premenopausal breast cancer patients who had completed chemotherapy conceived by intercourse alone within 3 months of beginning to attempt conception, a study showed.

This single-center study provides some guidance for women and the physicians caring for them that an attempt at natural conception is worthwhile if ovarian function has returned after chemotherapy, said Nikita Sinha.

Speaking at the annual meeting of the American Society for Reproductive Medicine, Ms. Sinha, a medical student at the University of California, San Francisco, said that this is a worthwhile strategy, “even for patients with limited ovarian reserve, prior to using cryopreserved tissue.” Cytotoxicity of chemotherapy was not associated with decreased chances for conception, she said.

Ms. Sinha and her colleagues designed a prospective cohort study to follow women aged 18-44 years who had been diagnosed with breast cancer and had received a fertility preservation consult. A total of 297 women who had completed cancer treatment were contacted and asked to complete a survey that asked questions about their oncologic and reproductive history. Of these, 200 (67%) completed the survey, but 43 more patients were excluded because they had not received chemotherapy.

Of the remaining 157 women, 40 (25%) attempted to conceive. Return of ovarian function occurred in 36 of the 40 women (90%). Of these 36 women, 4 also began their attempts to conceive with assisted reproductive technology (ART) because of age, previous history of infertility, or a preimplantation genetic diagnosis of the BRCA mutation. Thus, a total of eight patients (20%) first attempted to conceive with ART.

Three-fourths of women in both groups had eggs or embryos cryopreserved before their chemotherapy. In the ART group, a total of five women (62.5%) became pregnant: One first attempted intrauterine insemination and became pregnant; two first attempted pregnancy by egg donation, and one became pregnant; and three of five women who attempted embryo transfer from cryopreserved eggs or embryos became pregnant.

Of the 32 women who first attempted to conceive by intercourse, 18 became pregnant after 3 months, and 16 women had a live birth, for a 50% live birth rate for this group. Of the remaining 14 women who did not become pregnant by intercourse, 8 went on to attempt conception by ART.

Of these eight women, intrauterine insemination was attempted by three, with two resulting pregnancies. The single patient who used letrozole became pregnant. Of the four patients who attempted frozen embryo transfer, two became pregnant, for a total of five pregnancies (62.5%).

Comparing the 18 women who became pregnant with the 14 women who did not, Ms. Sinha and her colleagues found no significant differences in age, parity, hormone receptor status, pre- or postchemotherapy antral follicle count, type of chemotherapy, or time since chemotherapy. Receiving leuprolide acetate during therapy was not a significant factor.

Of the patients who became pregnant, 2 of 28 (7%) have had a recurrence of their breast cancer; both of these patients are estrogen receptor positive, said Ms. Sinha. One of the 12 patients who didn’t become pregnant also has had a recurrence; she is estrogen receptor negative.

In this study, the winnowing process of patient selection resulted in a limited sample size, with the potential for selection bias, said Ms. Sinha. Data collection is ongoing for breast cancer patients who receive fertility preservation consultations at her facility, she said.

The women trying to conceive were, on average, 37 years old at their initial attempt at conception, and had completed chemotherapy about 4 years ago. Most patients received cytotoxic chemotherapy, and 25 (63%) had estrogen receptor–positive cancer.

Previous work had shown that up to 80% of women of reproductive age will have some ovarian function resume after treatment with gonadotoxic chemotherapy agents, said Ms. Sinha.

However, the fertility risk for cancer survivors is twofold, said Ms. Sinha. “While acute ovarian failure is a well-known risk, there remains an increased risk of early menopause despite resumption of menses, especially in younger aged women” who are cancer survivors, she said.

Ms. Sinha reported that her work was supported by the University of California, San Francisco Clinical and Translational Science Institute.

[email protected]

On Twitter @karioakes

SAN ANTONIO – Half of premenopausal breast cancer patients who had completed chemotherapy conceived by intercourse alone within 3 months of beginning to attempt conception, a study showed.

This single-center study provides some guidance for women and the physicians caring for them that an attempt at natural conception is worthwhile if ovarian function has returned after chemotherapy, said Nikita Sinha.

Speaking at the annual meeting of the American Society for Reproductive Medicine, Ms. Sinha, a medical student at the University of California, San Francisco, said that this is a worthwhile strategy, “even for patients with limited ovarian reserve, prior to using cryopreserved tissue.” Cytotoxicity of chemotherapy was not associated with decreased chances for conception, she said.

Ms. Sinha and her colleagues designed a prospective cohort study to follow women aged 18-44 years who had been diagnosed with breast cancer and had received a fertility preservation consult. A total of 297 women who had completed cancer treatment were contacted and asked to complete a survey that asked questions about their oncologic and reproductive history. Of these, 200 (67%) completed the survey, but 43 more patients were excluded because they had not received chemotherapy.

Of the remaining 157 women, 40 (25%) attempted to conceive. Return of ovarian function occurred in 36 of the 40 women (90%). Of these 36 women, 4 also began their attempts to conceive with assisted reproductive technology (ART) because of age, previous history of infertility, or a preimplantation genetic diagnosis of the BRCA mutation. Thus, a total of eight patients (20%) first attempted to conceive with ART.

Three-fourths of women in both groups had eggs or embryos cryopreserved before their chemotherapy. In the ART group, a total of five women (62.5%) became pregnant: One first attempted intrauterine insemination and became pregnant; two first attempted pregnancy by egg donation, and one became pregnant; and three of five women who attempted embryo transfer from cryopreserved eggs or embryos became pregnant.

Of the 32 women who first attempted to conceive by intercourse, 18 became pregnant after 3 months, and 16 women had a live birth, for a 50% live birth rate for this group. Of the remaining 14 women who did not become pregnant by intercourse, 8 went on to attempt conception by ART.

Of these eight women, intrauterine insemination was attempted by three, with two resulting pregnancies. The single patient who used letrozole became pregnant. Of the four patients who attempted frozen embryo transfer, two became pregnant, for a total of five pregnancies (62.5%).

Comparing the 18 women who became pregnant with the 14 women who did not, Ms. Sinha and her colleagues found no significant differences in age, parity, hormone receptor status, pre- or postchemotherapy antral follicle count, type of chemotherapy, or time since chemotherapy. Receiving leuprolide acetate during therapy was not a significant factor.

Of the patients who became pregnant, 2 of 28 (7%) have had a recurrence of their breast cancer; both of these patients are estrogen receptor positive, said Ms. Sinha. One of the 12 patients who didn’t become pregnant also has had a recurrence; she is estrogen receptor negative.

In this study, the winnowing process of patient selection resulted in a limited sample size, with the potential for selection bias, said Ms. Sinha. Data collection is ongoing for breast cancer patients who receive fertility preservation consultations at her facility, she said.

The women trying to conceive were, on average, 37 years old at their initial attempt at conception, and had completed chemotherapy about 4 years ago. Most patients received cytotoxic chemotherapy, and 25 (63%) had estrogen receptor–positive cancer.

Previous work had shown that up to 80% of women of reproductive age will have some ovarian function resume after treatment with gonadotoxic chemotherapy agents, said Ms. Sinha.

However, the fertility risk for cancer survivors is twofold, said Ms. Sinha. “While acute ovarian failure is a well-known risk, there remains an increased risk of early menopause despite resumption of menses, especially in younger aged women” who are cancer survivors, she said.

Ms. Sinha reported that her work was supported by the University of California, San Francisco Clinical and Translational Science Institute.

[email protected]

On Twitter @karioakes

SAN ANTONIO – Adding trastuzumab to the standard regimen for patients with early-stage breast cancer and low levels of HER2 does not improve outcomes, according to new findings presented at the San Antonio Breast Cancer Symposium.

In a randomized trial of more than 3,000 patients, the 5-year invasive disease–free survival (IDFS) was 89.6% for those who received trastuzumab, compared with 89.2% for those who did not (hazard ratio, 0.98 95% confidence interval, 0.77-1.26, P = .90). Even after stratification for HER2 IHC level, extent of lymph node involvement, or hormone receptor status, the findings remained similar.

Patients in both arms did well, explained lead study author Louis Fehrenbacher, MD, medical director of Kaiser Permanente Oncology Clinical Trials and an oncologist with the Kaiser Permanente Vallejo (Calif.) Medical Center. “But the primary endpoint of IDFS was not met and none of the secondary endpoints were met. No trends of efficacy were seen.”

