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Advances in Targeted Therapy for Breast Cancer
It is estimated that there were more than 3.1 million women living in the U.S. with a history of invasive breast cancer as of January 1, 2014, and an additional 231,840 women will be newly diagnosed with invasive breast cancer in 2015.1,2 The median age at the time of breast cancer diagnosis is 61 years. About 20% of breast cancers occur among women aged < 50 years, and 43% occur in women aged > 65 years.
The treatment and prognosis for breast cancer depend on the stage at diagnosis, the biologic characteristics of the tumor, and the age and health of the patient. The overall 5-year relative survival rate for female patients with breast cancer has improved from 75% to 90% from 1975 to 1977 and from 2003 to 2009, respectively, largely due to improvements in treatment (ie, chemotherapy, hormone therapy, and targeted drugs) and because of earlier diagnosis resulting from the widespread use of mammography and other screening tools.2
Estrogen Receptor-Positive Therapies
Women with breast cancer who test positive for hormone receptors are candidates for treatment with hormone therapy to reduce the likelihood of recurrence or as a core component of treatment for advanced disease. Currently available endocrine strategies for the treatment of estrogen receptor- (ER) positive breast cancer include targeting the ER with the antiestrogen drug tamoxifen. Another option is suppressing the amount of available ligand (estrogen) for the receptor either with gonadal suppression in premenopausal oophorectomy, or luteinizing hormonereleasing hormone agonists, or with the aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole in postmenopausal women and by downregulating the receptor with fulvestrant. Given their proven efficacy and generally favorable adverse effect (AE) profile, these endocrine therapies are widely used in the treatment of both early-stage and recurrent and/or metastatic breast cancer.
Recent studies have offered new treatments for patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Innovative hormonal and targeted therapies for advanced disease as well as new data on adjuvant hormonal therapy for young high-risk patients are changing the available therapeutic options.
Advanced Metastatic Treatments
Treatment for metastatic hormone receptor-positive breast cancer has shifted from traditional cytotoxic chemotherapies to targeted therapeutic options. Most treatment guidelines, including the National Comprehensive Cancer Network guidelines, recommend targeted therapy with AIs or selective ER modulators rather than chemotherapy, except in the case of visceral crisis.3
Until recently, there had been relatively little guidance to inform which hormonal therapy was most appropriate. Aromatase inhibitors were generally reserved for postmenopausal women, whereas tamoxifen was preferred in premenopausal women.
Fulvestrant
The FDA initially approved fulvestrant, a hormone receptor downregulator, in 2002 at a 250-mg dose, following progression on an anti-estrogen therapy, such as tamoxifen in postmenopausal women with stage IV breast cancer. The FDA approval was based on similar response rates for the already approved agent anastrozole.4 However, pharmacokinetic findings from the phase 3 EFECT trial in 2008 prompted researchers to explore a 500-mg dose of fulvestrant.5
The recently published FIRST study is a phase 2, randomized, open-label study comparing fulvestrant 500 mg with anastrozole 1 mg as first-line hormonal therapy for postmenopausal women with hormone receptorpositive advanced breast cancer. Fulvestrant was given 500 mg once monthly with an extra dose given on day 14 of month 1. The trial enrolled 233 patients. The median time to progression was 23.4 months for fulvestrant and 13.1 months for anastrozole. These results translate into a 34% reduction in the risk of progression.6
These outcomes suggest that fulvestrant is as viable and perhaps even preferred first-line therapy for postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer. The impressive results from this trial are likely, because the study used the 500-mg dose of fulvestrant, which is twice the dose used in the original trials. However, the 500-mg dose has previously been studied, and long-term outcome data suggest both safety and efficiency. The large randomized, double-blinded phase 3 CONFIRM trial, published in 2013, compared the 250-mg dose with the 500-mg dose and found that the higher dose was associated with a 19% reduction in the risk of death and a 4.1 month increase in median overall survival (OS) without any new safety concerns.5
Palbociclib
The FDA recently granted accelerated approval to palbociclib in combination with letrozole for the first-line therapy of advanced hormone receptor-positive, HER2-negative breast cancer in postmenopausal women. Palbociclib is an oral small-molecular inhibitor of cyclindependent kinases 4 and 6. Preclinical data suggested synergy with anti-estrogen therapies and inhibition of breast cancer cell growth.7
A phase 2, open-label randomized trial (PALOMA-1/TRIO-18) enrolled 165 patients. Progression-free survival (PFS) was 20.2 months for the palbociclib plus letrozole arm and 10.2 months for the letrozole alone arm. Significant toxicities were noted in the palbociclib arm, including 54% of people experiencing grade 3 to 4 neutropenia (vs 1% in the letrozole arm), leukopenia in 19% (vs 0%) and fatigue in 4% (vs 1%). A phase 3 trial is currently enrolling patients.7 While we await the results of the phase 3 trial and long-term follow-up data, palbociclib plus letrozole is a new, viable option for metastatic hormone receptor-positive advanced breast cancer.
Although many practitioners will continue to reasonably use any AI or selective ER modulator when treating metastatic breast cancer, both fulvestrant and palbociclib in combination with letrozole are new evidence-based, first-line options worth considering.
