Breast Cancer

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

When cancer care is centralized in a comprehensive fashion, the quality of care and the outcomes improve.^1,2 Unfortunately, because of the medical insurance structure in New York City, most patients of lower socioeconomic status do not receive their cancer care in such dedicated cancer centers. In New York City, the majority of the underserved vulnerable populations – that is, those without health insurance – receive their care from the public hospital system known as NYC Health and Hospitals. Cancer care in this system is not centralized and may result in fragmented implementation of various modalities of treatment. In addition, because there is no centralized care, needs such as early screening and prevention programs are often not addressed. This problem was evident in Queens in 2000 and before when many patients with late-stage cancers were presenting for cancer care. Queens, which is one of the 5 boroughs of New York City, has more than 2.3 million residents. It has 2 public hospitals, Elmhurst Hospital Center and Queens Hospital Center (QHC). In 2001, the plan was devised for the establishment of a cancer center at QHC, mainly because of the high rate of late-stage cancers that were being seen at presentation and recognition of the need for more comprehensive care. In 2002, the Queens Cancer Center (QCC) began to see patients. QCC is a single facility that provides medical, surgical, radiation, gynecologic, and urologic oncology all in one area of the QHC.

This study is an investigation of the possible impact on care for breast cancer patients of low socioeconomic status who were treated at a comprehensive cancer center, with specific consideration of the change or improvement in treatment modalities and outcomes. Data on treatment modalities and outcomes of cancer patients who were treated at the QHC during 2000, before the QCC was set up, were compared with data of patients treated during 2008 (2008 was selected because we have 5-year survival data for those patients). The public hospital system treats all patients regardless of their ability to pay, so the majority of patients in the system are of lower socioeconomic status. In addition, 92% of the patients seen QHC are from a minority population. These are the populations that tend to have a worse prognosis and often are not given optimal treatment.³ The payer mix of patients in the public hospital system is different than that of private hospitals. Most of the patients present at the hospital with no insurance and if they are diagnosed with cancer they may be converted to emergency Medicaid. About 10% of patients will not be converted because of their document status.
 

Patients and methods

We used the Queens Hospital Tumor Registry to identify the patients who had been diagnosed with and treated for breast cancer in 2000 and 2008. The electronic medical records were reviewed, and in the case of the 2000-year patients, the written charts were also reviewed. The study was approved by the Mount Sinai institutional review board. It was not necessary to obtain patient consent because it was a retrospective study.

Only patients diagnosed with stage 0, I, II, or III breast cancer who received their treatment at QHC were included in the study. Patients who were seen in consultation at QHC but not treated there were excluded. Statistics were done using the 2x2 chi-squared SPSS analysis; a P value of .05 was considered significant. The survival data was analyzed using SAS.

Results

There were 24 evaluable patients in 2000 and 78 evaluable patients in 2008 who had stage 0, I, II, or III primary breast cancer and were treated at QHC. The average age of the patients in 2000 was 53.5 years and 54.7 years in 2008. The mean age for both groups was 55 years. The patients were ethnically diverse in both groups with 46% black, 17% Hispanic, 25% ethnic Asian Indian, and 6% white (Figure 1).

The payer mix in 2000 was 9 patients (37.5%) self-pay, 7 (29%) Medicaid, and 8 (33%) Medicare. In 2008, 11 patients (14%) were self-pay, 46 (59%) Medicaid, 11 (14%) Medicare, and 10 (13%) were private insurance. In 2000, there were 3 (12%) patients with stage 0 disease, 5 (21%) with stage I; 9 (37.5%) with stage II, and 7 (29%) with stage III. In 2008 there were 28 (36%) patients with stage 0 disease, 15 (19%) with stage I, 17 (22%) with stage II, and 18 (23%) with stage III (Figure 2).

Discussion

There have been numerous studies reporting on disparities in the treatment of patients with breast cancer based on race or socioeconomic status.^4-18 Many studies have shown inferior survival for black women with breast cancer, but it is not entirely clear whether these differences are the result of the quality of medical care received or biologic differences.^14,19 A moderately large study from a metropolitan medical center in Detroit showed no difference in survival in their patients based on race when all of the patients received equal treatments.¹⁵ A meta-analysis of survival in black and white breast cancer patients showed that the black women had significantly poorer outcomes.¹⁹

Findings from a recent study showed that patients of lower socioeconomic status are more likely to undergo mastectomy than breast conserving therapy.²⁰ The study, which identified 727,927 patients with early-stage breast cancer during 1998-2011, found that the rate of breast conservation increased from 54% to 59% during that time period and that there were significant barriers to women receiving breast-conserving therapy based on their type of insurance and having a lower socioeconomic status.²⁰

The treatment of breast cancer is best delivered in a multimodality setting, but many inner-city public hospitals do not have such a facility for their patients. QHC is the only public hospital in New York City that has established a comprehensive cancer center. The patient population of QHC is overwhelmingly of minority origin (only 5% of patients are white). In addition, it is a safety net hospital, so no patient is turned away because they cannot pay, and most patients are of lower socioeconomic status and do not have insurance. The purpose of the cancer center was to provide a single site at which our patients could receive all their treatment. It was to ensure that our patients had easy access to care and treatment during all phases of their disease trajectory and did not “fall through the cracks” of the system. Those goals were addressed by having all of the center’s physicians in one place. Physicians involved in care included medical, surgical, and radiation oncologists, a gynecologic oncologist, a genitourinary oncologist, and a thoracic surgery oncologist. The support groups organized for the cancer patients included 3 oncology social workers, an oncology navigator, a nutritionist, a pastoral care supporter, and an oncology psychologist, all located in the same area. All of the clerical and financial aspects of care were also placed within the center. This made the experience as seamless as possible for both the patients and the treating physicians. A “survivors clinic” was established so the cancer patients could be seen by integrated primary care providers to address all noncancer-related health issues such as hypertension, diabetes, or heart disease. Finally, a robust clinical oncology research team was established in the same location. The research included several protocols for new drug treatments for breast cancer from pharmaceutical companies as well as the multi-institutional oncology groups.

Part of the mission of the cancer center was to reach out into the community of Queens to provide education about early detection, cancer prevention, and other public health issues such as tobacco cessation. We established a close working relationship with the Queens Public Library System to connect with their users and dispense information about cancer care and early detection. The Queens Library system is the largest in the United States, and everyone who lives in Queens has easy access to one of its 63 branch libraries. We arranged several lectures about breast cancer awareness in some of the branch libraries. We also procured a mobile mammogram unit for free screening events at the lectures, especially in neighborhoods with a large number residents who were of lower socioeconomic status.

To study the possible effect of these changes on our patients with breast cancer, we compared 2 groups of patients. One group was from the year 2000, a year before the cancer center was opened. The other was from the year 2008, the last year we could get real 5-year survival statistics. We explored how establishing the cancer center might have changed the patients’ stage at diagnosis, care, treatment modalities such as type of surgery, and outcomes. It is difficult to compare these 2 groups because of differences in the patients’ cancers, such as their receptor status, as well as differences in treatment options between the two time periods. However, we had no other way to compare the data to see if there were any trends.

There was a migration to earlier-stage cancer at diagnosis during the 6-year period after the cancer center was opened. It is likely that the educational sessions that were done in the community contributed to this migration. We also saw an increase in the number of mammograms done, from 6,300 in 2000 to 8,800 in 2008. This increase in screening also could account for more patients being identified with earlier-stage disease and might be attributable to the community education through the outreach programs.

As a quality control method, the cancer center has been evaluated by the Commission on Cancer every 3 years. At the 2013 evaluation, we received the Gold Commendation – the highest possible recognition for having 8 out of 8 commendations – and a 3-year accreditation.

There was a notable increase in the use of lumpectomy over mastectomy after the establishment of the cancer center, possibly due to the addition of 2 surgical oncologists to the cancer center’s care team. The integration of multimodiality care for each patient may also have increased the use of breast-conserving surgery.

There was a significant increase from 2000 to 2008 in the survival of patients treated for stage III breast cancer. New drugs and new patterns of adjuvant care might have been partly responsible for that change. The establishment of the comprehensive cancer center with access to new protocols ensured that patients received state-of-the-art cancer treatment. Moreover, the facility addressed all aspects of patient care throughout the disease trajectory by including designated social workers, psychologists, a nutritionist, pastoral care, and patient and survivor support groups to ensure that patients would keep coming to the center for their therapy, with no delays and very little loss to follow-up.

Most patients without insurance were able to acquire emergency Medicaid through the cancer center. This was done by having 2 financial counselors who met with every patient and who could facilitate access to Medicaid as needed. As a result of that, the percentage of patients with no coverage went from 86% in 2000 to 16% in 2008. Before this system was set up, patients who were designated self-pay would pay a fee as low as $15 for each visit and received thousands of dollars’ worth of care. Thus, by forming a cancer center and facilitating patient access to Medicaid, we were able to save money for this public institution because of the gain in revenue from Medicaid.

Our findings suggest that the development of comprehensive cancer centers within inner-city health systems can ensure better treatment for patients of lower socioeconomic status. We present evidence that this may result in increased survival, more sophisticated surgical options, and better patient quality of life. Moreover, this can be achieved while effectively increasing revenue for the public hospitals. Correcting the inequality of access to care and better therapeutic options by setting up comprehensive cancer centers could contribute to improved parity of outcomes for underserved populations.
 

The author acknowledges the statistical help of Brian Altonen, MPH.

When cancer care is centralized in a comprehensive fashion, the quality of care and the outcomes improve.^1,2 Unfortunately, because of the medical insurance structure in New York City, most patients of lower socioeconomic status do not receive their cancer care in such dedicated cancer centers. In New York City, the majority of the underserved vulnerable populations – that is, those without health insurance – receive their care from the public hospital system known as NYC Health and Hospitals. Cancer care in this system is not centralized and may result in fragmented implementation of various modalities of treatment. In addition, because there is no centralized care, needs such as early screening and prevention programs are often not addressed. This problem was evident in Queens in 2000 and before when many patients with late-stage cancers were presenting for cancer care. Queens, which is one of the 5 boroughs of New York City, has more than 2.3 million residents. It has 2 public hospitals, Elmhurst Hospital Center and Queens Hospital Center (QHC). In 2001, the plan was devised for the establishment of a cancer center at QHC, mainly because of the high rate of late-stage cancers that were being seen at presentation and recognition of the need for more comprehensive care. In 2002, the Queens Cancer Center (QCC) began to see patients. QCC is a single facility that provides medical, surgical, radiation, gynecologic, and urologic oncology all in one area of the QHC.

This study is an investigation of the possible impact on care for breast cancer patients of low socioeconomic status who were treated at a comprehensive cancer center, with specific consideration of the change or improvement in treatment modalities and outcomes. Data on treatment modalities and outcomes of cancer patients who were treated at the QHC during 2000, before the QCC was set up, were compared with data of patients treated during 2008 (2008 was selected because we have 5-year survival data for those patients). The public hospital system treats all patients regardless of their ability to pay, so the majority of patients in the system are of lower socioeconomic status. In addition, 92% of the patients seen QHC are from a minority population. These are the populations that tend to have a worse prognosis and often are not given optimal treatment.³ The payer mix of patients in the public hospital system is different than that of private hospitals. Most of the patients present at the hospital with no insurance and if they are diagnosed with cancer they may be converted to emergency Medicaid. About 10% of patients will not be converted because of their document status.
 

Patients and methods

We used the Queens Hospital Tumor Registry to identify the patients who had been diagnosed with and treated for breast cancer in 2000 and 2008. The electronic medical records were reviewed, and in the case of the 2000-year patients, the written charts were also reviewed. The study was approved by the Mount Sinai institutional review board. It was not necessary to obtain patient consent because it was a retrospective study.

Only patients diagnosed with stage 0, I, II, or III breast cancer who received their treatment at QHC were included in the study. Patients who were seen in consultation at QHC but not treated there were excluded. Statistics were done using the 2x2 chi-squared SPSS analysis; a P value of .05 was considered significant. The survival data was analyzed using SAS.

Results

There were 24 evaluable patients in 2000 and 78 evaluable patients in 2008 who had stage 0, I, II, or III primary breast cancer and were treated at QHC. The average age of the patients in 2000 was 53.5 years and 54.7 years in 2008. The mean age for both groups was 55 years. The patients were ethnically diverse in both groups with 46% black, 17% Hispanic, 25% ethnic Asian Indian, and 6% white (Figure 1).

The payer mix in 2000 was 9 patients (37.5%) self-pay, 7 (29%) Medicaid, and 8 (33%) Medicare. In 2008, 11 patients (14%) were self-pay, 46 (59%) Medicaid, 11 (14%) Medicare, and 10 (13%) were private insurance. In 2000, there were 3 (12%) patients with stage 0 disease, 5 (21%) with stage I; 9 (37.5%) with stage II, and 7 (29%) with stage III. In 2008 there were 28 (36%) patients with stage 0 disease, 15 (19%) with stage I, 17 (22%) with stage II, and 18 (23%) with stage III (Figure 2).

Discussion

There have been numerous studies reporting on disparities in the treatment of patients with breast cancer based on race or socioeconomic status.^4-18 Many studies have shown inferior survival for black women with breast cancer, but it is not entirely clear whether these differences are the result of the quality of medical care received or biologic differences.^14,19 A moderately large study from a metropolitan medical center in Detroit showed no difference in survival in their patients based on race when all of the patients received equal treatments.¹⁵ A meta-analysis of survival in black and white breast cancer patients showed that the black women had significantly poorer outcomes.¹⁹

Findings from a recent study showed that patients of lower socioeconomic status are more likely to undergo mastectomy than breast conserving therapy.²⁰ The study, which identified 727,927 patients with early-stage breast cancer during 1998-2011, found that the rate of breast conservation increased from 54% to 59% during that time period and that there were significant barriers to women receiving breast-conserving therapy based on their type of insurance and having a lower socioeconomic status.²⁰

The treatment of breast cancer is best delivered in a multimodality setting, but many inner-city public hospitals do not have such a facility for their patients. QHC is the only public hospital in New York City that has established a comprehensive cancer center. The patient population of QHC is overwhelmingly of minority origin (only 5% of patients are white). In addition, it is a safety net hospital, so no patient is turned away because they cannot pay, and most patients are of lower socioeconomic status and do not have insurance. The purpose of the cancer center was to provide a single site at which our patients could receive all their treatment. It was to ensure that our patients had easy access to care and treatment during all phases of their disease trajectory and did not “fall through the cracks” of the system. Those goals were addressed by having all of the center’s physicians in one place. Physicians involved in care included medical, surgical, and radiation oncologists, a gynecologic oncologist, a genitourinary oncologist, and a thoracic surgery oncologist. The support groups organized for the cancer patients included 3 oncology social workers, an oncology navigator, a nutritionist, a pastoral care supporter, and an oncology psychologist, all located in the same area. All of the clerical and financial aspects of care were also placed within the center. This made the experience as seamless as possible for both the patients and the treating physicians. A “survivors clinic” was established so the cancer patients could be seen by integrated primary care providers to address all noncancer-related health issues such as hypertension, diabetes, or heart disease. Finally, a robust clinical oncology research team was established in the same location. The research included several protocols for new drug treatments for breast cancer from pharmaceutical companies as well as the multi-institutional oncology groups.