Current guidelines classify a breast cancer as HER2 positive if immunohistochemistry testing shows high levels of HER2 protein, defined as IHC 3+, or increased copies of the HER2 gene in situ hybridization. Adding 1 year of treatment with trastuzumab to standard adjuvant chemotherapy has been found to significantly reduce cancer recurrence and to improve survival for patients with early-stage HER2-positive breast cancer.

However, data from some of the early trastuzumab clinical trials suggested that patients with HER2-low breast cancer may benefit from the HER2-targeted treatment as well.

In 2005, the “stunning” results from the NSABP B-31 trial, of trastuzumab used in HER2+ breast cancer, were presented at the annual meeting of the American Society of Clinical Oncology. The study criteria included having a FISH+ test greater than 2.0 or IHC 3+, and testing was initially performed at a local laboratory site. When testing was conducted by the NSABP, submitted tissue samples showed that 9.7% of patients were not HER2 IHC 3+ or FISH+ greater than 2.0.

There were 174 patients defined as HER2 low, and not HER2 +.

“When the analysis was performed looking at the benefit of using trastuzumab in these patients considered low, it was found that the result was essentially identical, the benefit was equal, and statistically there was no interaction between FISH testing of IHC testing,” said Dr. Fehrenbacher. “These results were bewildering as the hypothesis was that only the HER2 amplified patients would benefit.

Because of these results, the NCI [National Cancer Institute] and the NSABP [National Surgical Adjuvant Breast and Bowel Project] initiated another trial, the N9831, which also found the same benefit in patients who were HER2 low.

About 15% of breast cancers are HER2 positive and another 45% have low levels of HER2, but these patients are not currently treated with adjuvant trastuzumab. Therefore, the current study, the NSABP-B-47, was designed and conducted to see if these early results could be validated in a large, prospective, randomized trial.

The study included 3,270 patients with early-stage breast cancer that was either IHC 1+, IHC 2+, and/or ISH negative in the trial. The patients were randomized 1:1 to standard adjuvant chemotherapy with or without a year of trastuzumab.

The standard regimen consisted of either one of the two chemotherapy regimens, per physician choice: The non-anthracycline regimen is TC (docetaxel 75 mg/m², cyclophosphamide 600 mg/m²) administered intravenously every 3 weeks for six cycles; the anthracycline regimen is AC followed by weekly paclitaxel (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² administered intravenously either every 3 weeks or every 2 weeks. The same regimen applied to the group that received additional trastuzumab.

The primary endpoint was to determine whether the addition of trastuzumab to chemotherapy improved invasive disease-free survival.

At a median follow-up of 46.1 months, 264 patients had IDFS events. The 5-year estimates for recurrence-free interval, distant recurrence–free interval, and overall survival were not statistically different for patients receiving trastuzumab compared with those not receiving trastuzumab.

There was no difference in outcomes for IHC 1+ (HR for IDFS 0.88, 95% CI, 0.63-1.22) or IHC 2+ (HR for IDFS 1.14 95% CI, 0.79-1.65).

“The retrospective outcome difference between local tested HER2 + and center tested HER2-low patients identified in two major adjuvant trials are not readily explained,” said Dr. Fehrenbacher. “There is no benefit with trastuzumab therapy in patients with a FISH ratio of less than 2 and IHC staining intensity of 1+ or 2+.

SOURCE: Fehrenbacher et al. GS1-02

SAN ANTONIO – Adding trastuzumab to the standard regimen for patients with early-stage breast cancer and low levels of HER2 does not improve outcomes, according to new findings presented at the San Antonio Breast Cancer Symposium.

In a randomized trial of more than 3,000 patients, the 5-year invasive disease–free survival (IDFS) was 89.6% for those who received trastuzumab, compared with 89.2% for those who did not (hazard ratio, 0.98 95% confidence interval, 0.77-1.26, P = .90). Even after stratification for HER2 IHC level, extent of lymph node involvement, or hormone receptor status, the findings remained similar.

Patients in both arms did well, explained lead study author Louis Fehrenbacher, MD, medical director of Kaiser Permanente Oncology Clinical Trials and an oncologist with the Kaiser Permanente Vallejo (Calif.) Medical Center. “But the primary endpoint of IDFS was not met and none of the secondary endpoints were met. No trends of efficacy were seen.”

Current guidelines classify a breast cancer as HER2 positive if immunohistochemistry testing shows high levels of HER2 protein, defined as IHC 3+, or increased copies of the HER2 gene in situ hybridization. Adding 1 year of treatment with trastuzumab to standard adjuvant chemotherapy has been found to significantly reduce cancer recurrence and to improve survival for patients with early-stage HER2-positive breast cancer.

However, data from some of the early trastuzumab clinical trials suggested that patients with HER2-low breast cancer may benefit from the HER2-targeted treatment as well.

In 2005, the “stunning” results from the NSABP B-31 trial, of trastuzumab used in HER2+ breast cancer, were presented at the annual meeting of the American Society of Clinical Oncology. The study criteria included having a FISH+ test greater than 2.0 or IHC 3+, and testing was initially performed at a local laboratory site. When testing was conducted by the NSABP, submitted tissue samples showed that 9.7% of patients were not HER2 IHC 3+ or FISH+ greater than 2.0.

There were 174 patients defined as HER2 low, and not HER2 +.

“When the analysis was performed looking at the benefit of using trastuzumab in these patients considered low, it was found that the result was essentially identical, the benefit was equal, and statistically there was no interaction between FISH testing of IHC testing,” said Dr. Fehrenbacher. “These results were bewildering as the hypothesis was that only the HER2 amplified patients would benefit.

Because of these results, the NCI [National Cancer Institute] and the NSABP [National Surgical Adjuvant Breast and Bowel Project] initiated another trial, the N9831, which also found the same benefit in patients who were HER2 low.

About 15% of breast cancers are HER2 positive and another 45% have low levels of HER2, but these patients are not currently treated with adjuvant trastuzumab. Therefore, the current study, the NSABP-B-47, was designed and conducted to see if these early results could be validated in a large, prospective, randomized trial.

The study included 3,270 patients with early-stage breast cancer that was either IHC 1+, IHC 2+, and/or ISH negative in the trial. The patients were randomized 1:1 to standard adjuvant chemotherapy with or without a year of trastuzumab.

The standard regimen consisted of either one of the two chemotherapy regimens, per physician choice: The non-anthracycline regimen is TC (docetaxel 75 mg/m², cyclophosphamide 600 mg/m²) administered intravenously every 3 weeks for six cycles; the anthracycline regimen is AC followed by weekly paclitaxel (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² administered intravenously either every 3 weeks or every 2 weeks. The same regimen applied to the group that received additional trastuzumab.

The primary endpoint was to determine whether the addition of trastuzumab to chemotherapy improved invasive disease-free survival.

At a median follow-up of 46.1 months, 264 patients had IDFS events. The 5-year estimates for recurrence-free interval, distant recurrence–free interval, and overall survival were not statistically different for patients receiving trastuzumab compared with those not receiving trastuzumab.

There was no difference in outcomes for IHC 1+ (HR for IDFS 0.88, 95% CI, 0.63-1.22) or IHC 2+ (HR for IDFS 1.14 95% CI, 0.79-1.65).

“The retrospective outcome difference between local tested HER2 + and center tested HER2-low patients identified in two major adjuvant trials are not readily explained,” said Dr. Fehrenbacher. “There is no benefit with trastuzumab therapy in patients with a FISH ratio of less than 2 and IHC staining intensity of 1+ or 2+.

SOURCE: Fehrenbacher et al. GS1-02

SAN ANTONIO – Adding trastuzumab to the standard regimen for patients with early-stage breast cancer and low levels of HER2 does not improve outcomes, according to new findings presented at the San Antonio Breast Cancer Symposium.

In a randomized trial of more than 3,000 patients, the 5-year invasive disease–free survival (IDFS) was 89.6% for those who received trastuzumab, compared with 89.2% for those who did not (hazard ratio, 0.98 95% confidence interval, 0.77-1.26, P = .90). Even after stratification for HER2 IHC level, extent of lymph node involvement, or hormone receptor status, the findings remained similar.