Early-Stage Treatment Options
There are many acceptable therapeutic options for treating early stage breast cancer. Tamoxifen has traditionally been used in the adjuvant setting for premenopausal women, whereas AIs are often used in postmenopausal women. There has also been a long-standing debate about the role of ovarian suppression in premenopausal women.
The recently published phase 3 TEXT and SOFT trials attempted to provide answers to these long-standing therapeutic dilemmas. The SOFT trial randomly assigned 3,066 premenopausal women to 5 years of tamoxifen, 5 years of tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The TEXT trial randomly assigned 2,672 women to receive either exemestane plus ovarian suppression or tamoxifen plus ovarian suppression. The studies showed that subjecting all women receiving tamoxifen to ovarian suppression did not provide any significant benefit.8,9
However, the subgroup of women with high-risk disease who required adjuvant chemotherapy and remained premenopausal experienced improved outcomes from ovarian suppression. This high-risk subgroup when given tamoxifen plus ovarian suppression had a 4.5% absolute reduction in breast cancer recurrence at 5 years compared with the group that received tamoxifen alone. When this high-risk subgroup was given exemestane plus ovarian suppression, the women had a 7.7% absolute reduction in breast cancer recurrence at 5 years compared with the group that received tamoxifen alone.8
Ovarian suppression resulted in significant additional AEs, including depression and menopausal symptoms. The authors of the study also pointed out the additional risk of hypertension, musculoskeletal AEs, and decreased bone density. Furthermore, the OS data from these studies are premature, because the patients had fewer AEs than initially anticipated; this resulted in an only 5% mortality at publication.
The study design also raised several interesting questions. The primary endpoint was disease-free survival. The authors defined this as the time from randomization to the first appearance of invasive recurrence of breast cancer (local, regional, or distant), invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without breast cancer recurrence or second invasive cancer. When studying adjuvant therapy for diseases, such as breast cancer, which carry long-term survival, studies often use PFS with various modified definitions as a surrogate marker for OS. Clinicians are then left to decide whether this surrogate marker is an accurate predictor of OS or other important clinical outcomes.
In the combined analysis of the TEXT and SOFT trials, only 60% of the first recurrences, second invasive cancers, or deaths involved recurrence of breast cancer
at a distant site.9 Because locally recurrent breast cancer is highly treatable and often curable, clinicians must ask whether the increased toxicities of ovarian suppression are worth the large number of women who experienced local recurrence given the still relatively small absolute reduction in recurrence risk.
Last, the study authors retrospectively reviewed data from the International Breast Cancer Study Group and U.S. Intergroup trials and concluded that women aged < 35 years were most likely to be at high-risk for AEs.10,11 A subgroup analysis of women aged < 35 years in the SOFT trial noted that breast cancer recurred within 5 years in one-third of women receiving tamoxifen alone, whereas only in one-sixth of women receiving exemestane plus ovarian suppression.8 This is the basis for the conclusion that premenopausal women, particularly those aged < 35 years, with high-risk disease who receive chemotherapy and remain premenopausal after chemotherapy, benefit from ovarian suppression in combination with tamoxifen, and even more impressively from ovarian suppression combined with exemestane.
The problem is that the study did not risk-stratify patients based on those aged < 35 years, and the conclusion is based on a subgroup analysis using a primary endpoint that may not accurately predict OS. Nonetheless, although not definitive, the data from the TEXT and SOFT trials raise interesting therapeutic questions that require further study and certainly provide tempting therapeutic options in patients who are clinically at high risk for recurrence.
HER2-Positive Breast Cancer
Up to 20% of invasive breast cancers are a result of HER2 gene amplification or overexpression of the HER2 protein, a tyrosine kinase transmembrane receptor, resulting in a more aggressive phenotype and a poor prognosis. Anti-HER2 drugs have changed the landscape of the disease previously known as aggressive breast cancer with a poor survival rate.
Treatment with the anti-HER2 humanized monoclonal antibody trastuzumab in addition to chemotherapy, compared with chemotherapy alone, significantly improves PFS and OS among patients with HER2-positive metastatic as well as early breast cancer. However, in most patients with HER2-positive metastatic breast cancer, the disease progresses, highlighting the need for new, targeted therapies for advanced disease.
New Standard of Care
The original studies of trastuzumab showed improved OS in late-stage (metastatic) breast cancer from 20.3 to 25.1 months, and in early-stage breast cancer, it reduced the risk of cancer returning after surgery by an absolute risk of 9.5% and the risk of death by an absolute risk of 3%.
New therapies directed at HER2 are being developed, among them pertuzumab, a humanized monoclonal antibody that binds HER2 at a different epitope of the HER2 extracellular domain (subdomain 2) than that at which trastuzumab binds. Pertuzumab prevents HER2 from dimerizing with other ligand-activated HER receptors, most notably HER3. Like trastuzumab, pertuzumab stimulates antibody-dependent, cell-mediated cytotoxicity. Because pertuzumab and trastuzumab bind to different HER2 epitopes and have complementary mechanisms of action, these 2 agents, when given together, provide a more comprehensive blockade of HER2 signaling and result in greater antitumor activity than does either agent alone in HER2-positive tumor models.12 In phase 2 studies, a pertuzumab–trastuzumab regimen has shown activity in patients with HER2-positive metastatic breast cancer and in patients with early breast cancer.13
In the phase 3 CLEOPATRA study, the combination of pertuzumab plus trastuzumab plus docetaxel, used as first-line treatment for HER2-positive metastatic breast cancer compared with placebo plus trastuzumab plus docetaxel, significantly prolonged PFS (18.5 months vs 12.4 months), with no increase in cardiac toxic effects.12 In a recent updated follow-up of the CLEOPATRA study, the addition of pertuzumab to trastuzumab and docetaxel showed a significantly better median OS (56.5 months vs 40.8 months; hazard ratio, 0.68; P < .001).14 From these results, this combination regimen is now considered a first-line therapy for patients with HER2-positive metastatic breast cancer.