Part of the mission of the cancer center was to reach out into the community of Queens to provide education about early detection, cancer prevention, and other public health issues such as tobacco cessation. We established a close working relationship with the Queens Public Library System to connect with their users and dispense information about cancer care and early detection. The Queens Library system is the largest in the United States, and everyone who lives in Queens has easy access to one of its 63 branch libraries. We arranged several lectures about breast cancer awareness in some of the branch libraries. We also procured a mobile mammogram unit for free screening events at the lectures, especially in neighborhoods with a large number residents who were of lower socioeconomic status.

To study the possible effect of these changes on our patients with breast cancer, we compared 2 groups of patients. One group was from the year 2000, a year before the cancer center was opened. The other was from the year 2008, the last year we could get real 5-year survival statistics. We explored how establishing the cancer center might have changed the patients’ stage at diagnosis, care, treatment modalities such as type of surgery, and outcomes. It is difficult to compare these 2 groups because of differences in the patients’ cancers, such as their receptor status, as well as differences in treatment options between the two time periods. However, we had no other way to compare the data to see if there were any trends.

There was a migration to earlier-stage cancer at diagnosis during the 6-year period after the cancer center was opened. It is likely that the educational sessions that were done in the community contributed to this migration. We also saw an increase in the number of mammograms done, from 6,300 in 2000 to 8,800 in 2008. This increase in screening also could account for more patients being identified with earlier-stage disease and might be attributable to the community education through the outreach programs.

As a quality control method, the cancer center has been evaluated by the Commission on Cancer every 3 years. At the 2013 evaluation, we received the Gold Commendation – the highest possible recognition for having 8 out of 8 commendations – and a 3-year accreditation.

There was a notable increase in the use of lumpectomy over mastectomy after the establishment of the cancer center, possibly due to the addition of 2 surgical oncologists to the cancer center’s care team. The integration of multimodiality care for each patient may also have increased the use of breast-conserving surgery.

There was a significant increase from 2000 to 2008 in the survival of patients treated for stage III breast cancer. New drugs and new patterns of adjuvant care might have been partly responsible for that change. The establishment of the comprehensive cancer center with access to new protocols ensured that patients received state-of-the-art cancer treatment. Moreover, the facility addressed all aspects of patient care throughout the disease trajectory by including designated social workers, psychologists, a nutritionist, pastoral care, and patient and survivor support groups to ensure that patients would keep coming to the center for their therapy, with no delays and very little loss to follow-up.

Most patients without insurance were able to acquire emergency Medicaid through the cancer center. This was done by having 2 financial counselors who met with every patient and who could facilitate access to Medicaid as needed. As a result of that, the percentage of patients with no coverage went from 86% in 2000 to 16% in 2008. Before this system was set up, patients who were designated self-pay would pay a fee as low as $15 for each visit and received thousands of dollars’ worth of care. Thus, by forming a cancer center and facilitating patient access to Medicaid, we were able to save money for this public institution because of the gain in revenue from Medicaid.

Our findings suggest that the development of comprehensive cancer centers within inner-city health systems can ensure better treatment for patients of lower socioeconomic status. We present evidence that this may result in increased survival, more sophisticated surgical options, and better patient quality of life. Moreover, this can be achieved while effectively increasing revenue for the public hospitals. Correcting the inequality of access to care and better therapeutic options by setting up comprehensive cancer centers could contribute to improved parity of outcomes for underserved populations.
 

The author acknowledges the statistical help of Brian Altonen, MPH.

When cancer care is centralized in a comprehensive fashion, the quality of care and the outcomes improve.^1,2 Unfortunately, because of the medical insurance structure in New York City, most patients of lower socioeconomic status do not receive their cancer care in such dedicated cancer centers. In New York City, the majority of the underserved vulnerable populations – that is, those without health insurance – receive their care from the public hospital system known as NYC Health and Hospitals. Cancer care in this system is not centralized and may result in fragmented implementation of various modalities of treatment. In addition, because there is no centralized care, needs such as early screening and prevention programs are often not addressed. This problem was evident in Queens in 2000 and before when many patients with late-stage cancers were presenting for cancer care. Queens, which is one of the 5 boroughs of New York City, has more than 2.3 million residents. It has 2 public hospitals, Elmhurst Hospital Center and Queens Hospital Center (QHC). In 2001, the plan was devised for the establishment of a cancer center at QHC, mainly because of the high rate of late-stage cancers that were being seen at presentation and recognition of the need for more comprehensive care. In 2002, the Queens Cancer Center (QCC) began to see patients. QCC is a single facility that provides medical, surgical, radiation, gynecologic, and urologic oncology all in one area of the QHC.

This study is an investigation of the possible impact on care for breast cancer patients of low socioeconomic status who were treated at a comprehensive cancer center, with specific consideration of the change or improvement in treatment modalities and outcomes. Data on treatment modalities and outcomes of cancer patients who were treated at the QHC during 2000, before the QCC was set up, were compared with data of patients treated during 2008 (2008 was selected because we have 5-year survival data for those patients). The public hospital system treats all patients regardless of their ability to pay, so the majority of patients in the system are of lower socioeconomic status. In addition, 92% of the patients seen QHC are from a minority population. These are the populations that tend to have a worse prognosis and often are not given optimal treatment.³ The payer mix of patients in the public hospital system is different than that of private hospitals. Most of the patients present at the hospital with no insurance and if they are diagnosed with cancer they may be converted to emergency Medicaid. About 10% of patients will not be converted because of their document status.
 

Patients and methods

We used the Queens Hospital Tumor Registry to identify the patients who had been diagnosed with and treated for breast cancer in 2000 and 2008. The electronic medical records were reviewed, and in the case of the 2000-year patients, the written charts were also reviewed. The study was approved by the Mount Sinai institutional review board. It was not necessary to obtain patient consent because it was a retrospective study.

Only patients diagnosed with stage 0, I, II, or III breast cancer who received their treatment at QHC were included in the study. Patients who were seen in consultation at QHC but not treated there were excluded. Statistics were done using the 2x2 chi-squared SPSS analysis; a P value of .05 was considered significant. The survival data was analyzed using SAS.

Results

There were 24 evaluable patients in 2000 and 78 evaluable patients in 2008 who had stage 0, I, II, or III primary breast cancer and were treated at QHC. The average age of the patients in 2000 was 53.5 years and 54.7 years in 2008. The mean age for both groups was 55 years. The patients were ethnically diverse in both groups with 46% black, 17% Hispanic, 25% ethnic Asian Indian, and 6% white (Figure 1).

The payer mix in 2000 was 9 patients (37.5%) self-pay, 7 (29%) Medicaid, and 8 (33%) Medicare. In 2008, 11 patients (14%) were self-pay, 46 (59%) Medicaid, 11 (14%) Medicare, and 10 (13%) were private insurance. In 2000, there were 3 (12%) patients with stage 0 disease, 5 (21%) with stage I; 9 (37.5%) with stage II, and 7 (29%) with stage III. In 2008 there were 28 (36%) patients with stage 0 disease, 15 (19%) with stage I, 17 (22%) with stage II, and 18 (23%) with stage III (Figure 2).

Discussion

There have been numerous studies reporting on disparities in the treatment of patients with breast cancer based on race or socioeconomic status.^4-18 Many studies have shown inferior survival for black women with breast cancer, but it is not entirely clear whether these differences are the result of the quality of medical care received or biologic differences.^14,19 A moderately large study from a metropolitan medical center in Detroit showed no difference in survival in their patients based on race when all of the patients received equal treatments.¹⁵ A meta-analysis of survival in black and white breast cancer patients showed that the black women had significantly poorer outcomes.¹⁹

Findings from a recent study showed that patients of lower socioeconomic status are more likely to undergo mastectomy than breast conserving therapy.²⁰ The study, which identified 727,927 patients with early-stage breast cancer during 1998-2011, found that the rate of breast conservation increased from 54% to 59% during that time period and that there were significant barriers to women receiving breast-conserving therapy based on their type of insurance and having a lower socioeconomic status.²⁰

The treatment of breast cancer is best delivered in a multimodality setting, but many inner-city public hospitals do not have such a facility for their patients. QHC is the only public hospital in New York City that has established a comprehensive cancer center. The patient population of QHC is overwhelmingly of minority origin (only 5% of patients are white). In addition, it is a safety net hospital, so no patient is turned away because they cannot pay, and most patients are of lower socioeconomic status and do not have insurance. The purpose of the cancer center was to provide a single site at which our patients could receive all their treatment. It was to ensure that our patients had easy access to care and treatment during all phases of their disease trajectory and did not “fall through the cracks” of the system. Those goals were addressed by having all of the center’s physicians in one place. Physicians involved in care included medical, surgical, and radiation oncologists, a gynecologic oncologist, a genitourinary oncologist, and a thoracic surgery oncologist. The support groups organized for the cancer patients included 3 oncology social workers, an oncology navigator, a nutritionist, a pastoral care supporter, and an oncology psychologist, all located in the same area. All of the clerical and financial aspects of care were also placed within the center. This made the experience as seamless as possible for both the patients and the treating physicians. A “survivors clinic” was established so the cancer patients could be seen by integrated primary care providers to address all noncancer-related health issues such as hypertension, diabetes, or heart disease. Finally, a robust clinical oncology research team was established in the same location. The research included several protocols for new drug treatments for breast cancer from pharmaceutical companies as well as the multi-institutional oncology groups.

Part of the mission of the cancer center was to reach out into the community of Queens to provide education about early detection, cancer prevention, and other public health issues such as tobacco cessation. We established a close working relationship with the Queens Public Library System to connect with their users and dispense information about cancer care and early detection. The Queens Library system is the largest in the United States, and everyone who lives in Queens has easy access to one of its 63 branch libraries. We arranged several lectures about breast cancer awareness in some of the branch libraries. We also procured a mobile mammogram unit for free screening events at the lectures, especially in neighborhoods with a large number residents who were of lower socioeconomic status.

To study the possible effect of these changes on our patients with breast cancer, we compared 2 groups of patients. One group was from the year 2000, a year before the cancer center was opened. The other was from the year 2008, the last year we could get real 5-year survival statistics. We explored how establishing the cancer center might have changed the patients’ stage at diagnosis, care, treatment modalities such as type of surgery, and outcomes. It is difficult to compare these 2 groups because of differences in the patients’ cancers, such as their receptor status, as well as differences in treatment options between the two time periods. However, we had no other way to compare the data to see if there were any trends.

There was a migration to earlier-stage cancer at diagnosis during the 6-year period after the cancer center was opened. It is likely that the educational sessions that were done in the community contributed to this migration. We also saw an increase in the number of mammograms done, from 6,300 in 2000 to 8,800 in 2008. This increase in screening also could account for more patients being identified with earlier-stage disease and might be attributable to the community education through the outreach programs.

As a quality control method, the cancer center has been evaluated by the Commission on Cancer every 3 years. At the 2013 evaluation, we received the Gold Commendation – the highest possible recognition for having 8 out of 8 commendations – and a 3-year accreditation.

There was a notable increase in the use of lumpectomy over mastectomy after the establishment of the cancer center, possibly due to the addition of 2 surgical oncologists to the cancer center’s care team. The integration of multimodiality care for each patient may also have increased the use of breast-conserving surgery.

There was a significant increase from 2000 to 2008 in the survival of patients treated for stage III breast cancer. New drugs and new patterns of adjuvant care might have been partly responsible for that change. The establishment of the comprehensive cancer center with access to new protocols ensured that patients received state-of-the-art cancer treatment. Moreover, the facility addressed all aspects of patient care throughout the disease trajectory by including designated social workers, psychologists, a nutritionist, pastoral care, and patient and survivor support groups to ensure that patients would keep coming to the center for their therapy, with no delays and very little loss to follow-up.

Most patients without insurance were able to acquire emergency Medicaid through the cancer center. This was done by having 2 financial counselors who met with every patient and who could facilitate access to Medicaid as needed. As a result of that, the percentage of patients with no coverage went from 86% in 2000 to 16% in 2008. Before this system was set up, patients who were designated self-pay would pay a fee as low as $15 for each visit and received thousands of dollars’ worth of care. Thus, by forming a cancer center and facilitating patient access to Medicaid, we were able to save money for this public institution because of the gain in revenue from Medicaid.

Our findings suggest that the development of comprehensive cancer centers within inner-city health systems can ensure better treatment for patients of lower socioeconomic status. We present evidence that this may result in increased survival, more sophisticated surgical options, and better patient quality of life. Moreover, this can be achieved while effectively increasing revenue for the public hospitals. Correcting the inequality of access to care and better therapeutic options by setting up comprehensive cancer centers could contribute to improved parity of outcomes for underserved populations.
 

The author acknowledges the statistical help of Brian Altonen, MPH.

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

• GS4-02. Randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs. tamoxifen (T) plus OFS in premenopausal women with hormone receptor positive (HR+) early breast cancer (BC): Update of the combined TEXT and SOFT trials.

• GS2-07. MANTA – A randomized phase 2 study of fulvestrant in combination with the dual mTOR inhibitor AZD2014 or everolimus or fulvestrant alone in estrogen receptor-positive advanced or metastatic breast cancer.