Patients in both arms did well, explained lead study author Louis Fehrenbacher, MD, medical director of Kaiser Permanente Oncology Clinical Trials and an oncologist with the Kaiser Permanente Vallejo (Calif.) Medical Center. “But the primary endpoint of IDFS was not met and none of the secondary endpoints were met. No trends of efficacy were seen.”

Current guidelines classify a breast cancer as HER2 positive if immunohistochemistry testing shows high levels of HER2 protein, defined as IHC 3+, or increased copies of the HER2 gene in situ hybridization. Adding 1 year of treatment with trastuzumab to standard adjuvant chemotherapy has been found to significantly reduce cancer recurrence and to improve survival for patients with early-stage HER2-positive breast cancer.

However, data from some of the early trastuzumab clinical trials suggested that patients with HER2-low breast cancer may benefit from the HER2-targeted treatment as well.

In 2005, the “stunning” results from the NSABP B-31 trial, of trastuzumab used in HER2+ breast cancer, were presented at the annual meeting of the American Society of Clinical Oncology. The study criteria included having a FISH+ test greater than 2.0 or IHC 3+, and testing was initially performed at a local laboratory site. When testing was conducted by the NSABP, submitted tissue samples showed that 9.7% of patients were not HER2 IHC 3+ or FISH+ greater than 2.0.

There were 174 patients defined as HER2 low, and not HER2 +.

“When the analysis was performed looking at the benefit of using trastuzumab in these patients considered low, it was found that the result was essentially identical, the benefit was equal, and statistically there was no interaction between FISH testing of IHC testing,” said Dr. Fehrenbacher. “These results were bewildering as the hypothesis was that only the HER2 amplified patients would benefit.

Because of these results, the NCI [National Cancer Institute] and the NSABP [National Surgical Adjuvant Breast and Bowel Project] initiated another trial, the N9831, which also found the same benefit in patients who were HER2 low.

About 15% of breast cancers are HER2 positive and another 45% have low levels of HER2, but these patients are not currently treated with adjuvant trastuzumab. Therefore, the current study, the NSABP-B-47, was designed and conducted to see if these early results could be validated in a large, prospective, randomized trial.

The study included 3,270 patients with early-stage breast cancer that was either IHC 1+, IHC 2+, and/or ISH negative in the trial. The patients were randomized 1:1 to standard adjuvant chemotherapy with or without a year of trastuzumab.

The standard regimen consisted of either one of the two chemotherapy regimens, per physician choice: The non-anthracycline regimen is TC (docetaxel 75 mg/m², cyclophosphamide 600 mg/m²) administered intravenously every 3 weeks for six cycles; the anthracycline regimen is AC followed by weekly paclitaxel (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² administered intravenously either every 3 weeks or every 2 weeks. The same regimen applied to the group that received additional trastuzumab.

The primary endpoint was to determine whether the addition of trastuzumab to chemotherapy improved invasive disease-free survival.

At a median follow-up of 46.1 months, 264 patients had IDFS events. The 5-year estimates for recurrence-free interval, distant recurrence–free interval, and overall survival were not statistically different for patients receiving trastuzumab compared with those not receiving trastuzumab.

There was no difference in outcomes for IHC 1+ (HR for IDFS 0.88, 95% CI, 0.63-1.22) or IHC 2+ (HR for IDFS 1.14 95% CI, 0.79-1.65).

“The retrospective outcome difference between local tested HER2 + and center tested HER2-low patients identified in two major adjuvant trials are not readily explained,” said Dr. Fehrenbacher. “There is no benefit with trastuzumab therapy in patients with a FISH ratio of less than 2 and IHC staining intensity of 1+ or 2+.

SOURCE: Fehrenbacher et al. GS1-02

The risk of developing breast cancer is about 20% higher among women who are current or recent users of hormonal contraceptives, compared with women who never used them, according to a prospective cohort study that included current contraception formulations.

copyright Thinkstock

Lina S. Mørch, PhD, of the University of Copenhagen, and colleagues conducted a nationwide, prospective cohort study of 1,797,932 women in Denmark who were aged 15-49 years between 1995 and 2012. The risk of developing breast cancer among all women currently using or who had recently used hormonal contraception correlated to a relative risk (RR) of 1.20 (95% confidence interval [CI], 1.14-1.26). The report was published in the New England Journal of Medicine.

The risk of breast cancer was heavily associated with the length of time during which the women had taken hormonal contraceptives. Women with less than a year of exposure had the lowest risk elevation (RR 1.09, 95% CI, 0.96-1.23), while women with more than 10 years of exposure faced the greatest increase in risk (RR 1.38, 95% CI, 1.26-1.51, P = .002).

The increased risk persisted even after women had stopped taking contraceptives. Researchers found that contraception use of less than a year (RR 1.01, 95% CI, 0.88-1.15), between 1 year and 5 years (RR 1.07, 95% CI, 0.94-1.20), and between 5 years and 10 years (RR 1.30, 95% CI, 1.06-1.58) correlated to increased risks of breast cancer 5-10 years after cessation of use. The number of events in women who had used hormonal contraceptive for more than 10 years was too small to accurately determine risks and was not reported in the study.

The combinations and formulations of oral contraceptives had little effect on breast cancer risk elevation, the researchers found. Triphasic and monophasic formulations containing levonorgestrel had similar relative risk levels of 1.21 (95% CI, 1.04-1.41) and 1.45 (95% CI, 1.26-1.67), respectively (P = .07). The relative risk was similar for intrauterine devices containing levonorgestrel (RR 1.21, 95% CI, 1.11-1.33).

The difference in risk between current and recent users of hormonal contraception and women who never took it was 13 (CI, 10-16) per 100,000 person-years, which translates into an one extra breast cancer diagnosis for every 7,690 women using hormonal contraception for 1 year.

“The estimated number of additional breast cancers that were associated with hormonal contraception did not include extra cases diagnosed after the discontinuation of long-term use. Even so, the estimated number of additional breast cancers among premenopausal women that were attributable to hormonal contraception is likely to be low,” the researchers wrote. “This risk should be weighed against important benefits of hormonal contraceptives such as good contraceptive efficacy and reduced risks of ovarian, endometrial, and perhaps colorectal cancer (at least for combined oral contraceptives that were commonly used in the 1970s and 1980s).

”Dr. Mørch and a coauthor received grant support from the Novo Nordisk Foundation and became employed by Novo Nordisk Foundation after the study was accepted for publication. No other relevant disclosures were reported.

[email protected]

Source: Mørch L. et al. N Engl J Med 2017;377(23):2228-39.

*12/7/2017: The headline for this story has been corrected to reflect an association between contraception and breast cancer risk.

The risk of developing breast cancer is about 20% higher among women who are current or recent users of hormonal contraceptives, compared with women who never used them, according to a prospective cohort study that included current contraception formulations.

copyright Thinkstock

Lina S. Mørch, PhD, of the University of Copenhagen, and colleagues conducted a nationwide, prospective cohort study of 1,797,932 women in Denmark who were aged 15-49 years between 1995 and 2012. The risk of developing breast cancer among all women currently using or who had recently used hormonal contraception correlated to a relative risk (RR) of 1.20 (95% confidence interval [CI], 1.14-1.26). The report was published in the New England Journal of Medicine.

The risk of breast cancer was heavily associated with the length of time during which the women had taken hormonal contraceptives. Women with less than a year of exposure had the lowest risk elevation (RR 1.09, 95% CI, 0.96-1.23), while women with more than 10 years of exposure faced the greatest increase in risk (RR 1.38, 95% CI, 1.26-1.51, P = .002).

The increased risk persisted even after women had stopped taking contraceptives. Researchers found that contraception use of less than a year (RR 1.01, 95% CI, 0.88-1.15), between 1 year and 5 years (RR 1.07, 95% CI, 0.94-1.20), and between 5 years and 10 years (RR 1.30, 95% CI, 1.06-1.58) correlated to increased risks of breast cancer 5-10 years after cessation of use. The number of events in women who had used hormonal contraceptive for more than 10 years was too small to accurately determine risks and was not reported in the study.