However, the cost of cancer treatment has become a mounting concern during the past decade, as new therapies come down the pipeline with ever-increasing price tags. Trastuzumab costs about $4,500 a month, and the newer pertuzumab runs about 30% higher, at $6,000 a month. For a full course of treatment, the cost of the pertuzumab and trastuzumab combination could go as high as $195,000, depending on the duration of therapy and the choice of taxanes.
Conclusions
The landscape of therapeutic options in high-risk, young patients with early-stage breast cancer as well as patients with advanced or metastatic disease is changing rapidly.
Clinicians now have 2 new first-line options for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer. A phase 3 trial demonstrated that fulvestrant monotherapy offers improved PFS and some improvement in OS compared with anastrazole in postmenopausal women. A phase 2 trial showed that palbociclib plus letrozole offers improved PFS in postmenopausal women. Based on the SOFT and TEXT trials, clinicians treating high-risk premenopausal women now have some data to inform the debate about whether ovarian suppression should be added to hormone therapy.
Based on the CLEOPATRA trial, clinicians can now consider combination pertuzumab and trastuzumab and docetaxel as first-line therapy for patients with HER2-positive metastatic breast cancer.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Click here to read the digital edition.
1. American Cancer Society. Cancer facts & figures, 2015. Atlanta, GA: American Cancer Society; 2015.
2. American Cancer Society. Cancer treatment & survivorship facts & figures, 2014-2015. Atlanta, GA: American Cancer Society; 2014.
3. National Comprehensive Cancer Network. NCCN clinical Practice guidelines in oncology: breast Cancer. Version 1. 2015. Fort Washington, PA: National Comprehensive Cancer Network; 2015:BINV-19.
4. Howell A, Robertson JF, Quaresma Albano J. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002;20(16):3396-3403.
5. Di Leo A, Jerusalem G, Petruzelka L, et al. Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst. 2014;106(1):djt337.
6. Robertson JF, Lindemann JB, Llombart-Cussac A, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized ‘FIRST’ study. Breast Cancer Res Treat. 2012;136(2):503-511.
7. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25-35.
8. Francis PA, Regan MM, Fleming GF, et al; SOFT Investigators; International Breast Cancer Study Group. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372(5):436-446.
9. Pagani O. Regan MM, Walley BA, et al. TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371(2):107-118.
10. Aebi S, Gelber S, Castiglione-Gertsch M, et al. Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer? Lancet. 2000;355:1869-1874.
11. Goldhirsch A, Gelber RD, Yothers G, et al. Adjuvant therapy for very young women with breast cancer: need for tailored treatments. J Natl Cancer Inst Monogr. 2001;(30):44-51
12. Hudis CA. Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med. 2007;357(1):39-51.
13. Baselga J, Cortés J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-119.
14. Swain SM, Baselga J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734.
It is estimated that there were more than 3.1 million women living in the U.S. with a history of invasive breast cancer as of January 1, 2014, and an additional 231,840 women will be newly diagnosed with invasive breast cancer in 2015.1,2 The median age at the time of breast cancer diagnosis is 61 years. About 20% of breast cancers occur among women aged < 50 years, and 43% occur in women aged > 65 years.
The treatment and prognosis for breast cancer depend on the stage at diagnosis, the biologic characteristics of the tumor, and the age and health of the patient. The overall 5-year relative survival rate for female patients with breast cancer has improved from 75% to 90% from 1975 to 1977 and from 2003 to 2009, respectively, largely due to improvements in treatment (ie, chemotherapy, hormone therapy, and targeted drugs) and because of earlier diagnosis resulting from the widespread use of mammography and other screening tools.2
Estrogen Receptor-Positive Therapies
Women with breast cancer who test positive for hormone receptors are candidates for treatment with hormone therapy to reduce the likelihood of recurrence or as a core component of treatment for advanced disease. Currently available endocrine strategies for the treatment of estrogen receptor- (ER) positive breast cancer include targeting the ER with the antiestrogen drug tamoxifen. Another option is suppressing the amount of available ligand (estrogen) for the receptor either with gonadal suppression in premenopausal oophorectomy, or luteinizing hormonereleasing hormone agonists, or with the aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole in postmenopausal women and by downregulating the receptor with fulvestrant. Given their proven efficacy and generally favorable adverse effect (AE) profile, these endocrine therapies are widely used in the treatment of both early-stage and recurrent and/or metastatic breast cancer.