Dr. Rugo is professor of medicine, University of California, San Francisco, and director, breast oncology and clinical trials education, UCSF Helen Diller Family Comprehensive Cancer Center.

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

• GS4-02. Randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs. tamoxifen (T) plus OFS in premenopausal women with hormone receptor positive (HR+) early breast cancer (BC): Update of the combined TEXT and SOFT trials.

• GS2-07. MANTA – A randomized phase 2 study of fulvestrant in combination with the dual mTOR inhibitor AZD2014 or everolimus or fulvestrant alone in estrogen receptor-positive advanced or metastatic breast cancer.

Dr. Rugo is professor of medicine, University of California, San Francisco, and director, breast oncology and clinical trials education, UCSF Helen Diller Family Comprehensive Cancer Center.

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

• GS4-02. Randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs. tamoxifen (T) plus OFS in premenopausal women with hormone receptor positive (HR+) early breast cancer (BC): Update of the combined TEXT and SOFT trials.

• GS2-07. MANTA – A randomized phase 2 study of fulvestrant in combination with the dual mTOR inhibitor AZD2014 or everolimus or fulvestrant alone in estrogen receptor-positive advanced or metastatic breast cancer.

Dr. Rugo is professor of medicine, University of California, San Francisco, and director, breast oncology and clinical trials education, UCSF Helen Diller Family Comprehensive Cancer Center.

Introduction

Over the past several decades, while the incidence of breast cancer has increased, breast cancer mortality has decreased. This decrease is likely due to both early detection and advances in systemic therapy. However, with more widespread use of screening mammography, there are increasing concerns about potential overdiagnosis of cancer.¹ One key challenge is that breast cancer is a heterogeneous disease. Improved tools for determining breast cancer biology can help physicians individualize treatments. Patients with low-risk cancers can be approached with less aggressive treatments, thus preventing unnecessary toxicities, while those with higher-risk cancers remain treated appropriately with more aggressive therapies.

Traditionally, adjuvant chemotherapy was recommended based on tumor features such as stage (tumor size, regional nodal involvement), grade, expression of hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]) and human epidermal growth factor receptor-2 (HER2), and patient features (age, menopausal status). However, this approach is not accurate enough to guide individualized treatment approaches, which are based on the risk for recurrence and the reduction in this risk that can be achieved with various systemic treatments. In particular, women with low-risk hormone receptor (HR)–positive, HER2-negative breast cancers could be spared the toxicities of cytotoxic chemotherapies without compromising the prognosis.

Beyond chemotherapy, endocrine therapies also have risks, especially when given over extended periods of time. Recently, extended endocrine therapy has been shown to prevent late recurrences of HR-positive breast cancers. In the National Cancer Institute of Canada Clinical Trials Group’s MA.17R study, extended endocrine therapy with letrozole for a total of 10 years (beyond 5 years of an aromatase inhibitor [AI]) decreased the risk for breast cancer recurrence or the occurrence of contralateral breast cancer by 34%.² However, the overall survival was similar between the 2 groups and the disease-free survival benefits were not confirmed in other studies.^3–5 Identifying the subgroup of patients who benefit from this extended AI therapy is important in the era of personalized medicine. Several tumor genomic assays have been developed to provide additional prognostic and predictive information with the goal of individualizing adjuvant therapies for breast cancer. Although assays are also being evaluated in HER2-positive and triple-negative breast cancer, this review will focus on HR-positive, HER2-negative breast cancer.

Tests for Guiding Adjuvant Chemotherapy Decisions

Case Study

Initial Presentation

A 54-year-old postmenopausal woman with no significant past medical history presents with an abnormal screening mammogram, which shows a focal asymmetry in the 10 o’clock position at middle depth of the left breast. Further work-up with a diagnostic mammogram and ultrasound of the left breast shows a suspicious hypoechoic solid mass with irregular margins measuring 17 mm. The patient undergoes an ultrasound-guided core needle biopsy of the suspicious mass, the results of which are consistent with an invasive ductal carcinoma, Nottingham grade 2, ER strongly positive (95%), PR weakly positive (5%), HER2-negative, and Ki-67 of 15%. She undergoes a left partial mastectomy and sentinel lymph node biopsy, with final pathology demonstrating a single focus of invasive ductal carcinoma, measuring 2.2 cm in greatest dimension with no evidence of lymphovascular invasion. Margins are clear and 2 sentinel lymph nodes are negative for metastatic disease (final pathologic stage IIA, pT2 pN0 cM0). She is referred to medical oncology to discuss adjuvant systemic therapy.

• Can additional testing be used to determine prognosis and guide systemic therapy recommendations for early-stage HR-positive/HER2-negative breast cancer?

After a diagnosis of early-stage breast cancer, the key clinical question faced by the patient and medical oncologist is: what is the individual’s risk for a metastatic breast cancer recurrence and thus the risk for death due to breast cancer? Once the risk for recurrence is established, systemic adjuvant chemotherapy, endocrine therapy, and/or HER2-directed therapy are considered based on the receptor status (ER/PR and HER2) to reduce this risk. HR-positive, HER2-negative breast cancer is the most common type of breast cancer. Although adjuvant endocrine therapy has significantly reduced the risk for recurrence and improved survival for patients with HR-positive breast cancer,⁶ the role of adjuvant chemotherapy for this subset of breast cancer remains unclear. Prior to genomic testing, the recommendation for adjuvant chemotherapy for HR-positive/HER2-negative tumors was primarily based on patient age and tumor stage and grade. However, chemotherapy overtreatment remained a concern given the potential short- and long-term risks of chemotherapy. Further studies into HR-positive/HER2-negative tumors have shown that these tumors can be divided into 2 main subtypes, luminal A and luminal B.⁷ These subtypes represent unique biology and differ in terms of prognosis and response to endocrine therapy and chemotherapy. Luminal A tumors are strongly endocrine responsive and have a good prognosis, while luminal B tumors are less endocrine responsive and are associated with a poorer prognosis; the addition of adjuvant chemotherapy is often considered for luminal B tumors.⁸ Several tests, including tumor genomic assays, are now available to help with delineating the tumor subtype and aid in decision-making regarding adjuvant chemotherapy for HR-positive/HER2-negative breast cancers.

Ki-67 Assays, Including IHC4 and PEPI

Proliferation is a hallmark of cancer cells.⁹ Ki-67, a nuclear nonhistone protein whose expression varies in intensity throughout the cell cycle, has been used as a measurement of tumor cell proliferation.¹⁰ Two large meta-analyses have demonstrated that high Ki-67 expression in breast tumors is independently associated with worse disease-free and overall survival rates.^11,12 Ki-67 expression has also been used to classify HR-positive tumors as luminal A or B. After classifying tumor subtypes based on intrinsic gene expression profiling, Cheang and colleagues determined that a Ki-67 cut point of 13.25% differentiated luminal A and B tumors.¹³ However, the ideal cut point for Ki-67 remains unclear, as the sensitivity and specificity in this study was 77% and 78%, respectively. Others have combined Ki-67 with standard ER, PR, and HER2 testing. This immunohistochemical 4 (IHC4) score, which weighs each of these variables, was validated in postmenopausal patients from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial who had ER-positive tumors and did not receive chemotherapy.¹⁴ The prognostic information from the IHC4 was similar to that seen with the 21-gene recurrence score (Oncotype DX), which is discussed later in this article. The key challenge with Ki-67 testing currently is the lack of a validated test methodology and intra-observer variability in interpreting the Ki-67 results.¹⁵ Recent series have suggested that Ki-67 be considered as a continuous marker rather than a set cut point.¹⁶ These issues continue to impact the clinical utility of Ki-67 for decision-making for adjuvant chemotherapy.

Ki-67 and the preoperative endocrine prognostic index (PEPI) score have been explored in the neoadjuvant setting to separate postmenopausal women with endocrine-sensitive versus intrinsically resistant disease and identify patients at risk for recurrent disease.¹⁷ The on-treatment levels of Ki-67 in response to endocrine therapy have been shown to be more prognostic than baseline values, and a decrease in Ki-67 as early as 2 weeks after initiation of neoadjuvant endocrine therapy is associated with endocrine-sensitive tumors and improved outcome. The PEPI score was developed through retrospective analysis of the P024 trial¹⁸ to evaluate the relationship between post-neoadjuvant endocrine therapy tumor characteristics and risk for early relapse. The score was subsequently validated in an independent data set from the IMPACT (Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen) trial.¹⁹ Patients with low pathological stage (0 or 1) and a favorable biomarker profile (PEPI score 0) at surgery had the best prognosis in the absence of chemotherapy. On the other hand, higher pathological stage at surgery and a poor biomarker profile with loss of ER positivity or persistently elevated Ki-67 (PEPI score of 3) identified de novo endocrine-resistant tumors that are higher risk for early relapse.²⁰ The ongoing Alliance A011106 ALTERNATE trial (ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment in postmenopausal women, NCT01953588) is a phase 3 study to prospectively test this hypothesis.

21-Gene Recurrence Score (Onco type DX Assay)

The 21-gene Oncotype DX assay is conducted on paraffin-embedded tumor tissue and measures the expression of 16 cancer related genes and 5 reference genes using quantitative polymerase chain reaction (PCR). The genes included in this assay are mainly related to proliferation (including Ki-67), invasion, and HER2 or estrogen signaling.²¹ Originally, the 21-gene recurrence score assay was analyzed as a prognostic biomarker tool in a prospective-retrospective biomarker substudy of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 clinical trial in which patients with node-negative, ER-positive tumors were randomly assigned to receive tamoxifen or placebo without chemotherapy.²² Using the standard reported values of low risk (< 18), intermediate risk (18–30), or high risk (≥ 31) for recurrence, among the tamoxifen-treated patients, cancers with a high-risk recurrence score had a significantly worse rate of distant recurrence and overall survival.²¹ Inferior breast cancer survival in cancers with a high recurrence score was also confirmed in other series of endocrine-treated patients with node-negative and node-positive disease.^23–25

The predictive utility of the 21-gene recurrence score for endocrine therapy has also been evaluated. A comparison of the placebo- and tamoxifen-treated patients from the NSABP B-14 trial demonstrated that the 21-gene recurrence score predicted benefit from tamoxifen in cancers with low- or intermediate-risk recurrence scores.²⁶ However, there was no benefit from the use of tamoxifen over placebo in cancers with high-risk recurrence scores. To date, this intriguing data has not been prospectively confirmed, and thus the 21-gene recurrence score is not used to avoid endocrine therapy.

The 21-gene recurrence score is primarily used by oncologists to aid in decision-making regarding adjuvant chemotherapy in patients with node-negative and node-positive (with up to 3 positive lymph nodes), HR-positive/HER2-negative breast cancers. The predictive utility of the 21-gene recurrence score for adjuvant chemotherapy was initially tested using tumor samples from the NSABP B-20 study. This study initially compared adjuvant tamoxifen alone with tamoxifen plus chemotherapy in patients with node-negative, HR-positive tumors. The prospective-retrospective biomarker analysis showed that the patients with high-risk 21-gene recurrence scores benefited from the addition of chemotherapy, whereas those with low or intermediate risk did not have an improved freedom from distant recurrence with chemotherapy.²⁷ Similarly, an analysis from the prospective phase 3 Southwest Oncology Group (SWOG) 8814 trial comparing tamoxifen to tamoxifen with chemotherapy showed that for node-positive tumors, chemotherapy benefit was only seen in those with high 21-gene recurrence scores.²⁴

Prospective studies are now starting to report results regarding the predictive role of the 21-gene recurrence score. The TAILORx (Trial Assigning Individualized Options for Treatment) trial includes women with node-negative, HR-positive/HER2-negative tumors measuring 0.6 to 5 cm. All patients were treated with standard-of-care endocrine therapy for at least 5 years. Chemotherapy was determined based on the 21-gene recurrence score results on the primary tumor. The 21-gene recurrence score cutoffs were changed to low (0–10), intermediate (11–25), and high (≥ 26). Patients with scores of 26 or higher were treated with chemotherapy, and those with intermediate scores were randomly assigned to chemotherapy or no chemotherapy; results from this cohort are still pending. However, excellent breast cancer outcomes with endocrine therapy alone were reported from the 1626 (15.9% of total cohort) prospectively followed patients with low recurrence score tumors. The 5-year invasive disease-free survival was 93.8%, with overall survival of 98%.²⁸ Given that 5 years is appropriate follow-up to see any chemotherapy benefit, this data supports the recommendation for no chemotherapy in this cohort of patients with very low 21-gene recurrence scores.

The RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) trial is evaluating women with 1 to 3 node-positive, HR-positive, HER2-negative tumors. In this trial, patients with 21-gene recurrence scores of 0 to 25 were assigned to adjuvant chemotherapy or none. Those with scores of 26 or higher were assigned to chemotherapy. All patients received standard adjuvant endocrine therapy. This study has completed accrual and results are pending. Of note, TAILORx and RxPONDER did not investigate the potential lack of benefit of endocrine therapy in cancers with high recurrence scores. Furthermore, despite data suggesting that chemotherapy may not even benefit women with 4 or more nodes involved but who have a low recurrence score,²⁴ due to the lack of prospective data in this cohort and the quite high risk for distant recurrence, chemotherapy continues to be the standard of care for these patients.

PAM50 (Breast Cancer Prognostic Gene Signature)

Using microarray and quantitative reverse transcriptase PCR (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tissues, the Breast Cancer Prognostic Gene Signature (PAM50) assay was initially developed to identify intrinsic breast cancer subtypes, including luminal A, luminal B, HER2-enriched, and basal-like.^7,29 Based on the prediction analysis of microarray (PAM) method, the assay measures the expression levels of 50 genes, provides a risk category (low, intermediate, and high), and generates a numerical risk of recurrence score (ROR). The intrinsic subtype and ROR have been shown to add significant prognostic value to the clinicopathological characteristics of tumors. Clinical validity of PAM50 was evaluated in postmenopausal women with HR-positive early-stage breast cancer treated in the prospective ATAC and ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) trials.^30,31 In 1017 patients with ER-positive breast cancer treated with anastrozole or tamoxifen in the ATAC trial, ROR added significant prognostic information beyond the clinical treatment score (integrated prognostic information from nodal status, tumor size, histopathologic grade, age, and anastrozole or tamoxifen treatment) in all patients. Also, compared with the 21-gene recurrence score, ROR provided more prognostic information in ER-positive, node-negative disease and better differentiation of intermediate- and higher-risk groups. Fewer patients were categorized as intermediate risk by ROR and more as high risk, which could reduce the uncertainty in the estimate of clinical benefit from chemotherapy.³⁰ The clinical utility of PAM50 as a prognostic model was also validated in 1478 postmenopausal women with ER-positive early-stage breast cancer enrolled in the ABCSG-8 trial. In this study, ROR assigned 47% of patients with node-negative disease to the low-risk category. In this low-risk group, the 10-year metastasis risk was less than 3.5%, indicating lack of benefit from additional chemotherapy.³¹ A key limitation of the PAM50 is the lack of any prospective studies with this assay.