The combinations and formulations of oral contraceptives had little effect on breast cancer risk elevation, the researchers found. Triphasic and monophasic formulations containing levonorgestrel had similar relative risk levels of 1.21 (95% CI, 1.04-1.41) and 1.45 (95% CI, 1.26-1.67), respectively (P = .07). The relative risk was similar for intrauterine devices containing levonorgestrel (RR 1.21, 95% CI, 1.11-1.33).

The difference in risk between current and recent users of hormonal contraception and women who never took it was 13 (CI, 10-16) per 100,000 person-years, which translates into an one extra breast cancer diagnosis for every 7,690 women using hormonal contraception for 1 year.

“The estimated number of additional breast cancers that were associated with hormonal contraception did not include extra cases diagnosed after the discontinuation of long-term use. Even so, the estimated number of additional breast cancers among premenopausal women that were attributable to hormonal contraception is likely to be low,” the researchers wrote. “This risk should be weighed against important benefits of hormonal contraceptives such as good contraceptive efficacy and reduced risks of ovarian, endometrial, and perhaps colorectal cancer (at least for combined oral contraceptives that were commonly used in the 1970s and 1980s).

”Dr. Mørch and a coauthor received grant support from the Novo Nordisk Foundation and became employed by Novo Nordisk Foundation after the study was accepted for publication. No other relevant disclosures were reported.

[email protected]

Source: Mørch L. et al. N Engl J Med 2017;377(23):2228-39.

*12/7/2017: The headline for this story has been corrected to reflect an association between contraception and breast cancer risk.

The risk of developing breast cancer is about 20% higher among women who are current or recent users of hormonal contraceptives, compared with women who never used them, according to a prospective cohort study that included current contraception formulations.

copyright Thinkstock

Lina S. Mørch, PhD, of the University of Copenhagen, and colleagues conducted a nationwide, prospective cohort study of 1,797,932 women in Denmark who were aged 15-49 years between 1995 and 2012. The risk of developing breast cancer among all women currently using or who had recently used hormonal contraception correlated to a relative risk (RR) of 1.20 (95% confidence interval [CI], 1.14-1.26). The report was published in the New England Journal of Medicine.

The risk of breast cancer was heavily associated with the length of time during which the women had taken hormonal contraceptives. Women with less than a year of exposure had the lowest risk elevation (RR 1.09, 95% CI, 0.96-1.23), while women with more than 10 years of exposure faced the greatest increase in risk (RR 1.38, 95% CI, 1.26-1.51, P = .002).

The increased risk persisted even after women had stopped taking contraceptives. Researchers found that contraception use of less than a year (RR 1.01, 95% CI, 0.88-1.15), between 1 year and 5 years (RR 1.07, 95% CI, 0.94-1.20), and between 5 years and 10 years (RR 1.30, 95% CI, 1.06-1.58) correlated to increased risks of breast cancer 5-10 years after cessation of use. The number of events in women who had used hormonal contraceptive for more than 10 years was too small to accurately determine risks and was not reported in the study.

The combinations and formulations of oral contraceptives had little effect on breast cancer risk elevation, the researchers found. Triphasic and monophasic formulations containing levonorgestrel had similar relative risk levels of 1.21 (95% CI, 1.04-1.41) and 1.45 (95% CI, 1.26-1.67), respectively (P = .07). The relative risk was similar for intrauterine devices containing levonorgestrel (RR 1.21, 95% CI, 1.11-1.33).

The difference in risk between current and recent users of hormonal contraception and women who never took it was 13 (CI, 10-16) per 100,000 person-years, which translates into an one extra breast cancer diagnosis for every 7,690 women using hormonal contraception for 1 year.

“The estimated number of additional breast cancers that were associated with hormonal contraception did not include extra cases diagnosed after the discontinuation of long-term use. Even so, the estimated number of additional breast cancers among premenopausal women that were attributable to hormonal contraception is likely to be low,” the researchers wrote. “This risk should be weighed against important benefits of hormonal contraceptives such as good contraceptive efficacy and reduced risks of ovarian, endometrial, and perhaps colorectal cancer (at least for combined oral contraceptives that were commonly used in the 1970s and 1980s).

”Dr. Mørch and a coauthor received grant support from the Novo Nordisk Foundation and became employed by Novo Nordisk Foundation after the study was accepted for publication. No other relevant disclosures were reported.

[email protected]

Source: Mørch L. et al. N Engl J Med 2017;377(23):2228-39.

*12/7/2017: The headline for this story has been corrected to reflect an association between contraception and breast cancer risk.

Twenty-four years’ worth of data from the Netherlands’ mammography screening program suggest that it has achieved only a marginal impact on breast cancer mortality, according to a paper published online Dec. 5 in the British Medical Journal.

Researchers used data on the stage-specific incidence of breast cancer in the Netherlands during 1989-2012 and estimated the mortality effect of a nationwide, population-based mammography breast cancer screening program, which was introduced in 1988 and targeted women aged 50-75 years.

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This amounted to a 50% increase in in situ and stage 1 cancers diagnosed among women who were invited to screening, compared with those younger than 50 years. Even in a best-case scenario, the advent of digital mammography would mean 10,038 overdiagnosed cancers for 640 breast cancer deaths prevented by screening.

“Thus for 1 woman who would not die from breast cancer because of screening, about 16 women would be overdiagnosed with an in situ or a stage 1 cancer,” the authors wrote. “Hence, the advent of digital technologies has probably worsened the overdiagnosis problem without clear evidence for improvements in the ability of screening to curb the risk of breast cancer death.”

The study was partly supported by the International Prevention Research Institute. No conflicts of interest were declared.

SOURCE: Autier P et al. BMJ. 2017 Dec 5;359:j5224.

Twenty-four years’ worth of data from the Netherlands’ mammography screening program suggest that it has achieved only a marginal impact on breast cancer mortality, according to a paper published online Dec. 5 in the British Medical Journal.

Researchers used data on the stage-specific incidence of breast cancer in the Netherlands during 1989-2012 and estimated the mortality effect of a nationwide, population-based mammography breast cancer screening program, which was introduced in 1988 and targeted women aged 50-75 years.

copyright/Thinkstock

This amounted to a 50% increase in in situ and stage 1 cancers diagnosed among women who were invited to screening, compared with those younger than 50 years. Even in a best-case scenario, the advent of digital mammography would mean 10,038 overdiagnosed cancers for 640 breast cancer deaths prevented by screening.

“Thus for 1 woman who would not die from breast cancer because of screening, about 16 women would be overdiagnosed with an in situ or a stage 1 cancer,” the authors wrote. “Hence, the advent of digital technologies has probably worsened the overdiagnosis problem without clear evidence for improvements in the ability of screening to curb the risk of breast cancer death.”

The study was partly supported by the International Prevention Research Institute. No conflicts of interest were declared.

SOURCE: Autier P et al. BMJ. 2017 Dec 5;359:j5224.

Twenty-four years’ worth of data from the Netherlands’ mammography screening program suggest that it has achieved only a marginal impact on breast cancer mortality, according to a paper published online Dec. 5 in the British Medical Journal.

Researchers used data on the stage-specific incidence of breast cancer in the Netherlands during 1989-2012 and estimated the mortality effect of a nationwide, population-based mammography breast cancer screening program, which was introduced in 1988 and targeted women aged 50-75 years.

copyright/Thinkstock

This amounted to a 50% increase in in situ and stage 1 cancers diagnosed among women who were invited to screening, compared with those younger than 50 years. Even in a best-case scenario, the advent of digital mammography would mean 10,038 overdiagnosed cancers for 640 breast cancer deaths prevented by screening.

“Thus for 1 woman who would not die from breast cancer because of screening, about 16 women would be overdiagnosed with an in situ or a stage 1 cancer,” the authors wrote. “Hence, the advent of digital technologies has probably worsened the overdiagnosis problem without clear evidence for improvements in the ability of screening to curb the risk of breast cancer death.”

The study was partly supported by the International Prevention Research Institute. No conflicts of interest were declared.

SOURCE: Autier P et al. BMJ. 2017 Dec 5;359:j5224.

MONTREAL – African American breast cancer survivors who participated in fitness tracking and an online support program saw small but significant reductions in weight and improvement in quality of life, according to a new study.