Recent studies have offered new treatments for patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Innovative hormonal and targeted therapies for advanced disease as well as new data on adjuvant hormonal therapy for young high-risk patients are changing the available therapeutic options.
Advanced Metastatic Treatments
Treatment for metastatic hormone receptor-positive breast cancer has shifted from traditional cytotoxic chemotherapies to targeted therapeutic options. Most treatment guidelines, including the National Comprehensive Cancer Network guidelines, recommend targeted therapy with AIs or selective ER modulators rather than chemotherapy, except in the case of visceral crisis.3
Until recently, there had been relatively little guidance to inform which hormonal therapy was most appropriate. Aromatase inhibitors were generally reserved for postmenopausal women, whereas tamoxifen was preferred in premenopausal women.
Fulvestrant
The FDA initially approved fulvestrant, a hormone receptor downregulator, in 2002 at a 250-mg dose, following progression on an anti-estrogen therapy, such as tamoxifen in postmenopausal women with stage IV breast cancer. The FDA approval was based on similar response rates for the already approved agent anastrozole.4 However, pharmacokinetic findings from the phase 3 EFECT trial in 2008 prompted researchers to explore a 500-mg dose of fulvestrant.5
The recently published FIRST study is a phase 2, randomized, open-label study comparing fulvestrant 500 mg with anastrozole 1 mg as first-line hormonal therapy for postmenopausal women with hormone receptorpositive advanced breast cancer. Fulvestrant was given 500 mg once monthly with an extra dose given on day 14 of month 1. The trial enrolled 233 patients. The median time to progression was 23.4 months for fulvestrant and 13.1 months for anastrozole. These results translate into a 34% reduction in the risk of progression.6
These outcomes suggest that fulvestrant is as viable and perhaps even preferred first-line therapy for postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer. The impressive results from this trial are likely, because the study used the 500-mg dose of fulvestrant, which is twice the dose used in the original trials. However, the 500-mg dose has previously been studied, and long-term outcome data suggest both safety and efficiency. The large randomized, double-blinded phase 3 CONFIRM trial, published in 2013, compared the 250-mg dose with the 500-mg dose and found that the higher dose was associated with a 19% reduction in the risk of death and a 4.1 month increase in median overall survival (OS) without any new safety concerns.5
Palbociclib
The FDA recently granted accelerated approval to palbociclib in combination with letrozole for the first-line therapy of advanced hormone receptor-positive, HER2-negative breast cancer in postmenopausal women. Palbociclib is an oral small-molecular inhibitor of cyclindependent kinases 4 and 6. Preclinical data suggested synergy with anti-estrogen therapies and inhibition of breast cancer cell growth.7
A phase 2, open-label randomized trial (PALOMA-1/TRIO-18) enrolled 165 patients. Progression-free survival (PFS) was 20.2 months for the palbociclib plus letrozole arm and 10.2 months for the letrozole alone arm. Significant toxicities were noted in the palbociclib arm, including 54% of people experiencing grade 3 to 4 neutropenia (vs 1% in the letrozole arm), leukopenia in 19% (vs 0%) and fatigue in 4% (vs 1%). A phase 3 trial is currently enrolling patients.7 While we await the results of the phase 3 trial and long-term follow-up data, palbociclib plus letrozole is a new, viable option for metastatic hormone receptor-positive advanced breast cancer.
Although many practitioners will continue to reasonably use any AI or selective ER modulator when treating metastatic breast cancer, both fulvestrant and palbociclib in combination with letrozole are new evidence-based, first-line options worth considering.
Early-Stage Treatment Options
There are many acceptable therapeutic options for treating early stage breast cancer. Tamoxifen has traditionally been used in the adjuvant setting for premenopausal women, whereas AIs are often used in postmenopausal women. There has also been a long-standing debate about the role of ovarian suppression in premenopausal women.
The recently published phase 3 TEXT and SOFT trials attempted to provide answers to these long-standing therapeutic dilemmas. The SOFT trial randomly assigned 3,066 premenopausal women to 5 years of tamoxifen, 5 years of tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The TEXT trial randomly assigned 2,672 women to receive either exemestane plus ovarian suppression or tamoxifen plus ovarian suppression. The studies showed that subjecting all women receiving tamoxifen to ovarian suppression did not provide any significant benefit.8,9
However, the subgroup of women with high-risk disease who required adjuvant chemotherapy and remained premenopausal experienced improved outcomes from ovarian suppression. This high-risk subgroup when given tamoxifen plus ovarian suppression had a 4.5% absolute reduction in breast cancer recurrence at 5 years compared with the group that received tamoxifen alone. When this high-risk subgroup was given exemestane plus ovarian suppression, the women had a 7.7% absolute reduction in breast cancer recurrence at 5 years compared with the group that received tamoxifen alone.8
Ovarian suppression resulted in significant additional AEs, including depression and menopausal symptoms. The authors of the study also pointed out the additional risk of hypertension, musculoskeletal AEs, and decreased bone density. Furthermore, the OS data from these studies are premature, because the patients had fewer AEs than initially anticipated; this resulted in an only 5% mortality at publication.