PAM50 has been designed to be carried out in any qualified pathology laboratory. Moreover, the ROR score provides additional prognostic information about risk of late recurrence, which will be discussed in the next section.

70-Gene Breast Cancer Recurrence Assay (MammaPrint)

MammaPrint is a 70-gene assay that was initially developed using an unsupervised, hierarchical clustering algorithm on whole-genome expression arrays with early-stage breast cancer. Among 295 consecutive patients who had MammaPrint testing, those classified with a good-prognosis tumor signature (n = 115) had an excellent 10-year survival rate (94.5%) compared to those with a poor-prognosis signature (54.5%), and the signature remained prognostic upon multivariate analysis.³² Subsequently, a pooled analysis comparing outcomes by MammaPrint score in patients with node-negative or 1 to 3 node-positive breast cancers treated as per discretion of their medical team with either adjuvant chemotherapy plus endocrine therapy or endocrine therapy alone reported that only those patients with a high-risk score benefited from chemotherapy.³³ Recently, a prospective phase 3 study (MINDACT [Microarray In Node negative Disease may Avoid ChemoTherapy]) evaluating the utility of MammaPrint for adjuvant chemotherapy decision-making reported results.³⁴ In this study, 6693 women with early-stage breast cancer were assessed by clinical risk and genomic risk using MammaPrint. Those with low clinical and genomic risk did not receive chemotherapy, while those with high clinical and genomic risk all received chemotherapy. The primary goal of the study was to assess whether forgoing chemotherapy would be associated with a low rate of recurrence in those patients with a low-risk prognostic MammaPrint signature but high clinical risk. A total of 1550 patients (23.2%) were in the discordant group, and the majority of these patients had HR-positive disease (98.1%). Without chemotherapy, the rate of survival without distant metastasis at 5 years in this group was 94.7% (95% confidence interval [CI] 92.5% to 96.2%), which met the primary endpoint. Of note, initially, MammaPrint was only available for fresh tissue analysis, but recent advances in RNA processing now allow for this analysis on FFPE tissue.³⁵

Summary

These genomic and biomarker assays can identify different subsets of HR-positive breast cancers, including those patients who have tumors with an excellent prognosis with endocrine therapies alone. Thus, we now have the tools to help avoid the toxicities of chemotherapy in many women with early-stage breast cancer.

Tests for Assessing Risk for Late Recurrence

Case Continued

The patient undergoes 21-gene recurrence score testing, which shows a low recurrence score of 10, estimating the 10-year risk of distant recurrence to be approximately 7% with 5 years of tamoxifen. Chemotherapy is not recommended. The patient completes adjuvant whole breast radiation therapy, and then, based on data supporting AIs over tamoxifen in postmenopausal women, she is started on anastrozole.⁴¹ She initially experiences mild side effects from treatment, including fatigue, arthralgia, and vaginal dryness, but her symptoms are able to be managed. As she approaches 5 years of adjuvant endocrine therapy with anastrozole, she is struggling with rotator cuff injury and is anxious about recurrence, but has no evidence of recurrent cancer. Her bone density scan in the beginning of her fourth year of therapy shows a decrease in bone mineral density, with the lowest T score of –1.5 at the left femoral neck, consistent with osteopenia. She has been treated with calcium and vitamin D supplements.

• How long should this patient continue treatment with anastrozole?

The risk for recurrence is highest during the first 5 years after diagnosis for all patients with early breast cancer.⁴² Although HR-positive breast cancers have a better prognosis than HR-negative disease, the pattern of recurrence is different between the 2 groups, and it is estimated that approximately half of the recurrences among patients with HR-positive early breast cancer occur after the first 5 years from diagnosis. Annualized hazard of recurrence in HR-positive breast cancer has been shown to remain elevated and fairly stable beyond 10 years, even for those with low tumor burden and node-negative disease.⁴³ Prospective trials showed that for women with HR-positive early breast cancer, 5 years of adjuvant tamoxifen could substantially reduce recurrence rates and improve survival, and this became the standard of care.⁴⁴ AIs are considered the standard of care for adjuvant endocrine therapy in most postmenopausal women, as they result in a significantly lower recurrence rate compared with tamoxifen, either as initial adjuvant therapy or sequentially following 2 to 3 years of tamoxifen.⁴⁵

Due to the risk for later recurrences with HR-positive breast cancer, more patients and oncologists are considering extended endocrine therapy. This is based on results from the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) and aTTOM (Adjuvant Tamoxifen–To Offer More?) studies, both of which showed that women with HR-positive breast cancer who continued tamoxifen for 10 years had a lower late recurrence rate and a lower breast cancer mortality rate compared with those who stopped at 5 years.^46,47 Furthermore, the NCIC MA.17 trial evaluated extended endocrine therapy in postmenopausal women with 5 years of letrozole following 5 years of tamoxifen. Letrozole was shown to improve both disease-free and distant disease-free survival. The overall survival benefit was limited to patients with node-positive disease.⁴⁸ A summary of studies of extended endocrine therapy for HR-positive breast cancers is shown in Table 2.^2,3,46–49

However, extending AI therapy from 5 years to 10 years is not clearly beneficial. In the MA.17R trial, although longer AI therapy resulted in significantly better disease-free survival (95% versus 91%, hazard ratio 0.66, P = 0.01), this was primarily due to a lower incidence of contralateral breast cancer in those taking the AI compared with placebo. The distant recurrence risks were similar and low (4.4% versus 5.5%), and there was no overall survival difference.² Also, the NSABP B-42 study, which was presented at the 2016 San Antonio Breast Cancer Symposium, did not meet its predefined endpoint for benefit from extending adjuvant AI therapy with letrozole beyond 5 years.³ Thus, the absolute benefit from extended endocrine therapy has been modest across these studies. Although endocrine therapy is considered relatively safe and well tolerated, side effects can be significant and even associated with morbidity. Ideally, extended endocrine therapy should be offered to the subset of patients who would benefit the most. Several genomic diagnostic assays, including the EndoPredict test, PAM50, and the Breast Cancer Index (BCI) tests, specifically assess the risk for late recurrence in HR-positive cancers.

PAM50

Studies suggest that the ROR score also has value in predicting late recurrences. Analysis of data in patients enrolled in the ABCSG-8 trial showed that ROR could identify patients with endocrine-sensitive disease who are at low risk for late relapse and could be spared from unwanted toxicities of extended endocrine therapies. In 1246 ABCSG-8 patients between years 5 and 15, the PAM50 ROR demonstrated an absolute risk of distant recurrence of 2.4% in the low-risk group, as compared with 17.5% in the high-risk group.⁵⁰ Also, a combined analysis of patients from both the ATAC and ABCSG-8 trials demonstrated the utility of ROR in identifying this subgroup of patients with low risk for late relapse.⁵¹

EndoPredict

EndoPredict is another quantitative RT-PCR–based assay which uses FFPE tissues to calculate a risk score based on 8 cancer-related and 3 reference genes. The score is combined with clinicopathological factors including tumor size and nodal status to make a comprehensive risk score (EPclin). EPclin is used to dichotomize patients into EndoPredict low- and high-risk groups. EndoPredict has been validated in 2 cohorts of patients enrolled in separate randomized studies, ABCSG-6 and ABCSG-8. EP provided prognostic information beyond clinicopathological variables to predict distant recurrence in patients with HR-positive/HER2-negative early breast cancer.³⁷ More important, EndoPredict has been shown to predict early (years 0–5) versus late (> 5 years after diagnosis) recurrences and identify a low-risk subset of patients who would not be expected to benefit from further treatment beyond 5 years of endocrine therapy.⁵² Recently, EndoPredict and EPclin were compared with the 21-gene (Oncotype DX) recurrence score in a patient population from the TransATAC study. Both EndoPredict and EPclin provided more prognostic information compared to the 21-gene recurrence score and identified early and late relapse events.⁵³ EndoPredict is the first multigene expression assay that could be routinely performed in decentralized molecular pathological laboratories with a short turnaround time.⁵⁴

Breast Cancer Index

The BCI is a RT-PCR–based gene expression assay that consists of 2 gene expression biomarkers: molecular grade index (MGI) and HOXB13/IL17BR (H/I). The BCI was developed as a prognostic test to assess risk for breast cancer recurrence using a cohort of ER-positive patients (n = 588) treated with adjuvant tamoxifen versus observation from the prospective randomized Stockholm trial.³⁸ In this blinded retrospective study, H/I and MGI were measured and a continuous risk model (BCI) was developed in the tamoxifen-treated group. More than 50% of the patients in this group were classified as having a low risk of recurrence. The rate of distant recurrence or death in this low-risk group at 10 years was less than 3%. The performance of the BCI model was then tested in the untreated arm of the Stockholm trial. In the untreated arm, BCI classified 53%, 27%, and 20% of patients as low, intermediate, and high risk, respectively. The rate of distant metastasis at 10 years in these risk groups was 8.3% (95% CI 4.7% to 14.4%), 22.9% (95% CI 14.5% to 35.2%), and 28.5% (95% CI 17.9% to 43.6%), respectively, and the rate of breast cancer–specific mortality was 5.1% (95% CI 1.3% to 8.7%), 19.8% (95% CI 10.0% to 28.6%), and 28.8% (95% CI 15.3% to 40.2%).³⁸

The prognostic and predictive values of the BCI have been validated in other large, randomized studies and in patients with both node-negative and node-positive disease.^39,55 The predictive value of the endocrine-response biomarker, the H/I ratio, has been demonstrated in randomized studies. In the MA.17 trial, a high H/I ratio was associated with increased risk for late recurrence in the absence of letrozole. However, extended endocrine therapy with letrozole in patients with high H/I ratios predicted benefit from therapy and decreased the probability of late disease recurrence.⁵⁶ BCI was also compared to IHC4 and the 21-gene recurrence score in the TransATAC study and was the only test to show prognostic significance for both early (0–5 years) and late (5–10 year) recurrence.⁴⁰

The impact of the BCI results on physicians’ recommendations for extended endocrine therapy was assessed by a prospective study. This study showed that the test result had a significant effect on both physician treatment recommendation and patient satisfaction. BCI testing resulted in a change in physician recommendations for extended endocrine therapy, with an overall decrease in recommendations for extended endocrine therapy from 74% to 54%. Knowledge of the test result also led to improved patient satisfaction and decreased anxiety.⁵⁷

Summary

Due to the risk for late recurrence, extended endocrine therapy is being recommended for many patients with HR-positive breast cancers. Multiple genomic assays are being developed to better understand an individual’s risk for late recurrence and the potential for benefit from extended endocrine therapies. However, none of the assays has been validated in prospective randomized studies. Further validation is needed prior to routine use of these assays.

Case Continued

A BCI test is done and the result shows 4.3% BCI low-risk category in years 5–10, which is consistent with a low likelihood of benefit from extended endocrine therapy. After discussing the results of the BCI test in the context of no survival benefit from extending AIs beyond 5 years, both the patient and her oncologist feel comfortable with discontinuing endocrine therapy at the end of 5 years.

Conclusion

Reduction in breast cancer mortality is mainly the result of improved systemic treatments. With advances in breast cancer screening tools in recent years, the rate of cancer detection has increased. This has raised concerns regarding overdiagnosis. To prevent unwanted toxicities associated with overtreatment, better treatment decision tools are needed. Several genomic assays are currently available and widely used to provide prognostic and predictive information and aid in decisions regarding appropriate use of adjuvant chemotherapy in HR-positive/HER2-negative early-stage breast cancer. Ongoing studies are refining the cutoffs for these assays and expanding the applicability to node-positive breast cancers. Furthermore, with several studies now showing benefit from the use of extended endocrine therapy, some of these assays may be able to identify the subset of patients who are at increased risk for late recurrence and who might benefit from extended endocrine therapy. Advances in molecular testing has enabled clinicians to offer more personalized treatments to their patients, improve patients’ compliance, and decrease anxiety and conflict associated with management decisions. Although small numbers of patients with HER2-positive and triple-negative breast cancers were also included in some of these studies, use of genomic assays in this subset of patients is very limited and currently not recommended.

Introduction

Over the past several decades, while the incidence of breast cancer has increased, breast cancer mortality has decreased. This decrease is likely due to both early detection and advances in systemic therapy. However, with more widespread use of screening mammography, there are increasing concerns about potential overdiagnosis of cancer.¹ One key challenge is that breast cancer is a heterogeneous disease. Improved tools for determining breast cancer biology can help physicians individualize treatments. Patients with low-risk cancers can be approached with less aggressive treatments, thus preventing unnecessary toxicities, while those with higher-risk cancers remain treated appropriately with more aggressive therapies.

Traditionally, adjuvant chemotherapy was recommended based on tumor features such as stage (tumor size, regional nodal involvement), grade, expression of hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]) and human epidermal growth factor receptor-2 (HER2), and patient features (age, menopausal status). However, this approach is not accurate enough to guide individualized treatment approaches, which are based on the risk for recurrence and the reduction in this risk that can be achieved with various systemic treatments. In particular, women with low-risk hormone receptor (HR)–positive, HER2-negative breast cancers could be spared the toxicities of cytotoxic chemotherapies without compromising the prognosis.