Further, patients who reported a low baseline quality of life (QOL) achieved as much or more weight loss as did those whose QOL was initially high, said Jeanne Ferrante, MD, MPH, professor of family medicine and community health at Robert Wood Johnson Medical School, New Brunswick, N.J.

shironosov/Thinkstock

Dr. Ferrante reported no conflicts of interest.

[email protected]

On Twitter @karioakes

MONTREAL – African American breast cancer survivors who participated in fitness tracking and an online support program saw small but significant reductions in weight and improvement in quality of life, according to a new study.

Further, patients who reported a low baseline quality of life (QOL) achieved as much or more weight loss as did those whose QOL was initially high, said Jeanne Ferrante, MD, MPH, professor of family medicine and community health at Robert Wood Johnson Medical School, New Brunswick, N.J.

shironosov/Thinkstock

Dr. Ferrante reported no conflicts of interest.

[email protected]

On Twitter @karioakes

MONTREAL – African American breast cancer survivors who participated in fitness tracking and an online support program saw small but significant reductions in weight and improvement in quality of life, according to a new study.

Further, patients who reported a low baseline quality of life (QOL) achieved as much or more weight loss as did those whose QOL was initially high, said Jeanne Ferrante, MD, MPH, professor of family medicine and community health at Robert Wood Johnson Medical School, New Brunswick, N.J.

shironosov/Thinkstock

Dr. Ferrante reported no conflicts of interest.

[email protected]

On Twitter @karioakes

The Food and Drug Administration has approved trastuzumab-dkst (Ogivri) as a biosimilar to trastuzumab (Herceptin) for the treatment of patients with HER2+ breast or metastatic gastric or gastroesophageal junction adenocarcinoma.

This is the first biosimilar approved in the United States for the treatment of breast cancer or gastric cancer and the second biosimilar approved for the treatment of cancer, the FDA said in a statement.

[email protected]

The Food and Drug Administration has approved trastuzumab-dkst (Ogivri) as a biosimilar to trastuzumab (Herceptin) for the treatment of patients with HER2+ breast or metastatic gastric or gastroesophageal junction adenocarcinoma.

This is the first biosimilar approved in the United States for the treatment of breast cancer or gastric cancer and the second biosimilar approved for the treatment of cancer, the FDA said in a statement.

[email protected]

The Food and Drug Administration has approved trastuzumab-dkst (Ogivri) as a biosimilar to trastuzumab (Herceptin) for the treatment of patients with HER2+ breast or metastatic gastric or gastroesophageal junction adenocarcinoma.

This is the first biosimilar approved in the United States for the treatment of breast cancer or gastric cancer and the second biosimilar approved for the treatment of cancer, the FDA said in a statement.

[email protected]

Oncology Practice Associate Editor William J. Gradishar, MD, reveals several anticipated studies from the 40th annual San Antonio Breast Cancer Symposium, set to begin on Wednesday, Dec. 6:

Dr. Gradishar is the Betsy Bramsen Professor of Breast Oncology, professor of medicine, and interim chief of the division of hematology/oncology, Northwestern University Feinberg School of Medicine, Chicago, and deputy director for the Clinical Network and director of the Maggie Daley Center for Women’s Cancer Care, Robert H. Lurie Comprehensive Cancer Center Network of Northwestern University, Chicago.

Oncology Practice Associate Editor William J. Gradishar, MD, reveals several anticipated studies from the 40th annual San Antonio Breast Cancer Symposium, set to begin on Wednesday, Dec. 6:

Dr. Gradishar is the Betsy Bramsen Professor of Breast Oncology, professor of medicine, and interim chief of the division of hematology/oncology, Northwestern University Feinberg School of Medicine, Chicago, and deputy director for the Clinical Network and director of the Maggie Daley Center for Women’s Cancer Care, Robert H. Lurie Comprehensive Cancer Center Network of Northwestern University, Chicago.

Oncology Practice Associate Editor William J. Gradishar, MD, reveals several anticipated studies from the 40th annual San Antonio Breast Cancer Symposium, set to begin on Wednesday, Dec. 6:

Dr. Gradishar is the Betsy Bramsen Professor of Breast Oncology, professor of medicine, and interim chief of the division of hematology/oncology, Northwestern University Feinberg School of Medicine, Chicago, and deputy director for the Clinical Network and director of the Maggie Daley Center for Women’s Cancer Care, Robert H. Lurie Comprehensive Cancer Center Network of Northwestern University, Chicago.

The Food and Drug Administration approved a new genetic sequencing test that detects mutations across 324 genes in tumor biopsy specimens with an accuracy of 94.6%.

The FoundationOne CDx (F1CDx) test from Foundation Medicine “can identify which patients with any of five tumor types” – non–small-cell lung cancer, melanoma, breast cancer, colorectal cancer, or ovarian cancer – “may benefit from 15 different FDA-approved targeted treatment options,” as well as clinical trial eligibility, “with one test report, avoiding duplicative biopsies,” the agency said in a statement.

[email protected]

The Food and Drug Administration approved a new genetic sequencing test that detects mutations across 324 genes in tumor biopsy specimens with an accuracy of 94.6%.

The FoundationOne CDx (F1CDx) test from Foundation Medicine “can identify which patients with any of five tumor types” – non–small-cell lung cancer, melanoma, breast cancer, colorectal cancer, or ovarian cancer – “may benefit from 15 different FDA-approved targeted treatment options,” as well as clinical trial eligibility, “with one test report, avoiding duplicative biopsies,” the agency said in a statement.

[email protected]

The Food and Drug Administration approved a new genetic sequencing test that detects mutations across 324 genes in tumor biopsy specimens with an accuracy of 94.6%.

The FoundationOne CDx (F1CDx) test from Foundation Medicine “can identify which patients with any of five tumor types” – non–small-cell lung cancer, melanoma, breast cancer, colorectal cancer, or ovarian cancer – “may benefit from 15 different FDA-approved targeted treatment options,” as well as clinical trial eligibility, “with one test report, avoiding duplicative biopsies,” the agency said in a statement.

[email protected]

As our understanding of the biology of breast cancer has improved, treatment has become increasingly personalized. Targeted therapies continue to significantly improve patient outcomes in multiple subtypes, with several recent drug approvals. Here, we discuss some of these latest developments.

A disease of many faces

Clinically speaking, breast cancers can be divided into at least 5 subtypes on the basis of the genes they express (Figure 1). The luminal subtypes make up the largest proportion and are characterized by the expression of hormone receptor (HR) genes. Luminal A tumors are negative for human epidermal growth factor receptor 2 (HER2; HER2-negative), whereas luminal B tumors often co-express the HER2 genes.¹

The remainder of HER2-positive patients fall into the HER2-enriched category, in which HER2 expression is the defining characteristic. Basal-like tumors, meanwhile, represent the most heterogeneous subtype, overlapping to a large extent with tumors dubbed “triple-negative” because of their lack of either HER2 or ESR1 and PGR gene expression. The fifth subtype is known as normal breast-like and remains poorly characterized.

In recent years, there have been significant advancements in the genomic characterization of breast cancer that have begun to provide a more comprehensive understanding of the driver molecular mechanisms, which has helped to explain some of the limitations of current targeted approaches and to reveal new possible treatments, with a shift toward increasingly personalized strategies.²
 

HER2: what’s neu?

An estimated 18%-20% of breast tumors are HER2 positive, displaying amplification of the HER2/neu gene or overexpression of its protein product.³ Historically, HER2 positivity correlated with a highly aggressive and metastatic form of disease, conferring poor prognosis.^4,5 The HER2-targeted monoclonal antibody (mAb), trastuzumab serves as a prime example of the power of personalized medicine. Evidence suggests that trastuzumab has altered the natural history of HER2-positive breast cancer, such that trastuzumab-treated patients with HER2-positive breast cancer now have a better prognosis than do patients with HER2-negative disease.^6,7

Several additional HER2-targeted drugs have joined trastuzumab on the market, including other mAbs, small molecule tyrosine kinase inhibitors (TKIs), and an antibody–drug conjugate that combines the specificity of a mAb with the anti-tumor potency of a cytotoxic drug. These drugs have further improved patient outcomes in both early and advanced disease settings (Table 1).