The study design also raised several interesting questions. The primary endpoint was disease-free survival. The authors defined this as the time from randomization to the first appearance of invasive recurrence of breast cancer (local, regional, or distant), invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without breast cancer recurrence or second invasive cancer. When studying adjuvant therapy for diseases, such as breast cancer, which carry long-term survival, studies often use PFS with various modified definitions as a surrogate marker for OS. Clinicians are then left to decide whether this surrogate marker is an accurate predictor of OS or other important clinical outcomes.
In the combined analysis of the TEXT and SOFT trials, only 60% of the first recurrences, second invasive cancers, or deaths involved recurrence of breast cancer
at a distant site.9 Because locally recurrent breast cancer is highly treatable and often curable, clinicians must ask whether the increased toxicities of ovarian suppression are worth the large number of women who experienced local recurrence given the still relatively small absolute reduction in recurrence risk.
Last, the study authors retrospectively reviewed data from the International Breast Cancer Study Group and U.S. Intergroup trials and concluded that women aged < 35 years were most likely to be at high-risk for AEs.10,11 A subgroup analysis of women aged < 35 years in the SOFT trial noted that breast cancer recurred within 5 years in one-third of women receiving tamoxifen alone, whereas only in one-sixth of women receiving exemestane plus ovarian suppression.8 This is the basis for the conclusion that premenopausal women, particularly those aged < 35 years, with high-risk disease who receive chemotherapy and remain premenopausal after chemotherapy, benefit from ovarian suppression in combination with tamoxifen, and even more impressively from ovarian suppression combined with exemestane.
The problem is that the study did not risk-stratify patients based on those aged < 35 years, and the conclusion is based on a subgroup analysis using a primary endpoint that may not accurately predict OS. Nonetheless, although not definitive, the data from the TEXT and SOFT trials raise interesting therapeutic questions that require further study and certainly provide tempting therapeutic options in patients who are clinically at high risk for recurrence.
HER2-Positive Breast Cancer
Up to 20% of invasive breast cancers are a result of HER2 gene amplification or overexpression of the HER2 protein, a tyrosine kinase transmembrane receptor, resulting in a more aggressive phenotype and a poor prognosis. Anti-HER2 drugs have changed the landscape of the disease previously known as aggressive breast cancer with a poor survival rate.
Treatment with the anti-HER2 humanized monoclonal antibody trastuzumab in addition to chemotherapy, compared with chemotherapy alone, significantly improves PFS and OS among patients with HER2-positive metastatic as well as early breast cancer. However, in most patients with HER2-positive metastatic breast cancer, the disease progresses, highlighting the need for new, targeted therapies for advanced disease.
New Standard of Care
The original studies of trastuzumab showed improved OS in late-stage (metastatic) breast cancer from 20.3 to 25.1 months, and in early-stage breast cancer, it reduced the risk of cancer returning after surgery by an absolute risk of 9.5% and the risk of death by an absolute risk of 3%.
New therapies directed at HER2 are being developed, among them pertuzumab, a humanized monoclonal antibody that binds HER2 at a different epitope of the HER2 extracellular domain (subdomain 2) than that at which trastuzumab binds. Pertuzumab prevents HER2 from dimerizing with other ligand-activated HER receptors, most notably HER3. Like trastuzumab, pertuzumab stimulates antibody-dependent, cell-mediated cytotoxicity. Because pertuzumab and trastuzumab bind to different HER2 epitopes and have complementary mechanisms of action, these 2 agents, when given together, provide a more comprehensive blockade of HER2 signaling and result in greater antitumor activity than does either agent alone in HER2-positive tumor models.12 In phase 2 studies, a pertuzumab–trastuzumab regimen has shown activity in patients with HER2-positive metastatic breast cancer and in patients with early breast cancer.13
In the phase 3 CLEOPATRA study, the combination of pertuzumab plus trastuzumab plus docetaxel, used as first-line treatment for HER2-positive metastatic breast cancer compared with placebo plus trastuzumab plus docetaxel, significantly prolonged PFS (18.5 months vs 12.4 months), with no increase in cardiac toxic effects.12 In a recent updated follow-up of the CLEOPATRA study, the addition of pertuzumab to trastuzumab and docetaxel showed a significantly better median OS (56.5 months vs 40.8 months; hazard ratio, 0.68; P < .001).14 From these results, this combination regimen is now considered a first-line therapy for patients with HER2-positive metastatic breast cancer.
However, the cost of cancer treatment has become a mounting concern during the past decade, as new therapies come down the pipeline with ever-increasing price tags. Trastuzumab costs about $4,500 a month, and the newer pertuzumab runs about 30% higher, at $6,000 a month. For a full course of treatment, the cost of the pertuzumab and trastuzumab combination could go as high as $195,000, depending on the duration of therapy and the choice of taxanes.
Conclusions
The landscape of therapeutic options in high-risk, young patients with early-stage breast cancer as well as patients with advanced or metastatic disease is changing rapidly.
Clinicians now have 2 new first-line options for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer. A phase 3 trial demonstrated that fulvestrant monotherapy offers improved PFS and some improvement in OS compared with anastrazole in postmenopausal women. A phase 2 trial showed that palbociclib plus letrozole offers improved PFS in postmenopausal women. Based on the SOFT and TEXT trials, clinicians treating high-risk premenopausal women now have some data to inform the debate about whether ovarian suppression should be added to hormone therapy.