Beyond chemotherapy, endocrine therapies also have risks, especially when given over extended periods of time. Recently, extended endocrine therapy has been shown to prevent late recurrences of HR-positive breast cancers. In the National Cancer Institute of Canada Clinical Trials Group’s MA.17R study, extended endocrine therapy with letrozole for a total of 10 years (beyond 5 years of an aromatase inhibitor [AI]) decreased the risk for breast cancer recurrence or the occurrence of contralateral breast cancer by 34%.² However, the overall survival was similar between the 2 groups and the disease-free survival benefits were not confirmed in other studies.^3–5 Identifying the subgroup of patients who benefit from this extended AI therapy is important in the era of personalized medicine. Several tumor genomic assays have been developed to provide additional prognostic and predictive information with the goal of individualizing adjuvant therapies for breast cancer. Although assays are also being evaluated in HER2-positive and triple-negative breast cancer, this review will focus on HR-positive, HER2-negative breast cancer.

Tests for Guiding Adjuvant Chemotherapy Decisions

Case Study

Initial Presentation

A 54-year-old postmenopausal woman with no significant past medical history presents with an abnormal screening mammogram, which shows a focal asymmetry in the 10 o’clock position at middle depth of the left breast. Further work-up with a diagnostic mammogram and ultrasound of the left breast shows a suspicious hypoechoic solid mass with irregular margins measuring 17 mm. The patient undergoes an ultrasound-guided core needle biopsy of the suspicious mass, the results of which are consistent with an invasive ductal carcinoma, Nottingham grade 2, ER strongly positive (95%), PR weakly positive (5%), HER2-negative, and Ki-67 of 15%. She undergoes a left partial mastectomy and sentinel lymph node biopsy, with final pathology demonstrating a single focus of invasive ductal carcinoma, measuring 2.2 cm in greatest dimension with no evidence of lymphovascular invasion. Margins are clear and 2 sentinel lymph nodes are negative for metastatic disease (final pathologic stage IIA, pT2 pN0 cM0). She is referred to medical oncology to discuss adjuvant systemic therapy.

• Can additional testing be used to determine prognosis and guide systemic therapy recommendations for early-stage HR-positive/HER2-negative breast cancer?

After a diagnosis of early-stage breast cancer, the key clinical question faced by the patient and medical oncologist is: what is the individual’s risk for a metastatic breast cancer recurrence and thus the risk for death due to breast cancer? Once the risk for recurrence is established, systemic adjuvant chemotherapy, endocrine therapy, and/or HER2-directed therapy are considered based on the receptor status (ER/PR and HER2) to reduce this risk. HR-positive, HER2-negative breast cancer is the most common type of breast cancer. Although adjuvant endocrine therapy has significantly reduced the risk for recurrence and improved survival for patients with HR-positive breast cancer,⁶ the role of adjuvant chemotherapy for this subset of breast cancer remains unclear. Prior to genomic testing, the recommendation for adjuvant chemotherapy for HR-positive/HER2-negative tumors was primarily based on patient age and tumor stage and grade. However, chemotherapy overtreatment remained a concern given the potential short- and long-term risks of chemotherapy. Further studies into HR-positive/HER2-negative tumors have shown that these tumors can be divided into 2 main subtypes, luminal A and luminal B.⁷ These subtypes represent unique biology and differ in terms of prognosis and response to endocrine therapy and chemotherapy. Luminal A tumors are strongly endocrine responsive and have a good prognosis, while luminal B tumors are less endocrine responsive and are associated with a poorer prognosis; the addition of adjuvant chemotherapy is often considered for luminal B tumors.⁸ Several tests, including tumor genomic assays, are now available to help with delineating the tumor subtype and aid in decision-making regarding adjuvant chemotherapy for HR-positive/HER2-negative breast cancers.

Ki-67 Assays, Including IHC4 and PEPI

Proliferation is a hallmark of cancer cells.⁹ Ki-67, a nuclear nonhistone protein whose expression varies in intensity throughout the cell cycle, has been used as a measurement of tumor cell proliferation.¹⁰ Two large meta-analyses have demonstrated that high Ki-67 expression in breast tumors is independently associated with worse disease-free and overall survival rates.^11,12 Ki-67 expression has also been used to classify HR-positive tumors as luminal A or B. After classifying tumor subtypes based on intrinsic gene expression profiling, Cheang and colleagues determined that a Ki-67 cut point of 13.25% differentiated luminal A and B tumors.¹³ However, the ideal cut point for Ki-67 remains unclear, as the sensitivity and specificity in this study was 77% and 78%, respectively. Others have combined Ki-67 with standard ER, PR, and HER2 testing. This immunohistochemical 4 (IHC4) score, which weighs each of these variables, was validated in postmenopausal patients from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial who had ER-positive tumors and did not receive chemotherapy.¹⁴ The prognostic information from the IHC4 was similar to that seen with the 21-gene recurrence score (Oncotype DX), which is discussed later in this article. The key challenge with Ki-67 testing currently is the lack of a validated test methodology and intra-observer variability in interpreting the Ki-67 results.¹⁵ Recent series have suggested that Ki-67 be considered as a continuous marker rather than a set cut point.¹⁶ These issues continue to impact the clinical utility of Ki-67 for decision-making for adjuvant chemotherapy.

Ki-67 and the preoperative endocrine prognostic index (PEPI) score have been explored in the neoadjuvant setting to separate postmenopausal women with endocrine-sensitive versus intrinsically resistant disease and identify patients at risk for recurrent disease.¹⁷ The on-treatment levels of Ki-67 in response to endocrine therapy have been shown to be more prognostic than baseline values, and a decrease in Ki-67 as early as 2 weeks after initiation of neoadjuvant endocrine therapy is associated with endocrine-sensitive tumors and improved outcome. The PEPI score was developed through retrospective analysis of the P024 trial¹⁸ to evaluate the relationship between post-neoadjuvant endocrine therapy tumor characteristics and risk for early relapse. The score was subsequently validated in an independent data set from the IMPACT (Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen) trial.¹⁹ Patients with low pathological stage (0 or 1) and a favorable biomarker profile (PEPI score 0) at surgery had the best prognosis in the absence of chemotherapy. On the other hand, higher pathological stage at surgery and a poor biomarker profile with loss of ER positivity or persistently elevated Ki-67 (PEPI score of 3) identified de novo endocrine-resistant tumors that are higher risk for early relapse.²⁰ The ongoing Alliance A011106 ALTERNATE trial (ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment in postmenopausal women, NCT01953588) is a phase 3 study to prospectively test this hypothesis.

21-Gene Recurrence Score (Onco type DX Assay)

The 21-gene Oncotype DX assay is conducted on paraffin-embedded tumor tissue and measures the expression of 16 cancer related genes and 5 reference genes using quantitative polymerase chain reaction (PCR). The genes included in this assay are mainly related to proliferation (including Ki-67), invasion, and HER2 or estrogen signaling.²¹ Originally, the 21-gene recurrence score assay was analyzed as a prognostic biomarker tool in a prospective-retrospective biomarker substudy of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 clinical trial in which patients with node-negative, ER-positive tumors were randomly assigned to receive tamoxifen or placebo without chemotherapy.²² Using the standard reported values of low risk (< 18), intermediate risk (18–30), or high risk (≥ 31) for recurrence, among the tamoxifen-treated patients, cancers with a high-risk recurrence score had a significantly worse rate of distant recurrence and overall survival.²¹ Inferior breast cancer survival in cancers with a high recurrence score was also confirmed in other series of endocrine-treated patients with node-negative and node-positive disease.^23–25

The predictive utility of the 21-gene recurrence score for endocrine therapy has also been evaluated. A comparison of the placebo- and tamoxifen-treated patients from the NSABP B-14 trial demonstrated that the 21-gene recurrence score predicted benefit from tamoxifen in cancers with low- or intermediate-risk recurrence scores.²⁶ However, there was no benefit from the use of tamoxifen over placebo in cancers with high-risk recurrence scores. To date, this intriguing data has not been prospectively confirmed, and thus the 21-gene recurrence score is not used to avoid endocrine therapy.

The 21-gene recurrence score is primarily used by oncologists to aid in decision-making regarding adjuvant chemotherapy in patients with node-negative and node-positive (with up to 3 positive lymph nodes), HR-positive/HER2-negative breast cancers. The predictive utility of the 21-gene recurrence score for adjuvant chemotherapy was initially tested using tumor samples from the NSABP B-20 study. This study initially compared adjuvant tamoxifen alone with tamoxifen plus chemotherapy in patients with node-negative, HR-positive tumors. The prospective-retrospective biomarker analysis showed that the patients with high-risk 21-gene recurrence scores benefited from the addition of chemotherapy, whereas those with low or intermediate risk did not have an improved freedom from distant recurrence with chemotherapy.²⁷ Similarly, an analysis from the prospective phase 3 Southwest Oncology Group (SWOG) 8814 trial comparing tamoxifen to tamoxifen with chemotherapy showed that for node-positive tumors, chemotherapy benefit was only seen in those with high 21-gene recurrence scores.²⁴

Prospective studies are now starting to report results regarding the predictive role of the 21-gene recurrence score. The TAILORx (Trial Assigning Individualized Options for Treatment) trial includes women with node-negative, HR-positive/HER2-negative tumors measuring 0.6 to 5 cm. All patients were treated with standard-of-care endocrine therapy for at least 5 years. Chemotherapy was determined based on the 21-gene recurrence score results on the primary tumor. The 21-gene recurrence score cutoffs were changed to low (0–10), intermediate (11–25), and high (≥ 26). Patients with scores of 26 or higher were treated with chemotherapy, and those with intermediate scores were randomly assigned to chemotherapy or no chemotherapy; results from this cohort are still pending. However, excellent breast cancer outcomes with endocrine therapy alone were reported from the 1626 (15.9% of total cohort) prospectively followed patients with low recurrence score tumors. The 5-year invasive disease-free survival was 93.8%, with overall survival of 98%.²⁸ Given that 5 years is appropriate follow-up to see any chemotherapy benefit, this data supports the recommendation for no chemotherapy in this cohort of patients with very low 21-gene recurrence scores.

The RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) trial is evaluating women with 1 to 3 node-positive, HR-positive, HER2-negative tumors. In this trial, patients with 21-gene recurrence scores of 0 to 25 were assigned to adjuvant chemotherapy or none. Those with scores of 26 or higher were assigned to chemotherapy. All patients received standard adjuvant endocrine therapy. This study has completed accrual and results are pending. Of note, TAILORx and RxPONDER did not investigate the potential lack of benefit of endocrine therapy in cancers with high recurrence scores. Furthermore, despite data suggesting that chemotherapy may not even benefit women with 4 or more nodes involved but who have a low recurrence score,²⁴ due to the lack of prospective data in this cohort and the quite high risk for distant recurrence, chemotherapy continues to be the standard of care for these patients.

PAM50 (Breast Cancer Prognostic Gene Signature)

Using microarray and quantitative reverse transcriptase PCR (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tissues, the Breast Cancer Prognostic Gene Signature (PAM50) assay was initially developed to identify intrinsic breast cancer subtypes, including luminal A, luminal B, HER2-enriched, and basal-like.^7,29 Based on the prediction analysis of microarray (PAM) method, the assay measures the expression levels of 50 genes, provides a risk category (low, intermediate, and high), and generates a numerical risk of recurrence score (ROR). The intrinsic subtype and ROR have been shown to add significant prognostic value to the clinicopathological characteristics of tumors. Clinical validity of PAM50 was evaluated in postmenopausal women with HR-positive early-stage breast cancer treated in the prospective ATAC and ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) trials.^30,31 In 1017 patients with ER-positive breast cancer treated with anastrozole or tamoxifen in the ATAC trial, ROR added significant prognostic information beyond the clinical treatment score (integrated prognostic information from nodal status, tumor size, histopathologic grade, age, and anastrozole or tamoxifen treatment) in all patients. Also, compared with the 21-gene recurrence score, ROR provided more prognostic information in ER-positive, node-negative disease and better differentiation of intermediate- and higher-risk groups. Fewer patients were categorized as intermediate risk by ROR and more as high risk, which could reduce the uncertainty in the estimate of clinical benefit from chemotherapy.³⁰ The clinical utility of PAM50 as a prognostic model was also validated in 1478 postmenopausal women with ER-positive early-stage breast cancer enrolled in the ABCSG-8 trial. In this study, ROR assigned 47% of patients with node-negative disease to the low-risk category. In this low-risk group, the 10-year metastasis risk was less than 3.5%, indicating lack of benefit from additional chemotherapy.³¹ A key limitation of the PAM50 is the lack of any prospective studies with this assay.

PAM50 has been designed to be carried out in any qualified pathology laboratory. Moreover, the ROR score provides additional prognostic information about risk of late recurrence, which will be discussed in the next section.

70-Gene Breast Cancer Recurrence Assay (MammaPrint)

MammaPrint is a 70-gene assay that was initially developed using an unsupervised, hierarchical clustering algorithm on whole-genome expression arrays with early-stage breast cancer. Among 295 consecutive patients who had MammaPrint testing, those classified with a good-prognosis tumor signature (n = 115) had an excellent 10-year survival rate (94.5%) compared to those with a poor-prognosis signature (54.5%), and the signature remained prognostic upon multivariate analysis.³² Subsequently, a pooled analysis comparing outcomes by MammaPrint score in patients with node-negative or 1 to 3 node-positive breast cancers treated as per discretion of their medical team with either adjuvant chemotherapy plus endocrine therapy or endocrine therapy alone reported that only those patients with a high-risk score benefited from chemotherapy.³³ Recently, a prospective phase 3 study (MINDACT [Microarray In Node negative Disease may Avoid ChemoTherapy]) evaluating the utility of MammaPrint for adjuvant chemotherapy decision-making reported results.³⁴ In this study, 6693 women with early-stage breast cancer were assessed by clinical risk and genomic risk using MammaPrint. Those with low clinical and genomic risk did not receive chemotherapy, while those with high clinical and genomic risk all received chemotherapy. The primary goal of the study was to assess whether forgoing chemotherapy would be associated with a low rate of recurrence in those patients with a low-risk prognostic MammaPrint signature but high clinical risk. A total of 1550 patients (23.2%) were in the discordant group, and the majority of these patients had HR-positive disease (98.1%). Without chemotherapy, the rate of survival without distant metastasis at 5 years in this group was 94.7% (95% confidence interval [CI] 92.5% to 96.2%), which met the primary endpoint. Of note, initially, MammaPrint was only available for fresh tissue analysis, but recent advances in RNA processing now allow for this analysis on FFPE tissue.³⁵

Summary

These genomic and biomarker assays can identify different subsets of HR-positive breast cancers, including those patients who have tumors with an excellent prognosis with endocrine therapies alone. Thus, we now have the tools to help avoid the toxicities of chemotherapy in many women with early-stage breast cancer.

