2. Treatment decision tools

Adjuvant systemic treatments reduce the risk of breast cancer recurrence following the local treatment of primary stage I–III breast cancers. International expert groups recommend determining the histologic grade and ER, PR, Ki-67 and HER2 status in all breast cancer patients, in order to assist prognosis and determine therapeutic options, including hormone therapy, chemotherapy and anti-HER2 therapy.

For patients with HR+ breast cancers receiving hormonal therapy, the risk of distant recurrence is under 20% and therefore, many patients may potentially be spared of chemotherapy. The web-based prognostification and treatment benefit tools and genomic assays have been incorporated into treatment planning for patients with early-stage HR+ breast cancer, which lead to get more information about prognosis and prediction of treatment response. These assays supplement the traditional histopathologic markers and help identify patients at high risk of recurrence. They also provide a more quantitative approach to risk assessment and enable individualization of treatment. This has both quality of life and health care cost implications because patients who will not benefit from a certain treatment can be spared both the toxicity and the expense [3].

One of the available genetic prognostic platforms (MammaPrint®, Oncotype DX®, Prosigna® or EndoPredict®) may be used in node-negative ER+ patients to establish a prognostic category and decide with the patient whether adjuvant treatment may be limited to hormonal therapy.

#### 2.1. Genomic tools: oncotype Dx

death from cancer in women, during last 3 decades, deaths due to breast cancer have decreased by one-third or more. It is due in part to increased screening, as well as more effective loco-regional and systemic treatment options have been established over last decades. The risk of relapse varies substantially on the basis of individual disease. Thus, accurate estimates regarding recurrence and survival are critical for selecting patients with breast cancer who will benefit from adjuvant therapy. Decisions about the type of treatment have traditionally been based on the histopathologic parameters including lymph node status, tumor size, histologic grade, histologic subtype, patient age, and estrogen receptor (ER)/progesterone receptor (PR) status. However, these characteristics fail to characterize the biologic heterogeneity of tumors, which has important implications for treatment benefit. The advent of microarray gene expression profiles as well as sequencing of the whole genome has brought several multigene platforms into clinical use. Many of these platforms incorporate traditional markers (e.g., ER, PR, and HER2) as well as additional cancer-associated genes. Approximately 75–80% of all breast cancers are luminal A or luminal B subtypes which are hormone-

Here, the genetic and online tools which guide the adjuvant systemic treatment, options of endocrine therapy and systemic cytotoxic chemotherapy in patients with early stage HR+,

Adjuvant systemic treatments reduce the risk of breast cancer recurrence following the local treatment of primary stage I–III breast cancers. International expert groups recommend determining the histologic grade and ER, PR, Ki-67 and HER2 status in all breast cancer patients, in order to assist prognosis and determine therapeutic options, including hormone therapy,

For patients with HR+ breast cancers receiving hormonal therapy, the risk of distant recurrence is under 20% and therefore, many patients may potentially be spared of chemotherapy. The web-based prognostification and treatment benefit tools and genomic assays have been incorporated into treatment planning for patients with early-stage HR+ breast cancer, which lead to get more information about prognosis and prediction of treatment response. These assays supplement the traditional histopathologic markers and help identify patients at high risk of recurrence. They also provide a more quantitative approach to risk assessment and enable individualization of treatment. This has both quality of life and health care cost implications because patients who will not benefit from a certain treatment can be spared both the toxicity

One of the available genetic prognostic platforms (MammaPrint®, Oncotype DX®, Prosigna® or EndoPredict®) may be used in node-negative ER+ patients to establish a prognostic category and decide with the patient whether adjuvant treatment may be limited to hor-

dependent based on the presence of ER and/or PR on tumor cells [2].

HER2 -negative breast cancer will be discussed.

2. Treatment decision tools

124 Breast Cancer and Surgery

chemotherapy and anti-HER2 therapy.

and the expense [3].

monal therapy.

Oncotype DX contains five reference genes (ACTB, GAPDH, GUS, RPLPO and TFRC) and 16 cancer-related genes. RNA is extracted from formalin-fixed paraffin-embedded tumor tissue, using quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR). The recurrence score (RS) is the result of a mathematical formula of the weighted expression of each gene, ranging from 0 to 100. The cutoff points are divided into three categories: low risk (RS < 18), intermediate risk (RS 18–30), and high risk (RS > 31). The RS has been proved to be a predictor of 10-year distant recurrence for early breast cancer through NSABP B-14 in multivariate analyses including age, tumor size, tumor grade, ER status and HER2 status [4]. Furthermore, patients with low or intermediate RS had large improvements in disease-free survival (DFS) if treated with tamoxifen (TAM), which indicated that RS was helpful in evaluating treatment response to endocrine therapy in early breast cancer. Habel et al. [5] conducted a case–control study among women with ER+, node-negative breast cancer treated with TAM and compared these with untreated patients. The RS was associated with the risk of breast cancer death in both groups (P = 0.003 and P = 0.03). Thus, the RS was strongly related to long-term mortality of breast cancer among ER+ breast cancer patients treated with endocrine therapy.