Based on the CLEOPATRA trial, clinicians can now consider combination pertuzumab and trastuzumab and docetaxel as first-line therapy for patients with HER2-positive metastatic breast cancer.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Click here to read the digital edition.
It is estimated that there were more than 3.1 million women living in the U.S. with a history of invasive breast cancer as of January 1, 2014, and an additional 231,840 women will be newly diagnosed with invasive breast cancer in 2015.1,2 The median age at the time of breast cancer diagnosis is 61 years. About 20% of breast cancers occur among women aged < 50 years, and 43% occur in women aged > 65 years.
The treatment and prognosis for breast cancer depend on the stage at diagnosis, the biologic characteristics of the tumor, and the age and health of the patient. The overall 5-year relative survival rate for female patients with breast cancer has improved from 75% to 90% from 1975 to 1977 and from 2003 to 2009, respectively, largely due to improvements in treatment (ie, chemotherapy, hormone therapy, and targeted drugs) and because of earlier diagnosis resulting from the widespread use of mammography and other screening tools.2
Estrogen Receptor-Positive Therapies
Women with breast cancer who test positive for hormone receptors are candidates for treatment with hormone therapy to reduce the likelihood of recurrence or as a core component of treatment for advanced disease. Currently available endocrine strategies for the treatment of estrogen receptor- (ER) positive breast cancer include targeting the ER with the antiestrogen drug tamoxifen. Another option is suppressing the amount of available ligand (estrogen) for the receptor either with gonadal suppression in premenopausal oophorectomy, or luteinizing hormonereleasing hormone agonists, or with the aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole in postmenopausal women and by downregulating the receptor with fulvestrant. Given their proven efficacy and generally favorable adverse effect (AE) profile, these endocrine therapies are widely used in the treatment of both early-stage and recurrent and/or metastatic breast cancer.
Recent studies have offered new treatments for patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Innovative hormonal and targeted therapies for advanced disease as well as new data on adjuvant hormonal therapy for young high-risk patients are changing the available therapeutic options.
Advanced Metastatic Treatments
Treatment for metastatic hormone receptor-positive breast cancer has shifted from traditional cytotoxic chemotherapies to targeted therapeutic options. Most treatment guidelines, including the National Comprehensive Cancer Network guidelines, recommend targeted therapy with AIs or selective ER modulators rather than chemotherapy, except in the case of visceral crisis.3
Until recently, there had been relatively little guidance to inform which hormonal therapy was most appropriate. Aromatase inhibitors were generally reserved for postmenopausal women, whereas tamoxifen was preferred in premenopausal women.
Fulvestrant
The FDA initially approved fulvestrant, a hormone receptor downregulator, in 2002 at a 250-mg dose, following progression on an anti-estrogen therapy, such as tamoxifen in postmenopausal women with stage IV breast cancer. The FDA approval was based on similar response rates for the already approved agent anastrozole.4 However, pharmacokinetic findings from the phase 3 EFECT trial in 2008 prompted researchers to explore a 500-mg dose of fulvestrant.5
The recently published FIRST study is a phase 2, randomized, open-label study comparing fulvestrant 500 mg with anastrozole 1 mg as first-line hormonal therapy for postmenopausal women with hormone receptorpositive advanced breast cancer. Fulvestrant was given 500 mg once monthly with an extra dose given on day 14 of month 1. The trial enrolled 233 patients. The median time to progression was 23.4 months for fulvestrant and 13.1 months for anastrozole. These results translate into a 34% reduction in the risk of progression.6
These outcomes suggest that fulvestrant is as viable and perhaps even preferred first-line therapy for postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer. The impressive results from this trial are likely, because the study used the 500-mg dose of fulvestrant, which is twice the dose used in the original trials. However, the 500-mg dose has previously been studied, and long-term outcome data suggest both safety and efficiency. The large randomized, double-blinded phase 3 CONFIRM trial, published in 2013, compared the 250-mg dose with the 500-mg dose and found that the higher dose was associated with a 19% reduction in the risk of death and a 4.1 month increase in median overall survival (OS) without any new safety concerns.5
Palbociclib
The FDA recently granted accelerated approval to palbociclib in combination with letrozole for the first-line therapy of advanced hormone receptor-positive, HER2-negative breast cancer in postmenopausal women. Palbociclib is an oral small-molecular inhibitor of cyclindependent kinases 4 and 6. Preclinical data suggested synergy with anti-estrogen therapies and inhibition of breast cancer cell growth.7
A phase 2, open-label randomized trial (PALOMA-1/TRIO-18) enrolled 165 patients. Progression-free survival (PFS) was 20.2 months for the palbociclib plus letrozole arm and 10.2 months for the letrozole alone arm. Significant toxicities were noted in the palbociclib arm, including 54% of people experiencing grade 3 to 4 neutropenia (vs 1% in the letrozole arm), leukopenia in 19% (vs 0%) and fatigue in 4% (vs 1%). A phase 3 trial is currently enrolling patients.7 While we await the results of the phase 3 trial and long-term follow-up data, palbociclib plus letrozole is a new, viable option for metastatic hormone receptor-positive advanced breast cancer.
Although many practitioners will continue to reasonably use any AI or selective ER modulator when treating metastatic breast cancer, both fulvestrant and palbociclib in combination with letrozole are new evidence-based, first-line options worth considering.