Tucatinib (ONT-380) has shown significant promise in this respect. In a phase 1 trial, ONT-380 had significant efficacy in patients with and without central nervous system metastases; the overall response rate (ORR) in the CNS was 36%. ONT-380 is also notable for its specificity for HER2, without significant inhibition of HER1 and EGFR, which could translate into a better toxicity profile.¹²
 

Doubling down on resistant tumors

Since the success of HER2-targeted therapy is limited by the development of resistance, there has been significant interest in assessing the potential of dual HER2 blockade, exploiting the unique mechanisms of action of different drugs in combination therapy, and ensuring more complete inhibition of the HER2 pathway. Although numerous different combinations have been tested, a double antibody combination has proved most effective.

In fact, dual HER2 targeting with trastuzumab and pertuzumab in combination with chemotherapy has replaced a trastuzumab-chemotherapy regimen as the new standard of care in the metastatic setting. A 6-month improvement in progression-free survival (PFS) sealed FDA approval for the combination and in a recently published final analysis of the trial overall survival (OS) was also improved to a level unprecedented in the first-line setting.^13,14The double antibody combination has also been successful in the neoadjuvant setting. Approval followed the results of the phase 2 NeoSphere trial, in which the combination was associated with a significant improvement in pathologic complete response (pCR) rate, a measure that acts as a surrogate for improved survival in the neoadjuvant setting. In a 5-year analysis of the NeoSphere trial, improved pCR did indeed translate into improved PFS and DFS.^15,16

The results of the phase 3 APHINITY trial evaluating this combination in the adjuvant setting have been hotly anticipated. In a presentation at the 2017 American Society of Clinical Oncology (ASCO) meeting in June, the study authors reported that in 4,085 patients with operable HER2-positive disease, it significantly reduced the risk of disease recurrence or death compared with trastuzumab and chemotherapy alone.¹⁷

There is an ongoing effort to determine if it is possible to de-escalate treatment by removing the chemotherapy component. At least in the neoadjuvant setting, pCR rates in the chemotherapy-free arms of several studies suggest that a proportion of patients might benefit from this strategy^15,18,19 and the challenge now is to identify them. To that end, the phase 2 PAMELA trial identified the HER2-enriched subtype as a strong predictor of response to neoadjuvant dual blockade (lapatinib and trastuzumab) without chemotherapy. The pCR rate was 40.6% for the combination in patients with the HER2-enriched subtype of breast cancer and only 10% in patients with non–HER2-enriched tumors.²⁰

Targeting resistance to endocrine therapy

Another coup for personalized medicine in breast cancer is the treatment of hormone receptor–positive cases with endocrine therapy, which has become the cornerstone of treatment in the metastatic and adjuvant settings. Those drugs are designed to block the growth-stimulating effects of the estrogen and progesterone hormones on tumor cells. They include the selective estrogen receptor (ER) modulator tamoxifen, aromatase inhibitors (AIs) such as letrozole, anastrozole, and exemestane, which work by blocking the activity of the aromatase enzyme that converts androgens into estrogens, and the selective estrogen-receptor down-regulator fulvestrant.

As with HER2-targeted therapy, patients treated with endocrine therapy often develop resistance. Activation of alternate signaling cascades, such as the P13K–Akt–mTOR (phosphatidylinositol-3-kinase–Akt–mammalian target of rapamycin) pathway, or downstream targets of ER signaling, including the cyclin-dependent kinases, CDK4 and CDK6, have emerged as important mechanisms of resistance.^21,22

Drugs directed against these secondary targets, aimed to enhance the efficacy of endocrine therapies, have shown significant promise (Table 2). The mTOR inhibitor everolimus received FDA approval in 2012 in combination with exemestane for the treatment of advanced HR-positive, HER2-negative breast cancer.²³ More recently, everolimus has also proven effective in combination with either fulvestrant or letrozole, according to the phase 2 PrECOG 0102 and BOLERO-4 studies, both doubling PFS compared with endocrine therapy alone.^24,25

Teasing out ‘HER2-positive’ subtypes

Until recently, “HER2-positive” and “HR-positive” tumors have been treated as separate subtypes, despite the fact that about half of HER2-positive tumors fall into the luminal A subtype and are also HR-positive. Patients were typically treated with HER2-targeted therapy regardless of their endocrine status because of the aggressive nature of HER2-positive disease.

Increasingly, researchers are reconsidering this view, especially as several studies have shown differential response rates to HER2-targeted therapy in HR-positive compared with HR-negative patients and accumulating evidence suggests that there is significant crosstalk between the HER2 and HR pathways, which may be responsible for the development of resistance with both treatment paradigms.

Findings from several studies have shown a benefit to combining HER2-targeted and hormonal therapies in patients with luminal (HR-positive), HER2-positive disease. In the metastatic setting, the results of the phase 2 PERTAIN study, presented at the 2017 ASCO annual meeting suggest that dual HER2 blockade could prove even more effective. The addition of pertuzumab to a combination of trastuzumab and an AI improved PFS by more than 3 months (median PFS, 19.89 vs 15.8 months; HR, 0.65; P = .007).³³

The clinical application of these combinations may be limited by the additional cost – several studies have suggested that they are not cost effective – and toxicity, but have served to drive the development of new clinical trial designs as the importance of considering luminal and nonluminal HER2-positive tumors has become increasingly apparent.
 

PARP inhibitors make a dent in BRCA1/2-mutated cancers

The most renowned breast cancer genes, BRCA1 and BRCA2 are present in about 5%-10% of all breast cancers. They play a central role in the homologous recombination pathway that fixes double-strand breaks in the DNA. Genome sequencing studies have revealed that the presence of the BRCA1/2 genes and other DNA repair defects is highest among patients with the basal-like subtype of breast cancer, in particular those who have triple-negative disease.^34,35

This type of breast cancer has proved stubbornly resistant to efforts to improve patient outcomes with targeted therapies. BRCA1/2 mutations and other DNA repair defects that confer a so-called BRCAness phenotype, render tumor cells dependent on other pathways for DNA repair and there has been considerable interest in therapeutically exploiting this through the development of inhibitors of the poly(ADP-ribose) polymerase (PARP) enzyme, which is involved in the repair of single-strand breaks in the DNA. The double damage to DNA repair mechanisms through PARP inhibition in patients with BRCA1/2-mutant tumors proves overwhelming to cancerous cells.

Despite more than a decade of investigation in breast cancer, PARP inhibitors have yet to yield any FDA-approved treatment options. That may be set to change imminently, following the success of olaparib (Table 3). In the first randomized phase 3 trial of a PARP inhibitor in breast cancer (OlympiAD), olaparib was compared with standard chemotherapy in patients with BRCA1/2-mutated MBC who had received up to 2 previous lines of chemotherapy. Olaparib reduced the risk of disease progression by 42% compared with standard chemotherapy and was well tolerated.³⁶

As our understanding of the biology of breast cancer has improved, treatment has become increasingly personalized. Targeted therapies continue to significantly improve patient outcomes in multiple subtypes, with several recent drug approvals. Here, we discuss some of these latest developments.

A disease of many faces

Clinically speaking, breast cancers can be divided into at least 5 subtypes on the basis of the genes they express (Figure 1). The luminal subtypes make up the largest proportion and are characterized by the expression of hormone receptor (HR) genes. Luminal A tumors are negative for human epidermal growth factor receptor 2 (HER2; HER2-negative), whereas luminal B tumors often co-express the HER2 genes.¹

The remainder of HER2-positive patients fall into the HER2-enriched category, in which HER2 expression is the defining characteristic. Basal-like tumors, meanwhile, represent the most heterogeneous subtype, overlapping to a large extent with tumors dubbed “triple-negative” because of their lack of either HER2 or ESR1 and PGR gene expression. The fifth subtype is known as normal breast-like and remains poorly characterized.

In recent years, there have been significant advancements in the genomic characterization of breast cancer that have begun to provide a more comprehensive understanding of the driver molecular mechanisms, which has helped to explain some of the limitations of current targeted approaches and to reveal new possible treatments, with a shift toward increasingly personalized strategies.²
 

HER2: what’s neu?