Tests for Assessing Risk for Late Recurrence

Case Continued

The patient undergoes 21-gene recurrence score testing, which shows a low recurrence score of 10, estimating the 10-year risk of distant recurrence to be approximately 7% with 5 years of tamoxifen. Chemotherapy is not recommended. The patient completes adjuvant whole breast radiation therapy, and then, based on data supporting AIs over tamoxifen in postmenopausal women, she is started on anastrozole.⁴¹ She initially experiences mild side effects from treatment, including fatigue, arthralgia, and vaginal dryness, but her symptoms are able to be managed. As she approaches 5 years of adjuvant endocrine therapy with anastrozole, she is struggling with rotator cuff injury and is anxious about recurrence, but has no evidence of recurrent cancer. Her bone density scan in the beginning of her fourth year of therapy shows a decrease in bone mineral density, with the lowest T score of –1.5 at the left femoral neck, consistent with osteopenia. She has been treated with calcium and vitamin D supplements.

• How long should this patient continue treatment with anastrozole?

The risk for recurrence is highest during the first 5 years after diagnosis for all patients with early breast cancer.⁴² Although HR-positive breast cancers have a better prognosis than HR-negative disease, the pattern of recurrence is different between the 2 groups, and it is estimated that approximately half of the recurrences among patients with HR-positive early breast cancer occur after the first 5 years from diagnosis. Annualized hazard of recurrence in HR-positive breast cancer has been shown to remain elevated and fairly stable beyond 10 years, even for those with low tumor burden and node-negative disease.⁴³ Prospective trials showed that for women with HR-positive early breast cancer, 5 years of adjuvant tamoxifen could substantially reduce recurrence rates and improve survival, and this became the standard of care.⁴⁴ AIs are considered the standard of care for adjuvant endocrine therapy in most postmenopausal women, as they result in a significantly lower recurrence rate compared with tamoxifen, either as initial adjuvant therapy or sequentially following 2 to 3 years of tamoxifen.⁴⁵

Due to the risk for later recurrences with HR-positive breast cancer, more patients and oncologists are considering extended endocrine therapy. This is based on results from the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) and aTTOM (Adjuvant Tamoxifen–To Offer More?) studies, both of which showed that women with HR-positive breast cancer who continued tamoxifen for 10 years had a lower late recurrence rate and a lower breast cancer mortality rate compared with those who stopped at 5 years.^46,47 Furthermore, the NCIC MA.17 trial evaluated extended endocrine therapy in postmenopausal women with 5 years of letrozole following 5 years of tamoxifen. Letrozole was shown to improve both disease-free and distant disease-free survival. The overall survival benefit was limited to patients with node-positive disease.⁴⁸ A summary of studies of extended endocrine therapy for HR-positive breast cancers is shown in Table 2.^2,3,46–49

However, extending AI therapy from 5 years to 10 years is not clearly beneficial. In the MA.17R trial, although longer AI therapy resulted in significantly better disease-free survival (95% versus 91%, hazard ratio 0.66, P = 0.01), this was primarily due to a lower incidence of contralateral breast cancer in those taking the AI compared with placebo. The distant recurrence risks were similar and low (4.4% versus 5.5%), and there was no overall survival difference.² Also, the NSABP B-42 study, which was presented at the 2016 San Antonio Breast Cancer Symposium, did not meet its predefined endpoint for benefit from extending adjuvant AI therapy with letrozole beyond 5 years.³ Thus, the absolute benefit from extended endocrine therapy has been modest across these studies. Although endocrine therapy is considered relatively safe and well tolerated, side effects can be significant and even associated with morbidity. Ideally, extended endocrine therapy should be offered to the subset of patients who would benefit the most. Several genomic diagnostic assays, including the EndoPredict test, PAM50, and the Breast Cancer Index (BCI) tests, specifically assess the risk for late recurrence in HR-positive cancers.

PAM50

Studies suggest that the ROR score also has value in predicting late recurrences. Analysis of data in patients enrolled in the ABCSG-8 trial showed that ROR could identify patients with endocrine-sensitive disease who are at low risk for late relapse and could be spared from unwanted toxicities of extended endocrine therapies. In 1246 ABCSG-8 patients between years 5 and 15, the PAM50 ROR demonstrated an absolute risk of distant recurrence of 2.4% in the low-risk group, as compared with 17.5% in the high-risk group.⁵⁰ Also, a combined analysis of patients from both the ATAC and ABCSG-8 trials demonstrated the utility of ROR in identifying this subgroup of patients with low risk for late relapse.⁵¹

EndoPredict

EndoPredict is another quantitative RT-PCR–based assay which uses FFPE tissues to calculate a risk score based on 8 cancer-related and 3 reference genes. The score is combined with clinicopathological factors including tumor size and nodal status to make a comprehensive risk score (EPclin). EPclin is used to dichotomize patients into EndoPredict low- and high-risk groups. EndoPredict has been validated in 2 cohorts of patients enrolled in separate randomized studies, ABCSG-6 and ABCSG-8. EP provided prognostic information beyond clinicopathological variables to predict distant recurrence in patients with HR-positive/HER2-negative early breast cancer.³⁷ More important, EndoPredict has been shown to predict early (years 0–5) versus late (> 5 years after diagnosis) recurrences and identify a low-risk subset of patients who would not be expected to benefit from further treatment beyond 5 years of endocrine therapy.⁵² Recently, EndoPredict and EPclin were compared with the 21-gene (Oncotype DX) recurrence score in a patient population from the TransATAC study. Both EndoPredict and EPclin provided more prognostic information compared to the 21-gene recurrence score and identified early and late relapse events.⁵³ EndoPredict is the first multigene expression assay that could be routinely performed in decentralized molecular pathological laboratories with a short turnaround time.⁵⁴

Breast Cancer Index

The BCI is a RT-PCR–based gene expression assay that consists of 2 gene expression biomarkers: molecular grade index (MGI) and HOXB13/IL17BR (H/I). The BCI was developed as a prognostic test to assess risk for breast cancer recurrence using a cohort of ER-positive patients (n = 588) treated with adjuvant tamoxifen versus observation from the prospective randomized Stockholm trial.³⁸ In this blinded retrospective study, H/I and MGI were measured and a continuous risk model (BCI) was developed in the tamoxifen-treated group. More than 50% of the patients in this group were classified as having a low risk of recurrence. The rate of distant recurrence or death in this low-risk group at 10 years was less than 3%. The performance of the BCI model was then tested in the untreated arm of the Stockholm trial. In the untreated arm, BCI classified 53%, 27%, and 20% of patients as low, intermediate, and high risk, respectively. The rate of distant metastasis at 10 years in these risk groups was 8.3% (95% CI 4.7% to 14.4%), 22.9% (95% CI 14.5% to 35.2%), and 28.5% (95% CI 17.9% to 43.6%), respectively, and the rate of breast cancer–specific mortality was 5.1% (95% CI 1.3% to 8.7%), 19.8% (95% CI 10.0% to 28.6%), and 28.8% (95% CI 15.3% to 40.2%).³⁸

The prognostic and predictive values of the BCI have been validated in other large, randomized studies and in patients with both node-negative and node-positive disease.^39,55 The predictive value of the endocrine-response biomarker, the H/I ratio, has been demonstrated in randomized studies. In the MA.17 trial, a high H/I ratio was associated with increased risk for late recurrence in the absence of letrozole. However, extended endocrine therapy with letrozole in patients with high H/I ratios predicted benefit from therapy and decreased the probability of late disease recurrence.⁵⁶ BCI was also compared to IHC4 and the 21-gene recurrence score in the TransATAC study and was the only test to show prognostic significance for both early (0–5 years) and late (5–10 year) recurrence.⁴⁰

The impact of the BCI results on physicians’ recommendations for extended endocrine therapy was assessed by a prospective study. This study showed that the test result had a significant effect on both physician treatment recommendation and patient satisfaction. BCI testing resulted in a change in physician recommendations for extended endocrine therapy, with an overall decrease in recommendations for extended endocrine therapy from 74% to 54%. Knowledge of the test result also led to improved patient satisfaction and decreased anxiety.⁵⁷

Summary

Due to the risk for late recurrence, extended endocrine therapy is being recommended for many patients with HR-positive breast cancers. Multiple genomic assays are being developed to better understand an individual’s risk for late recurrence and the potential for benefit from extended endocrine therapies. However, none of the assays has been validated in prospective randomized studies. Further validation is needed prior to routine use of these assays.

Case Continued

A BCI test is done and the result shows 4.3% BCI low-risk category in years 5–10, which is consistent with a low likelihood of benefit from extended endocrine therapy. After discussing the results of the BCI test in the context of no survival benefit from extending AIs beyond 5 years, both the patient and her oncologist feel comfortable with discontinuing endocrine therapy at the end of 5 years.

Conclusion

Reduction in breast cancer mortality is mainly the result of improved systemic treatments. With advances in breast cancer screening tools in recent years, the rate of cancer detection has increased. This has raised concerns regarding overdiagnosis. To prevent unwanted toxicities associated with overtreatment, better treatment decision tools are needed. Several genomic assays are currently available and widely used to provide prognostic and predictive information and aid in decisions regarding appropriate use of adjuvant chemotherapy in HR-positive/HER2-negative early-stage breast cancer. Ongoing studies are refining the cutoffs for these assays and expanding the applicability to node-positive breast cancers. Furthermore, with several studies now showing benefit from the use of extended endocrine therapy, some of these assays may be able to identify the subset of patients who are at increased risk for late recurrence and who might benefit from extended endocrine therapy. Advances in molecular testing has enabled clinicians to offer more personalized treatments to their patients, improve patients’ compliance, and decrease anxiety and conflict associated with management decisions. Although small numbers of patients with HER2-positive and triple-negative breast cancers were also included in some of these studies, use of genomic assays in this subset of patients is very limited and currently not recommended.

Introduction

Over the past several decades, while the incidence of breast cancer has increased, breast cancer mortality has decreased. This decrease is likely due to both early detection and advances in systemic therapy. However, with more widespread use of screening mammography, there are increasing concerns about potential overdiagnosis of cancer.¹ One key challenge is that breast cancer is a heterogeneous disease. Improved tools for determining breast cancer biology can help physicians individualize treatments. Patients with low-risk cancers can be approached with less aggressive treatments, thus preventing unnecessary toxicities, while those with higher-risk cancers remain treated appropriately with more aggressive therapies.

Traditionally, adjuvant chemotherapy was recommended based on tumor features such as stage (tumor size, regional nodal involvement), grade, expression of hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]) and human epidermal growth factor receptor-2 (HER2), and patient features (age, menopausal status). However, this approach is not accurate enough to guide individualized treatment approaches, which are based on the risk for recurrence and the reduction in this risk that can be achieved with various systemic treatments. In particular, women with low-risk hormone receptor (HR)–positive, HER2-negative breast cancers could be spared the toxicities of cytotoxic chemotherapies without compromising the prognosis.

Beyond chemotherapy, endocrine therapies also have risks, especially when given over extended periods of time. Recently, extended endocrine therapy has been shown to prevent late recurrences of HR-positive breast cancers. In the National Cancer Institute of Canada Clinical Trials Group’s MA.17R study, extended endocrine therapy with letrozole for a total of 10 years (beyond 5 years of an aromatase inhibitor [AI]) decreased the risk for breast cancer recurrence or the occurrence of contralateral breast cancer by 34%.² However, the overall survival was similar between the 2 groups and the disease-free survival benefits were not confirmed in other studies.^3–5 Identifying the subgroup of patients who benefit from this extended AI therapy is important in the era of personalized medicine. Several tumor genomic assays have been developed to provide additional prognostic and predictive information with the goal of individualizing adjuvant therapies for breast cancer. Although assays are also being evaluated in HER2-positive and triple-negative breast cancer, this review will focus on HR-positive, HER2-negative breast cancer.

Tests for Guiding Adjuvant Chemotherapy Decisions

Case Study

Initial Presentation

A 54-year-old postmenopausal woman with no significant past medical history presents with an abnormal screening mammogram, which shows a focal asymmetry in the 10 o’clock position at middle depth of the left breast. Further work-up with a diagnostic mammogram and ultrasound of the left breast shows a suspicious hypoechoic solid mass with irregular margins measuring 17 mm. The patient undergoes an ultrasound-guided core needle biopsy of the suspicious mass, the results of which are consistent with an invasive ductal carcinoma, Nottingham grade 2, ER strongly positive (95%), PR weakly positive (5%), HER2-negative, and Ki-67 of 15%. She undergoes a left partial mastectomy and sentinel lymph node biopsy, with final pathology demonstrating a single focus of invasive ductal carcinoma, measuring 2.2 cm in greatest dimension with no evidence of lymphovascular invasion. Margins are clear and 2 sentinel lymph nodes are negative for metastatic disease (final pathologic stage IIA, pT2 pN0 cM0). She is referred to medical oncology to discuss adjuvant systemic therapy.

• Can additional testing be used to determine prognosis and guide systemic therapy recommendations for early-stage HR-positive/HER2-negative breast cancer?

After a diagnosis of early-stage breast cancer, the key clinical question faced by the patient and medical oncologist is: what is the individual’s risk for a metastatic breast cancer recurrence and thus the risk for death due to breast cancer? Once the risk for recurrence is established, systemic adjuvant chemotherapy, endocrine therapy, and/or HER2-directed therapy are considered based on the receptor status (ER/PR and HER2) to reduce this risk. HR-positive, HER2-negative breast cancer is the most common type of breast cancer. Although adjuvant endocrine therapy has significantly reduced the risk for recurrence and improved survival for patients with HR-positive breast cancer,⁶ the role of adjuvant chemotherapy for this subset of breast cancer remains unclear. Prior to genomic testing, the recommendation for adjuvant chemotherapy for HR-positive/HER2-negative tumors was primarily based on patient age and tumor stage and grade. However, chemotherapy overtreatment remained a concern given the potential short- and long-term risks of chemotherapy. Further studies into HR-positive/HER2-negative tumors have shown that these tumors can be divided into 2 main subtypes, luminal A and luminal B.⁷ These subtypes represent unique biology and differ in terms of prognosis and response to endocrine therapy and chemotherapy. Luminal A tumors are strongly endocrine responsive and have a good prognosis, while luminal B tumors are less endocrine responsive and are associated with a poorer prognosis; the addition of adjuvant chemotherapy is often considered for luminal B tumors.⁸ Several tests, including tumor genomic assays, are now available to help with delineating the tumor subtype and aid in decision-making regarding adjuvant chemotherapy for HR-positive/HER2-negative breast cancers.