Early-Stage Treatment Options
There are many acceptable therapeutic options for treating early stage breast cancer. Tamoxifen has traditionally been used in the adjuvant setting for premenopausal women, whereas AIs are often used in postmenopausal women. There has also been a long-standing debate about the role of ovarian suppression in premenopausal women.
The recently published phase 3 TEXT and SOFT trials attempted to provide answers to these long-standing therapeutic dilemmas. The SOFT trial randomly assigned 3,066 premenopausal women to 5 years of tamoxifen, 5 years of tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The TEXT trial randomly assigned 2,672 women to receive either exemestane plus ovarian suppression or tamoxifen plus ovarian suppression. The studies showed that subjecting all women receiving tamoxifen to ovarian suppression did not provide any significant benefit.8,9
However, the subgroup of women with high-risk disease who required adjuvant chemotherapy and remained premenopausal experienced improved outcomes from ovarian suppression. This high-risk subgroup when given tamoxifen plus ovarian suppression had a 4.5% absolute reduction in breast cancer recurrence at 5 years compared with the group that received tamoxifen alone. When this high-risk subgroup was given exemestane plus ovarian suppression, the women had a 7.7% absolute reduction in breast cancer recurrence at 5 years compared with the group that received tamoxifen alone.8
Ovarian suppression resulted in significant additional AEs, including depression and menopausal symptoms. The authors of the study also pointed out the additional risk of hypertension, musculoskeletal AEs, and decreased bone density. Furthermore, the OS data from these studies are premature, because the patients had fewer AEs than initially anticipated; this resulted in an only 5% mortality at publication.
The study design also raised several interesting questions. The primary endpoint was disease-free survival. The authors defined this as the time from randomization to the first appearance of invasive recurrence of breast cancer (local, regional, or distant), invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without breast cancer recurrence or second invasive cancer. When studying adjuvant therapy for diseases, such as breast cancer, which carry long-term survival, studies often use PFS with various modified definitions as a surrogate marker for OS. Clinicians are then left to decide whether this surrogate marker is an accurate predictor of OS or other important clinical outcomes.
In the combined analysis of the TEXT and SOFT trials, only 60% of the first recurrences, second invasive cancers, or deaths involved recurrence of breast cancer
at a distant site.9 Because locally recurrent breast cancer is highly treatable and often curable, clinicians must ask whether the increased toxicities of ovarian suppression are worth the large number of women who experienced local recurrence given the still relatively small absolute reduction in recurrence risk.
Last, the study authors retrospectively reviewed data from the International Breast Cancer Study Group and U.S. Intergroup trials and concluded that women aged < 35 years were most likely to be at high-risk for AEs.10,11 A subgroup analysis of women aged < 35 years in the SOFT trial noted that breast cancer recurred within 5 years in one-third of women receiving tamoxifen alone, whereas only in one-sixth of women receiving exemestane plus ovarian suppression.8 This is the basis for the conclusion that premenopausal women, particularly those aged < 35 years, with high-risk disease who receive chemotherapy and remain premenopausal after chemotherapy, benefit from ovarian suppression in combination with tamoxifen, and even more impressively from ovarian suppression combined with exemestane.
The problem is that the study did not risk-stratify patients based on those aged < 35 years, and the conclusion is based on a subgroup analysis using a primary endpoint that may not accurately predict OS. Nonetheless, although not definitive, the data from the TEXT and SOFT trials raise interesting therapeutic questions that require further study and certainly provide tempting therapeutic options in patients who are clinically at high risk for recurrence.
HER2-Positive Breast Cancer
Up to 20% of invasive breast cancers are a result of HER2 gene amplification or overexpression of the HER2 protein, a tyrosine kinase transmembrane receptor, resulting in a more aggressive phenotype and a poor prognosis. Anti-HER2 drugs have changed the landscape of the disease previously known as aggressive breast cancer with a poor survival rate.
Treatment with the anti-HER2 humanized monoclonal antibody trastuzumab in addition to chemotherapy, compared with chemotherapy alone, significantly improves PFS and OS among patients with HER2-positive metastatic as well as early breast cancer. However, in most patients with HER2-positive metastatic breast cancer, the disease progresses, highlighting the need for new, targeted therapies for advanced disease.
New Standard of Care
The original studies of trastuzumab showed improved OS in late-stage (metastatic) breast cancer from 20.3 to 25.1 months, and in early-stage breast cancer, it reduced the risk of cancer returning after surgery by an absolute risk of 9.5% and the risk of death by an absolute risk of 3%.