An estimated 18%-20% of breast tumors are HER2 positive, displaying amplification of the HER2/neu gene or overexpression of its protein product.³ Historically, HER2 positivity correlated with a highly aggressive and metastatic form of disease, conferring poor prognosis.^4,5 The HER2-targeted monoclonal antibody (mAb), trastuzumab serves as a prime example of the power of personalized medicine. Evidence suggests that trastuzumab has altered the natural history of HER2-positive breast cancer, such that trastuzumab-treated patients with HER2-positive breast cancer now have a better prognosis than do patients with HER2-negative disease.^6,7

Several additional HER2-targeted drugs have joined trastuzumab on the market, including other mAbs, small molecule tyrosine kinase inhibitors (TKIs), and an antibody–drug conjugate that combines the specificity of a mAb with the anti-tumor potency of a cytotoxic drug. These drugs have further improved patient outcomes in both early and advanced disease settings (Table 1).

Tucatinib (ONT-380) has shown significant promise in this respect. In a phase 1 trial, ONT-380 had significant efficacy in patients with and without central nervous system metastases; the overall response rate (ORR) in the CNS was 36%. ONT-380 is also notable for its specificity for HER2, without significant inhibition of HER1 and EGFR, which could translate into a better toxicity profile.¹²
 

Doubling down on resistant tumors

Since the success of HER2-targeted therapy is limited by the development of resistance, there has been significant interest in assessing the potential of dual HER2 blockade, exploiting the unique mechanisms of action of different drugs in combination therapy, and ensuring more complete inhibition of the HER2 pathway. Although numerous different combinations have been tested, a double antibody combination has proved most effective.

In fact, dual HER2 targeting with trastuzumab and pertuzumab in combination with chemotherapy has replaced a trastuzumab-chemotherapy regimen as the new standard of care in the metastatic setting. A 6-month improvement in progression-free survival (PFS) sealed FDA approval for the combination and in a recently published final analysis of the trial overall survival (OS) was also improved to a level unprecedented in the first-line setting.^13,14The double antibody combination has also been successful in the neoadjuvant setting. Approval followed the results of the phase 2 NeoSphere trial, in which the combination was associated with a significant improvement in pathologic complete response (pCR) rate, a measure that acts as a surrogate for improved survival in the neoadjuvant setting. In a 5-year analysis of the NeoSphere trial, improved pCR did indeed translate into improved PFS and DFS.^15,16

The results of the phase 3 APHINITY trial evaluating this combination in the adjuvant setting have been hotly anticipated. In a presentation at the 2017 American Society of Clinical Oncology (ASCO) meeting in June, the study authors reported that in 4,085 patients with operable HER2-positive disease, it significantly reduced the risk of disease recurrence or death compared with trastuzumab and chemotherapy alone.¹⁷

There is an ongoing effort to determine if it is possible to de-escalate treatment by removing the chemotherapy component. At least in the neoadjuvant setting, pCR rates in the chemotherapy-free arms of several studies suggest that a proportion of patients might benefit from this strategy^15,18,19 and the challenge now is to identify them. To that end, the phase 2 PAMELA trial identified the HER2-enriched subtype as a strong predictor of response to neoadjuvant dual blockade (lapatinib and trastuzumab) without chemotherapy. The pCR rate was 40.6% for the combination in patients with the HER2-enriched subtype of breast cancer and only 10% in patients with non–HER2-enriched tumors.²⁰

Targeting resistance to endocrine therapy

Another coup for personalized medicine in breast cancer is the treatment of hormone receptor–positive cases with endocrine therapy, which has become the cornerstone of treatment in the metastatic and adjuvant settings. Those drugs are designed to block the growth-stimulating effects of the estrogen and progesterone hormones on tumor cells. They include the selective estrogen receptor (ER) modulator tamoxifen, aromatase inhibitors (AIs) such as letrozole, anastrozole, and exemestane, which work by blocking the activity of the aromatase enzyme that converts androgens into estrogens, and the selective estrogen-receptor down-regulator fulvestrant.

As with HER2-targeted therapy, patients treated with endocrine therapy often develop resistance. Activation of alternate signaling cascades, such as the P13K–Akt–mTOR (phosphatidylinositol-3-kinase–Akt–mammalian target of rapamycin) pathway, or downstream targets of ER signaling, including the cyclin-dependent kinases, CDK4 and CDK6, have emerged as important mechanisms of resistance.^21,22

Drugs directed against these secondary targets, aimed to enhance the efficacy of endocrine therapies, have shown significant promise (Table 2). The mTOR inhibitor everolimus received FDA approval in 2012 in combination with exemestane for the treatment of advanced HR-positive, HER2-negative breast cancer.²³ More recently, everolimus has also proven effective in combination with either fulvestrant or letrozole, according to the phase 2 PrECOG 0102 and BOLERO-4 studies, both doubling PFS compared with endocrine therapy alone.^24,25

Teasing out ‘HER2-positive’ subtypes

Until recently, “HER2-positive” and “HR-positive” tumors have been treated as separate subtypes, despite the fact that about half of HER2-positive tumors fall into the luminal A subtype and are also HR-positive. Patients were typically treated with HER2-targeted therapy regardless of their endocrine status because of the aggressive nature of HER2-positive disease.

Increasingly, researchers are reconsidering this view, especially as several studies have shown differential response rates to HER2-targeted therapy in HR-positive compared with HR-negative patients and accumulating evidence suggests that there is significant crosstalk between the HER2 and HR pathways, which may be responsible for the development of resistance with both treatment paradigms.

Findings from several studies have shown a benefit to combining HER2-targeted and hormonal therapies in patients with luminal (HR-positive), HER2-positive disease. In the metastatic setting, the results of the phase 2 PERTAIN study, presented at the 2017 ASCO annual meeting suggest that dual HER2 blockade could prove even more effective. The addition of pertuzumab to a combination of trastuzumab and an AI improved PFS by more than 3 months (median PFS, 19.89 vs 15.8 months; HR, 0.65; P = .007).³³

The clinical application of these combinations may be limited by the additional cost – several studies have suggested that they are not cost effective – and toxicity, but have served to drive the development of new clinical trial designs as the importance of considering luminal and nonluminal HER2-positive tumors has become increasingly apparent.
 

PARP inhibitors make a dent in BRCA1/2-mutated cancers

The most renowned breast cancer genes, BRCA1 and BRCA2 are present in about 5%-10% of all breast cancers. They play a central role in the homologous recombination pathway that fixes double-strand breaks in the DNA. Genome sequencing studies have revealed that the presence of the BRCA1/2 genes and other DNA repair defects is highest among patients with the basal-like subtype of breast cancer, in particular those who have triple-negative disease.^34,35

This type of breast cancer has proved stubbornly resistant to efforts to improve patient outcomes with targeted therapies. BRCA1/2 mutations and other DNA repair defects that confer a so-called BRCAness phenotype, render tumor cells dependent on other pathways for DNA repair and there has been considerable interest in therapeutically exploiting this through the development of inhibitors of the poly(ADP-ribose) polymerase (PARP) enzyme, which is involved in the repair of single-strand breaks in the DNA. The double damage to DNA repair mechanisms through PARP inhibition in patients with BRCA1/2-mutant tumors proves overwhelming to cancerous cells.

Despite more than a decade of investigation in breast cancer, PARP inhibitors have yet to yield any FDA-approved treatment options. That may be set to change imminently, following the success of olaparib (Table 3). In the first randomized phase 3 trial of a PARP inhibitor in breast cancer (OlympiAD), olaparib was compared with standard chemotherapy in patients with BRCA1/2-mutated MBC who had received up to 2 previous lines of chemotherapy. Olaparib reduced the risk of disease progression by 42% compared with standard chemotherapy and was well tolerated.³⁶

As our understanding of the biology of breast cancer has improved, treatment has become increasingly personalized. Targeted therapies continue to significantly improve patient outcomes in multiple subtypes, with several recent drug approvals. Here, we discuss some of these latest developments.

A disease of many faces

Clinically speaking, breast cancers can be divided into at least 5 subtypes on the basis of the genes they express (Figure 1). The luminal subtypes make up the largest proportion and are characterized by the expression of hormone receptor (HR) genes. Luminal A tumors are negative for human epidermal growth factor receptor 2 (HER2; HER2-negative), whereas luminal B tumors often co-express the HER2 genes.¹

The remainder of HER2-positive patients fall into the HER2-enriched category, in which HER2 expression is the defining characteristic. Basal-like tumors, meanwhile, represent the most heterogeneous subtype, overlapping to a large extent with tumors dubbed “triple-negative” because of their lack of either HER2 or ESR1 and PGR gene expression. The fifth subtype is known as normal breast-like and remains poorly characterized.