Ki-67 Assays, Including IHC4 and PEPI

Proliferation is a hallmark of cancer cells.⁹ Ki-67, a nuclear nonhistone protein whose expression varies in intensity throughout the cell cycle, has been used as a measurement of tumor cell proliferation.¹⁰ Two large meta-analyses have demonstrated that high Ki-67 expression in breast tumors is independently associated with worse disease-free and overall survival rates.^11,12 Ki-67 expression has also been used to classify HR-positive tumors as luminal A or B. After classifying tumor subtypes based on intrinsic gene expression profiling, Cheang and colleagues determined that a Ki-67 cut point of 13.25% differentiated luminal A and B tumors.¹³ However, the ideal cut point for Ki-67 remains unclear, as the sensitivity and specificity in this study was 77% and 78%, respectively. Others have combined Ki-67 with standard ER, PR, and HER2 testing. This immunohistochemical 4 (IHC4) score, which weighs each of these variables, was validated in postmenopausal patients from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial who had ER-positive tumors and did not receive chemotherapy.¹⁴ The prognostic information from the IHC4 was similar to that seen with the 21-gene recurrence score (Oncotype DX), which is discussed later in this article. The key challenge with Ki-67 testing currently is the lack of a validated test methodology and intra-observer variability in interpreting the Ki-67 results.¹⁵ Recent series have suggested that Ki-67 be considered as a continuous marker rather than a set cut point.¹⁶ These issues continue to impact the clinical utility of Ki-67 for decision-making for adjuvant chemotherapy.

Ki-67 and the preoperative endocrine prognostic index (PEPI) score have been explored in the neoadjuvant setting to separate postmenopausal women with endocrine-sensitive versus intrinsically resistant disease and identify patients at risk for recurrent disease.¹⁷ The on-treatment levels of Ki-67 in response to endocrine therapy have been shown to be more prognostic than baseline values, and a decrease in Ki-67 as early as 2 weeks after initiation of neoadjuvant endocrine therapy is associated with endocrine-sensitive tumors and improved outcome. The PEPI score was developed through retrospective analysis of the P024 trial¹⁸ to evaluate the relationship between post-neoadjuvant endocrine therapy tumor characteristics and risk for early relapse. The score was subsequently validated in an independent data set from the IMPACT (Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen) trial.¹⁹ Patients with low pathological stage (0 or 1) and a favorable biomarker profile (PEPI score 0) at surgery had the best prognosis in the absence of chemotherapy. On the other hand, higher pathological stage at surgery and a poor biomarker profile with loss of ER positivity or persistently elevated Ki-67 (PEPI score of 3) identified de novo endocrine-resistant tumors that are higher risk for early relapse.²⁰ The ongoing Alliance A011106 ALTERNATE trial (ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment in postmenopausal women, NCT01953588) is a phase 3 study to prospectively test this hypothesis.

21-Gene Recurrence Score (Onco type DX Assay)

The 21-gene Oncotype DX assay is conducted on paraffin-embedded tumor tissue and measures the expression of 16 cancer related genes and 5 reference genes using quantitative polymerase chain reaction (PCR). The genes included in this assay are mainly related to proliferation (including Ki-67), invasion, and HER2 or estrogen signaling.²¹ Originally, the 21-gene recurrence score assay was analyzed as a prognostic biomarker tool in a prospective-retrospective biomarker substudy of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 clinical trial in which patients with node-negative, ER-positive tumors were randomly assigned to receive tamoxifen or placebo without chemotherapy.²² Using the standard reported values of low risk (< 18), intermediate risk (18–30), or high risk (≥ 31) for recurrence, among the tamoxifen-treated patients, cancers with a high-risk recurrence score had a significantly worse rate of distant recurrence and overall survival.²¹ Inferior breast cancer survival in cancers with a high recurrence score was also confirmed in other series of endocrine-treated patients with node-negative and node-positive disease.^23–25

The predictive utility of the 21-gene recurrence score for endocrine therapy has also been evaluated. A comparison of the placebo- and tamoxifen-treated patients from the NSABP B-14 trial demonstrated that the 21-gene recurrence score predicted benefit from tamoxifen in cancers with low- or intermediate-risk recurrence scores.²⁶ However, there was no benefit from the use of tamoxifen over placebo in cancers with high-risk recurrence scores. To date, this intriguing data has not been prospectively confirmed, and thus the 21-gene recurrence score is not used to avoid endocrine therapy.

The 21-gene recurrence score is primarily used by oncologists to aid in decision-making regarding adjuvant chemotherapy in patients with node-negative and node-positive (with up to 3 positive lymph nodes), HR-positive/HER2-negative breast cancers. The predictive utility of the 21-gene recurrence score for adjuvant chemotherapy was initially tested using tumor samples from the NSABP B-20 study. This study initially compared adjuvant tamoxifen alone with tamoxifen plus chemotherapy in patients with node-negative, HR-positive tumors. The prospective-retrospective biomarker analysis showed that the patients with high-risk 21-gene recurrence scores benefited from the addition of chemotherapy, whereas those with low or intermediate risk did not have an improved freedom from distant recurrence with chemotherapy.²⁷ Similarly, an analysis from the prospective phase 3 Southwest Oncology Group (SWOG) 8814 trial comparing tamoxifen to tamoxifen with chemotherapy showed that for node-positive tumors, chemotherapy benefit was only seen in those with high 21-gene recurrence scores.²⁴

Prospective studies are now starting to report results regarding the predictive role of the 21-gene recurrence score. The TAILORx (Trial Assigning Individualized Options for Treatment) trial includes women with node-negative, HR-positive/HER2-negative tumors measuring 0.6 to 5 cm. All patients were treated with standard-of-care endocrine therapy for at least 5 years. Chemotherapy was determined based on the 21-gene recurrence score results on the primary tumor. The 21-gene recurrence score cutoffs were changed to low (0–10), intermediate (11–25), and high (≥ 26). Patients with scores of 26 or higher were treated with chemotherapy, and those with intermediate scores were randomly assigned to chemotherapy or no chemotherapy; results from this cohort are still pending. However, excellent breast cancer outcomes with endocrine therapy alone were reported from the 1626 (15.9% of total cohort) prospectively followed patients with low recurrence score tumors. The 5-year invasive disease-free survival was 93.8%, with overall survival of 98%.²⁸ Given that 5 years is appropriate follow-up to see any chemotherapy benefit, this data supports the recommendation for no chemotherapy in this cohort of patients with very low 21-gene recurrence scores.

The RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) trial is evaluating women with 1 to 3 node-positive, HR-positive, HER2-negative tumors. In this trial, patients with 21-gene recurrence scores of 0 to 25 were assigned to adjuvant chemotherapy or none. Those with scores of 26 or higher were assigned to chemotherapy. All patients received standard adjuvant endocrine therapy. This study has completed accrual and results are pending. Of note, TAILORx and RxPONDER did not investigate the potential lack of benefit of endocrine therapy in cancers with high recurrence scores. Furthermore, despite data suggesting that chemotherapy may not even benefit women with 4 or more nodes involved but who have a low recurrence score,²⁴ due to the lack of prospective data in this cohort and the quite high risk for distant recurrence, chemotherapy continues to be the standard of care for these patients.

PAM50 (Breast Cancer Prognostic Gene Signature)

Using microarray and quantitative reverse transcriptase PCR (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tissues, the Breast Cancer Prognostic Gene Signature (PAM50) assay was initially developed to identify intrinsic breast cancer subtypes, including luminal A, luminal B, HER2-enriched, and basal-like.^7,29 Based on the prediction analysis of microarray (PAM) method, the assay measures the expression levels of 50 genes, provides a risk category (low, intermediate, and high), and generates a numerical risk of recurrence score (ROR). The intrinsic subtype and ROR have been shown to add significant prognostic value to the clinicopathological characteristics of tumors. Clinical validity of PAM50 was evaluated in postmenopausal women with HR-positive early-stage breast cancer treated in the prospective ATAC and ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) trials.^30,31 In 1017 patients with ER-positive breast cancer treated with anastrozole or tamoxifen in the ATAC trial, ROR added significant prognostic information beyond the clinical treatment score (integrated prognostic information from nodal status, tumor size, histopathologic grade, age, and anastrozole or tamoxifen treatment) in all patients. Also, compared with the 21-gene recurrence score, ROR provided more prognostic information in ER-positive, node-negative disease and better differentiation of intermediate- and higher-risk groups. Fewer patients were categorized as intermediate risk by ROR and more as high risk, which could reduce the uncertainty in the estimate of clinical benefit from chemotherapy.³⁰ The clinical utility of PAM50 as a prognostic model was also validated in 1478 postmenopausal women with ER-positive early-stage breast cancer enrolled in the ABCSG-8 trial. In this study, ROR assigned 47% of patients with node-negative disease to the low-risk category. In this low-risk group, the 10-year metastasis risk was less than 3.5%, indicating lack of benefit from additional chemotherapy.³¹ A key limitation of the PAM50 is the lack of any prospective studies with this assay.

PAM50 has been designed to be carried out in any qualified pathology laboratory. Moreover, the ROR score provides additional prognostic information about risk of late recurrence, which will be discussed in the next section.

70-Gene Breast Cancer Recurrence Assay (MammaPrint)

MammaPrint is a 70-gene assay that was initially developed using an unsupervised, hierarchical clustering algorithm on whole-genome expression arrays with early-stage breast cancer. Among 295 consecutive patients who had MammaPrint testing, those classified with a good-prognosis tumor signature (n = 115) had an excellent 10-year survival rate (94.5%) compared to those with a poor-prognosis signature (54.5%), and the signature remained prognostic upon multivariate analysis.³² Subsequently, a pooled analysis comparing outcomes by MammaPrint score in patients with node-negative or 1 to 3 node-positive breast cancers treated as per discretion of their medical team with either adjuvant chemotherapy plus endocrine therapy or endocrine therapy alone reported that only those patients with a high-risk score benefited from chemotherapy.³³ Recently, a prospective phase 3 study (MINDACT [Microarray In Node negative Disease may Avoid ChemoTherapy]) evaluating the utility of MammaPrint for adjuvant chemotherapy decision-making reported results.³⁴ In this study, 6693 women with early-stage breast cancer were assessed by clinical risk and genomic risk using MammaPrint. Those with low clinical and genomic risk did not receive chemotherapy, while those with high clinical and genomic risk all received chemotherapy. The primary goal of the study was to assess whether forgoing chemotherapy would be associated with a low rate of recurrence in those patients with a low-risk prognostic MammaPrint signature but high clinical risk. A total of 1550 patients (23.2%) were in the discordant group, and the majority of these patients had HR-positive disease (98.1%). Without chemotherapy, the rate of survival without distant metastasis at 5 years in this group was 94.7% (95% confidence interval [CI] 92.5% to 96.2%), which met the primary endpoint. Of note, initially, MammaPrint was only available for fresh tissue analysis, but recent advances in RNA processing now allow for this analysis on FFPE tissue.³⁵

Summary

These genomic and biomarker assays can identify different subsets of HR-positive breast cancers, including those patients who have tumors with an excellent prognosis with endocrine therapies alone. Thus, we now have the tools to help avoid the toxicities of chemotherapy in many women with early-stage breast cancer.

Tests for Assessing Risk for Late Recurrence

Case Continued

The patient undergoes 21-gene recurrence score testing, which shows a low recurrence score of 10, estimating the 10-year risk of distant recurrence to be approximately 7% with 5 years of tamoxifen. Chemotherapy is not recommended. The patient completes adjuvant whole breast radiation therapy, and then, based on data supporting AIs over tamoxifen in postmenopausal women, she is started on anastrozole.⁴¹ She initially experiences mild side effects from treatment, including fatigue, arthralgia, and vaginal dryness, but her symptoms are able to be managed. As she approaches 5 years of adjuvant endocrine therapy with anastrozole, she is struggling with rotator cuff injury and is anxious about recurrence, but has no evidence of recurrent cancer. Her bone density scan in the beginning of her fourth year of therapy shows a decrease in bone mineral density, with the lowest T score of –1.5 at the left femoral neck, consistent with osteopenia. She has been treated with calcium and vitamin D supplements.

• How long should this patient continue treatment with anastrozole?

The risk for recurrence is highest during the first 5 years after diagnosis for all patients with early breast cancer.⁴² Although HR-positive breast cancers have a better prognosis than HR-negative disease, the pattern of recurrence is different between the 2 groups, and it is estimated that approximately half of the recurrences among patients with HR-positive early breast cancer occur after the first 5 years from diagnosis. Annualized hazard of recurrence in HR-positive breast cancer has been shown to remain elevated and fairly stable beyond 10 years, even for those with low tumor burden and node-negative disease.⁴³ Prospective trials showed that for women with HR-positive early breast cancer, 5 years of adjuvant tamoxifen could substantially reduce recurrence rates and improve survival, and this became the standard of care.⁴⁴ AIs are considered the standard of care for adjuvant endocrine therapy in most postmenopausal women, as they result in a significantly lower recurrence rate compared with tamoxifen, either as initial adjuvant therapy or sequentially following 2 to 3 years of tamoxifen.⁴⁵

Due to the risk for later recurrences with HR-positive breast cancer, more patients and oncologists are considering extended endocrine therapy. This is based on results from the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) and aTTOM (Adjuvant Tamoxifen–To Offer More?) studies, both of which showed that women with HR-positive breast cancer who continued tamoxifen for 10 years had a lower late recurrence rate and a lower breast cancer mortality rate compared with those who stopped at 5 years.^46,47 Furthermore, the NCIC MA.17 trial evaluated extended endocrine therapy in postmenopausal women with 5 years of letrozole following 5 years of tamoxifen. Letrozole was shown to improve both disease-free and distant disease-free survival. The overall survival benefit was limited to patients with node-positive disease.⁴⁸ A summary of studies of extended endocrine therapy for HR-positive breast cancers is shown in Table 2.^2,3,46–49

However, extending AI therapy from 5 years to 10 years is not clearly beneficial. In the MA.17R trial, although longer AI therapy resulted in significantly better disease-free survival (95% versus 91%, hazard ratio 0.66, P = 0.01), this was primarily due to a lower incidence of contralateral breast cancer in those taking the AI compared with placebo. The distant recurrence risks were similar and low (4.4% versus 5.5%), and there was no overall survival difference.² Also, the NSABP B-42 study, which was presented at the 2016 San Antonio Breast Cancer Symposium, did not meet its predefined endpoint for benefit from extending adjuvant AI therapy with letrozole beyond 5 years.³ Thus, the absolute benefit from extended endocrine therapy has been modest across these studies. Although endocrine therapy is considered relatively safe and well tolerated, side effects can be significant and even associated with morbidity. Ideally, extended endocrine therapy should be offered to the subset of patients who would benefit the most. Several genomic diagnostic assays, including the EndoPredict test, PAM50, and the Breast Cancer Index (BCI) tests, specifically assess the risk for late recurrence in HR-positive cancers.