New therapies directed at HER2 are being developed, among them pertuzumab, a humanized monoclonal antibody that binds HER2 at a different epitope of the HER2 extracellular domain (subdomain 2) than that at which trastuzumab binds. Pertuzumab prevents HER2 from dimerizing with other ligand-activated HER receptors, most notably HER3. Like trastuzumab, pertuzumab stimulates antibody-dependent, cell-mediated cytotoxicity. Because pertuzumab and trastuzumab bind to different HER2 epitopes and have complementary mechanisms of action, these 2 agents, when given together, provide a more comprehensive blockade of HER2 signaling and result in greater antitumor activity than does either agent alone in HER2-positive tumor models.12 In phase 2 studies, a pertuzumab–trastuzumab regimen has shown activity in patients with HER2-positive metastatic breast cancer and in patients with early breast cancer.13
In the phase 3 CLEOPATRA study, the combination of pertuzumab plus trastuzumab plus docetaxel, used as first-line treatment for HER2-positive metastatic breast cancer compared with placebo plus trastuzumab plus docetaxel, significantly prolonged PFS (18.5 months vs 12.4 months), with no increase in cardiac toxic effects.12 In a recent updated follow-up of the CLEOPATRA study, the addition of pertuzumab to trastuzumab and docetaxel showed a significantly better median OS (56.5 months vs 40.8 months; hazard ratio, 0.68; P < .001).14 From these results, this combination regimen is now considered a first-line therapy for patients with HER2-positive metastatic breast cancer.
However, the cost of cancer treatment has become a mounting concern during the past decade, as new therapies come down the pipeline with ever-increasing price tags. Trastuzumab costs about $4,500 a month, and the newer pertuzumab runs about 30% higher, at $6,000 a month. For a full course of treatment, the cost of the pertuzumab and trastuzumab combination could go as high as $195,000, depending on the duration of therapy and the choice of taxanes.
Conclusions
The landscape of therapeutic options in high-risk, young patients with early-stage breast cancer as well as patients with advanced or metastatic disease is changing rapidly.
Clinicians now have 2 new first-line options for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer. A phase 3 trial demonstrated that fulvestrant monotherapy offers improved PFS and some improvement in OS compared with anastrazole in postmenopausal women. A phase 2 trial showed that palbociclib plus letrozole offers improved PFS in postmenopausal women. Based on the SOFT and TEXT trials, clinicians treating high-risk premenopausal women now have some data to inform the debate about whether ovarian suppression should be added to hormone therapy.
Based on the CLEOPATRA trial, clinicians can now consider combination pertuzumab and trastuzumab and docetaxel as first-line therapy for patients with HER2-positive metastatic breast cancer.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
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1. American Cancer Society. Cancer facts & figures, 2015. Atlanta, GA: American Cancer Society; 2015.
2. American Cancer Society. Cancer treatment & survivorship facts & figures, 2014-2015. Atlanta, GA: American Cancer Society; 2014.
3. National Comprehensive Cancer Network. NCCN clinical Practice guidelines in oncology: breast Cancer. Version 1. 2015. Fort Washington, PA: National Comprehensive Cancer Network; 2015:BINV-19.
4. Howell A, Robertson JF, Quaresma Albano J. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002;20(16):3396-3403.
5. Di Leo A, Jerusalem G, Petruzelka L, et al. Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst. 2014;106(1):djt337.
6. Robertson JF, Lindemann JB, Llombart-Cussac A, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized ‘FIRST’ study. Breast Cancer Res Treat. 2012;136(2):503-511.
7. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25-35.
8. Francis PA, Regan MM, Fleming GF, et al; SOFT Investigators; International Breast Cancer Study Group. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372(5):436-446.
9. Pagani O. Regan MM, Walley BA, et al. TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371(2):107-118.
10. Aebi S, Gelber S, Castiglione-Gertsch M, et al. Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer? Lancet. 2000;355:1869-1874.
11. Goldhirsch A, Gelber RD, Yothers G, et al. Adjuvant therapy for very young women with breast cancer: need for tailored treatments. J Natl Cancer Inst Monogr. 2001;(30):44-51
12. Hudis CA. Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med. 2007;357(1):39-51.
13. Baselga J, Cortés J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-119.
14. Swain SM, Baselga J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734.
1. American Cancer Society. Cancer facts & figures, 2015. Atlanta, GA: American Cancer Society; 2015.
2. American Cancer Society. Cancer treatment & survivorship facts & figures, 2014-2015. Atlanta, GA: American Cancer Society; 2014.
3. National Comprehensive Cancer Network. NCCN clinical Practice guidelines in oncology: breast Cancer. Version 1. 2015. Fort Washington, PA: National Comprehensive Cancer Network; 2015:BINV-19.
4. Howell A, Robertson JF, Quaresma Albano J. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002;20(16):3396-3403.
5. Di Leo A, Jerusalem G, Petruzelka L, et al. Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst. 2014;106(1):djt337.
6. Robertson JF, Lindemann JB, Llombart-Cussac A, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized ‘FIRST’ study. Breast Cancer Res Treat. 2012;136(2):503-511.
7. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25-35.
8. Francis PA, Regan MM, Fleming GF, et al; SOFT Investigators; International Breast Cancer Study Group. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372(5):436-446.
9. Pagani O. Regan MM, Walley BA, et al. TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371(2):107-118.
10. Aebi S, Gelber S, Castiglione-Gertsch M, et al. Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer? Lancet. 2000;355:1869-1874.
11. Goldhirsch A, Gelber RD, Yothers G, et al. Adjuvant therapy for very young women with breast cancer: need for tailored treatments. J Natl Cancer Inst Monogr. 2001;(30):44-51
12. Hudis CA. Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med. 2007;357(1):39-51.
13. Baselga J, Cortés J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-119.
14. Swain SM, Baselga J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734.