In recent years, there have been significant advancements in the genomic characterization of breast cancer that have begun to provide a more comprehensive understanding of the driver molecular mechanisms, which has helped to explain some of the limitations of current targeted approaches and to reveal new possible treatments, with a shift toward increasingly personalized strategies.²
 

HER2: what’s neu?

An estimated 18%-20% of breast tumors are HER2 positive, displaying amplification of the HER2/neu gene or overexpression of its protein product.³ Historically, HER2 positivity correlated with a highly aggressive and metastatic form of disease, conferring poor prognosis.^4,5 The HER2-targeted monoclonal antibody (mAb), trastuzumab serves as a prime example of the power of personalized medicine. Evidence suggests that trastuzumab has altered the natural history of HER2-positive breast cancer, such that trastuzumab-treated patients with HER2-positive breast cancer now have a better prognosis than do patients with HER2-negative disease.^6,7

Several additional HER2-targeted drugs have joined trastuzumab on the market, including other mAbs, small molecule tyrosine kinase inhibitors (TKIs), and an antibody–drug conjugate that combines the specificity of a mAb with the anti-tumor potency of a cytotoxic drug. These drugs have further improved patient outcomes in both early and advanced disease settings (Table 1).

Tucatinib (ONT-380) has shown significant promise in this respect. In a phase 1 trial, ONT-380 had significant efficacy in patients with and without central nervous system metastases; the overall response rate (ORR) in the CNS was 36%. ONT-380 is also notable for its specificity for HER2, without significant inhibition of HER1 and EGFR, which could translate into a better toxicity profile.¹²
 

Doubling down on resistant tumors

Since the success of HER2-targeted therapy is limited by the development of resistance, there has been significant interest in assessing the potential of dual HER2 blockade, exploiting the unique mechanisms of action of different drugs in combination therapy, and ensuring more complete inhibition of the HER2 pathway. Although numerous different combinations have been tested, a double antibody combination has proved most effective.

In fact, dual HER2 targeting with trastuzumab and pertuzumab in combination with chemotherapy has replaced a trastuzumab-chemotherapy regimen as the new standard of care in the metastatic setting. A 6-month improvement in progression-free survival (PFS) sealed FDA approval for the combination and in a recently published final analysis of the trial overall survival (OS) was also improved to a level unprecedented in the first-line setting.^13,14The double antibody combination has also been successful in the neoadjuvant setting. Approval followed the results of the phase 2 NeoSphere trial, in which the combination was associated with a significant improvement in pathologic complete response (pCR) rate, a measure that acts as a surrogate for improved survival in the neoadjuvant setting. In a 5-year analysis of the NeoSphere trial, improved pCR did indeed translate into improved PFS and DFS.^15,16

The results of the phase 3 APHINITY trial evaluating this combination in the adjuvant setting have been hotly anticipated. In a presentation at the 2017 American Society of Clinical Oncology (ASCO) meeting in June, the study authors reported that in 4,085 patients with operable HER2-positive disease, it significantly reduced the risk of disease recurrence or death compared with trastuzumab and chemotherapy alone.¹⁷

There is an ongoing effort to determine if it is possible to de-escalate treatment by removing the chemotherapy component. At least in the neoadjuvant setting, pCR rates in the chemotherapy-free arms of several studies suggest that a proportion of patients might benefit from this strategy^15,18,19 and the challenge now is to identify them. To that end, the phase 2 PAMELA trial identified the HER2-enriched subtype as a strong predictor of response to neoadjuvant dual blockade (lapatinib and trastuzumab) without chemotherapy. The pCR rate was 40.6% for the combination in patients with the HER2-enriched subtype of breast cancer and only 10% in patients with non–HER2-enriched tumors.²⁰

Targeting resistance to endocrine therapy

Another coup for personalized medicine in breast cancer is the treatment of hormone receptor–positive cases with endocrine therapy, which has become the cornerstone of treatment in the metastatic and adjuvant settings. Those drugs are designed to block the growth-stimulating effects of the estrogen and progesterone hormones on tumor cells. They include the selective estrogen receptor (ER) modulator tamoxifen, aromatase inhibitors (AIs) such as letrozole, anastrozole, and exemestane, which work by blocking the activity of the aromatase enzyme that converts androgens into estrogens, and the selective estrogen-receptor down-regulator fulvestrant.

As with HER2-targeted therapy, patients treated with endocrine therapy often develop resistance. Activation of alternate signaling cascades, such as the P13K–Akt–mTOR (phosphatidylinositol-3-kinase–Akt–mammalian target of rapamycin) pathway, or downstream targets of ER signaling, including the cyclin-dependent kinases, CDK4 and CDK6, have emerged as important mechanisms of resistance.^21,22

Drugs directed against these secondary targets, aimed to enhance the efficacy of endocrine therapies, have shown significant promise (Table 2). The mTOR inhibitor everolimus received FDA approval in 2012 in combination with exemestane for the treatment of advanced HR-positive, HER2-negative breast cancer.²³ More recently, everolimus has also proven effective in combination with either fulvestrant or letrozole, according to the phase 2 PrECOG 0102 and BOLERO-4 studies, both doubling PFS compared with endocrine therapy alone.^24,25

Teasing out ‘HER2-positive’ subtypes

Until recently, “HER2-positive” and “HR-positive” tumors have been treated as separate subtypes, despite the fact that about half of HER2-positive tumors fall into the luminal A subtype and are also HR-positive. Patients were typically treated with HER2-targeted therapy regardless of their endocrine status because of the aggressive nature of HER2-positive disease.

Increasingly, researchers are reconsidering this view, especially as several studies have shown differential response rates to HER2-targeted therapy in HR-positive compared with HR-negative patients and accumulating evidence suggests that there is significant crosstalk between the HER2 and HR pathways, which may be responsible for the development of resistance with both treatment paradigms.

Findings from several studies have shown a benefit to combining HER2-targeted and hormonal therapies in patients with luminal (HR-positive), HER2-positive disease. In the metastatic setting, the results of the phase 2 PERTAIN study, presented at the 2017 ASCO annual meeting suggest that dual HER2 blockade could prove even more effective. The addition of pertuzumab to a combination of trastuzumab and an AI improved PFS by more than 3 months (median PFS, 19.89 vs 15.8 months; HR, 0.65; P = .007).³³

The clinical application of these combinations may be limited by the additional cost – several studies have suggested that they are not cost effective – and toxicity, but have served to drive the development of new clinical trial designs as the importance of considering luminal and nonluminal HER2-positive tumors has become increasingly apparent.
 

PARP inhibitors make a dent in BRCA1/2-mutated cancers

The most renowned breast cancer genes, BRCA1 and BRCA2 are present in about 5%-10% of all breast cancers. They play a central role in the homologous recombination pathway that fixes double-strand breaks in the DNA. Genome sequencing studies have revealed that the presence of the BRCA1/2 genes and other DNA repair defects is highest among patients with the basal-like subtype of breast cancer, in particular those who have triple-negative disease.^34,35

This type of breast cancer has proved stubbornly resistant to efforts to improve patient outcomes with targeted therapies. BRCA1/2 mutations and other DNA repair defects that confer a so-called BRCAness phenotype, render tumor cells dependent on other pathways for DNA repair and there has been considerable interest in therapeutically exploiting this through the development of inhibitors of the poly(ADP-ribose) polymerase (PARP) enzyme, which is involved in the repair of single-strand breaks in the DNA. The double damage to DNA repair mechanisms through PARP inhibition in patients with BRCA1/2-mutant tumors proves overwhelming to cancerous cells.

Despite more than a decade of investigation in breast cancer, PARP inhibitors have yet to yield any FDA-approved treatment options. That may be set to change imminently, following the success of olaparib (Table 3). In the first randomized phase 3 trial of a PARP inhibitor in breast cancer (OlympiAD), olaparib was compared with standard chemotherapy in patients with BRCA1/2-mutated MBC who had received up to 2 previous lines of chemotherapy. Olaparib reduced the risk of disease progression by 42% compared with standard chemotherapy and was well tolerated.³⁶