PAM50

Studies suggest that the ROR score also has value in predicting late recurrences. Analysis of data in patients enrolled in the ABCSG-8 trial showed that ROR could identify patients with endocrine-sensitive disease who are at low risk for late relapse and could be spared from unwanted toxicities of extended endocrine therapies. In 1246 ABCSG-8 patients between years 5 and 15, the PAM50 ROR demonstrated an absolute risk of distant recurrence of 2.4% in the low-risk group, as compared with 17.5% in the high-risk group.⁵⁰ Also, a combined analysis of patients from both the ATAC and ABCSG-8 trials demonstrated the utility of ROR in identifying this subgroup of patients with low risk for late relapse.⁵¹

EndoPredict

EndoPredict is another quantitative RT-PCR–based assay which uses FFPE tissues to calculate a risk score based on 8 cancer-related and 3 reference genes. The score is combined with clinicopathological factors including tumor size and nodal status to make a comprehensive risk score (EPclin). EPclin is used to dichotomize patients into EndoPredict low- and high-risk groups. EndoPredict has been validated in 2 cohorts of patients enrolled in separate randomized studies, ABCSG-6 and ABCSG-8. EP provided prognostic information beyond clinicopathological variables to predict distant recurrence in patients with HR-positive/HER2-negative early breast cancer.³⁷ More important, EndoPredict has been shown to predict early (years 0–5) versus late (> 5 years after diagnosis) recurrences and identify a low-risk subset of patients who would not be expected to benefit from further treatment beyond 5 years of endocrine therapy.⁵² Recently, EndoPredict and EPclin were compared with the 21-gene (Oncotype DX) recurrence score in a patient population from the TransATAC study. Both EndoPredict and EPclin provided more prognostic information compared to the 21-gene recurrence score and identified early and late relapse events.⁵³ EndoPredict is the first multigene expression assay that could be routinely performed in decentralized molecular pathological laboratories with a short turnaround time.⁵⁴

Breast Cancer Index

The BCI is a RT-PCR–based gene expression assay that consists of 2 gene expression biomarkers: molecular grade index (MGI) and HOXB13/IL17BR (H/I). The BCI was developed as a prognostic test to assess risk for breast cancer recurrence using a cohort of ER-positive patients (n = 588) treated with adjuvant tamoxifen versus observation from the prospective randomized Stockholm trial.³⁸ In this blinded retrospective study, H/I and MGI were measured and a continuous risk model (BCI) was developed in the tamoxifen-treated group. More than 50% of the patients in this group were classified as having a low risk of recurrence. The rate of distant recurrence or death in this low-risk group at 10 years was less than 3%. The performance of the BCI model was then tested in the untreated arm of the Stockholm trial. In the untreated arm, BCI classified 53%, 27%, and 20% of patients as low, intermediate, and high risk, respectively. The rate of distant metastasis at 10 years in these risk groups was 8.3% (95% CI 4.7% to 14.4%), 22.9% (95% CI 14.5% to 35.2%), and 28.5% (95% CI 17.9% to 43.6%), respectively, and the rate of breast cancer–specific mortality was 5.1% (95% CI 1.3% to 8.7%), 19.8% (95% CI 10.0% to 28.6%), and 28.8% (95% CI 15.3% to 40.2%).³⁸

The prognostic and predictive values of the BCI have been validated in other large, randomized studies and in patients with both node-negative and node-positive disease.^39,55 The predictive value of the endocrine-response biomarker, the H/I ratio, has been demonstrated in randomized studies. In the MA.17 trial, a high H/I ratio was associated with increased risk for late recurrence in the absence of letrozole. However, extended endocrine therapy with letrozole in patients with high H/I ratios predicted benefit from therapy and decreased the probability of late disease recurrence.⁵⁶ BCI was also compared to IHC4 and the 21-gene recurrence score in the TransATAC study and was the only test to show prognostic significance for both early (0–5 years) and late (5–10 year) recurrence.⁴⁰

The impact of the BCI results on physicians’ recommendations for extended endocrine therapy was assessed by a prospective study. This study showed that the test result had a significant effect on both physician treatment recommendation and patient satisfaction. BCI testing resulted in a change in physician recommendations for extended endocrine therapy, with an overall decrease in recommendations for extended endocrine therapy from 74% to 54%. Knowledge of the test result also led to improved patient satisfaction and decreased anxiety.⁵⁷

Summary

Due to the risk for late recurrence, extended endocrine therapy is being recommended for many patients with HR-positive breast cancers. Multiple genomic assays are being developed to better understand an individual’s risk for late recurrence and the potential for benefit from extended endocrine therapies. However, none of the assays has been validated in prospective randomized studies. Further validation is needed prior to routine use of these assays.

Case Continued

A BCI test is done and the result shows 4.3% BCI low-risk category in years 5–10, which is consistent with a low likelihood of benefit from extended endocrine therapy. After discussing the results of the BCI test in the context of no survival benefit from extending AIs beyond 5 years, both the patient and her oncologist feel comfortable with discontinuing endocrine therapy at the end of 5 years.

Conclusion

Reduction in breast cancer mortality is mainly the result of improved systemic treatments. With advances in breast cancer screening tools in recent years, the rate of cancer detection has increased. This has raised concerns regarding overdiagnosis. To prevent unwanted toxicities associated with overtreatment, better treatment decision tools are needed. Several genomic assays are currently available and widely used to provide prognostic and predictive information and aid in decisions regarding appropriate use of adjuvant chemotherapy in HR-positive/HER2-negative early-stage breast cancer. Ongoing studies are refining the cutoffs for these assays and expanding the applicability to node-positive breast cancers. Furthermore, with several studies now showing benefit from the use of extended endocrine therapy, some of these assays may be able to identify the subset of patients who are at increased risk for late recurrence and who might benefit from extended endocrine therapy. Advances in molecular testing has enabled clinicians to offer more personalized treatments to their patients, improve patients’ compliance, and decrease anxiety and conflict associated with management decisions. Although small numbers of patients with HER2-positive and triple-negative breast cancers were also included in some of these studies, use of genomic assays in this subset of patients is very limited and currently not recommended.

Silvia Formenti, MD, will open the CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) with a plenary talk on the potential for radiotherapy (RT) to convert irradiated metastatic breast tumors into individualized, in situ vaccines.

“DNA damage response contributes to immune rejection of tumors, a mechanism at least in part responsible for the success of platinum and RT combinations. RT-induced cell death can evoke T-cell memory, inducing effects outside the irradiated field, defined as abscopal. In the setting of metastatic cancer, however, the occurrence of abscopal effects is extremely rare because of the established immune-suppressive microenvironment. Thus, the proimmunogenic effect of radiotherapy is best exploited in combination with immunotherapy, and the combination of RT and immune checkpoint blockade has matured to reach clinical translation,” Dr. Formenti, of Weill Cornell Medicine, New York, wrote in the abstract.

Dr. Formenti and her colleagues have translated preclinical work into clinical trials in metastatic breast cancer, as well as other tumors. Her presentation will focus on the mechanisms and on the ongoing work to determine the appropriate RT dose and fractionation to achieve abscopal responses.

Dr. Formenti will present the opening plenary on Wednesday Dec. 6 at 9 a.m. in Hall 3 of the Henry B. Gonzalez Convention Center in San Antonio.

The rest of the SABCS schedule and abstracts to be presented are available here. The symposium is sponsored by the Cancer Therapy & Research Center at the University of Texas Health Science Center at San Antonio, the American Association for Cancer Research, and Baylor College of Medicine in Houston.

[email protected]

On Twitter @nikolaideslaura

Silvia Formenti, MD, will open the CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) with a plenary talk on the potential for radiotherapy (RT) to convert irradiated metastatic breast tumors into individualized, in situ vaccines.

“DNA damage response contributes to immune rejection of tumors, a mechanism at least in part responsible for the success of platinum and RT combinations. RT-induced cell death can evoke T-cell memory, inducing effects outside the irradiated field, defined as abscopal. In the setting of metastatic cancer, however, the occurrence of abscopal effects is extremely rare because of the established immune-suppressive microenvironment. Thus, the proimmunogenic effect of radiotherapy is best exploited in combination with immunotherapy, and the combination of RT and immune checkpoint blockade has matured to reach clinical translation,” Dr. Formenti, of Weill Cornell Medicine, New York, wrote in the abstract.

Dr. Formenti and her colleagues have translated preclinical work into clinical trials in metastatic breast cancer, as well as other tumors. Her presentation will focus on the mechanisms and on the ongoing work to determine the appropriate RT dose and fractionation to achieve abscopal responses.

Dr. Formenti will present the opening plenary on Wednesday Dec. 6 at 9 a.m. in Hall 3 of the Henry B. Gonzalez Convention Center in San Antonio.

The rest of the SABCS schedule and abstracts to be presented are available here. The symposium is sponsored by the Cancer Therapy & Research Center at the University of Texas Health Science Center at San Antonio, the American Association for Cancer Research, and Baylor College of Medicine in Houston.

[email protected]

On Twitter @nikolaideslaura

Silvia Formenti, MD, will open the CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) with a plenary talk on the potential for radiotherapy (RT) to convert irradiated metastatic breast tumors into individualized, in situ vaccines.

“DNA damage response contributes to immune rejection of tumors, a mechanism at least in part responsible for the success of platinum and RT combinations. RT-induced cell death can evoke T-cell memory, inducing effects outside the irradiated field, defined as abscopal. In the setting of metastatic cancer, however, the occurrence of abscopal effects is extremely rare because of the established immune-suppressive microenvironment. Thus, the proimmunogenic effect of radiotherapy is best exploited in combination with immunotherapy, and the combination of RT and immune checkpoint blockade has matured to reach clinical translation,” Dr. Formenti, of Weill Cornell Medicine, New York, wrote in the abstract.

Dr. Formenti and her colleagues have translated preclinical work into clinical trials in metastatic breast cancer, as well as other tumors. Her presentation will focus on the mechanisms and on the ongoing work to determine the appropriate RT dose and fractionation to achieve abscopal responses.

Dr. Formenti will present the opening plenary on Wednesday Dec. 6 at 9 a.m. in Hall 3 of the Henry B. Gonzalez Convention Center in San Antonio.

The rest of the SABCS schedule and abstracts to be presented are available here. The symposium is sponsored by the Cancer Therapy & Research Center at the University of Texas Health Science Center at San Antonio, the American Association for Cancer Research, and Baylor College of Medicine in Houston.

[email protected]

On Twitter @nikolaideslaura

VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.

While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.

Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.

Susan London, Frontline Medical News

VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.

While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.

Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.

Susan London, Frontline Medical News

VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.

While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.

Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.

Susan London, Frontline Medical News

NATIONAL HARBOR, MD. – The immune checkpoint inhibitor nivolumab has promising activity in mismatch repair–deficient noncolorectal cancers, according to preliminary findings from the first sub-arm of the National Cancer Institute’s landmark Molecular Analysis for Therapy Choice (NCI-MATCH) trial.

NCI-MATCH is a 1,173-site precision medicine trial launched in 2015 to study targeted therapies for patients with relapsed/refractory solid tumors, lymphomas, and myelomas. In the first substudy (arm Z1D), the investigators identified 4,900 subjects with samples that could be tested for “actionable molecular abnormalities,” and from among those, they identified 77 with loss of mismatch repair proteins MLH1 or MSH2. Ultimately 47 patients were treated with nivolumab in the substudy.

Sharon Worcester/Frontline Medical News

[email protected]

NATIONAL HARBOR, MD. – The immune checkpoint inhibitor nivolumab has promising activity in mismatch repair–deficient noncolorectal cancers, according to preliminary findings from the first sub-arm of the National Cancer Institute’s landmark Molecular Analysis for Therapy Choice (NCI-MATCH) trial.

NCI-MATCH is a 1,173-site precision medicine trial launched in 2015 to study targeted therapies for patients with relapsed/refractory solid tumors, lymphomas, and myelomas. In the first substudy (arm Z1D), the investigators identified 4,900 subjects with samples that could be tested for “actionable molecular abnormalities,” and from among those, they identified 77 with loss of mismatch repair proteins MLH1 or MSH2. Ultimately 47 patients were treated with nivolumab in the substudy.

Sharon Worcester/Frontline Medical News

[email protected]

NATIONAL HARBOR, MD. – The immune checkpoint inhibitor nivolumab has promising activity in mismatch repair–deficient noncolorectal cancers, according to preliminary findings from the first sub-arm of the National Cancer Institute’s landmark Molecular Analysis for Therapy Choice (NCI-MATCH) trial.

NCI-MATCH is a 1,173-site precision medicine trial launched in 2015 to study targeted therapies for patients with relapsed/refractory solid tumors, lymphomas, and myelomas. In the first substudy (arm Z1D), the investigators identified 4,900 subjects with samples that could be tested for “actionable molecular abnormalities,” and from among those, they identified 77 with loss of mismatch repair proteins MLH1 or MSH2. Ultimately 47 patients were treated with nivolumab in the substudy.

Sharon Worcester/Frontline Medical News

[email protected]