Paik et al. not only evaluated the relationship between the RS and clinical result of ER+, nodenegative early breast cancer but also explored the prognostic ability in late recurrence of breast cancer [4]. The 10-year distant recurrence rate was 6.8% in low-risk group, 14.3% in intermediate-risk group and 30.5% in high-risk group. The RS was shown to be related to distant relapse in patients who did not receive adjuvant chemotherapy, regardless of age and tumor size and performed better than both of them (P < 0.001).

RS can predict chemotherapy sensitivity in patients with ER+, node-negative breast cancer [6]. Paik et al. studied 651 cases of breast cancer who were enrolled in NSABP B-20 and randomly assigned them into a TAM group and a TAM combined with the chemotherapy group [chemotherapy regimen for cyclophosphamide & methotrexate & fluorouracil (CMF) or MF regimen, TAM + CMF/MF group] [4]. The 10-year follow-up results showed that patients with high RS had benefited from cytotoxic chemotherapy, with the 10-year metastasis rate being decreased by 27.6%. In contrast, the 10-year distant metastasis rate was decreased by an average of 1.1% in patients with low RS who received adjuvant chemotherapy. Therefore, patients with ER+ early breast cancer and high RS should benefit from chemotherapy, while patients with low RS cannot. RS can help select patients who experience little benefit of chemotherapy and can avoid the toxic effects of chemotherapy.

In a phase III trial, the Trial Assigning Individualized Options for Treatment (TAILORx), there was a prospective phase to further validate the function of RS in patients with HR+, HER2 negative, node-negative breast cancer. The results from TAILORx indicated that patients with very low RS results (<11) had excellent clinical outcome with a rate of 5-year freedom from distant recurrence with endocrine therapy at 99.3% and a rate of overall survival (OS) of 98.0%, even without chemotherapy [7]. As for its excellent utility in identifying patients with good outcome, Oncotype DX RS became the only gene-expression assay that was recommended at level I evidence in the AJCC Prognostic Stage Group. In patients with HR+, node-negative breast cancer, the RS showed excellent clinical utility to predict clinical outcomes.

In ECOG E2197, the predictive utility of RS on loco-regional recurrence (LRR) was evaluated in 388 patients with N0-N1 involvement and treated with breast conserving surgery, chemoendocrine therapy and breast irradiation. The 10-year rates of LRR for HR+ tumors were shown to be 3.8, 5.1 and 12.0% for low, intermediate and high risk of RS (P = 0.12) [8].

The MINDACT study was a randomized trial that included 6693 women with histologically proven operable N0/N1 invasive breast cancer without distant metastases [15]. Patients were recruited from 2007 to 2011. Initially, only patients without regional lymph node metastasis were enrolled. The study was amended to include patients with 1–3+ nodes in 2009. MammaPrint assay was used to determine participant's genomic risk and a modified version of Adjuvant! Online (version 8.0 with HER2 status) was used to determine clinical risk [16, 17]. Patients with both low clinical and low genomic risk were not treated with adjuvant chemotherapy; on the other hand, patients with high clinical and high genomic risk received adjuvant chemotherapy. The patients with discordant clinical and genomic risk results (high/low or low/ high) were randomized to receive chemotherapy or not to receive chemotherapy. All patients

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Patients at low clinical risk but high genomic risk who received chemotherapy had a 5-year distant metastasis free survival of 95.8% compared with 95.0% among those who did not receive chemotherapy. The adjusted hazard ratio for distant metastasis or death with chemotherapy versus no chemotherapy in this group was 1.17 (P = 0.66). Thus, a chemotherapy benefit is unlikely in women with tumors at low clinical risk regardless of genomic subtype. If a patient has ER/PgR-positive, HER2-negative, node negative, breast cancer, the MammaPrint (Agendia) assay should not be used in those with low clinical risk per MINDACT categorization to inform decisions on withholding adjuvant systemic chemotherapy because women in the low clinical risk category had excellent outcomes and did not

If a patient has HR+, HER2-negative, node-negative breast cancer, the MammaPrint assay may be used in those with high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy due to its ability to identify a good-prognosis population with potentially limited chemotherapy benefit. Women in the low clinical risk category did not benefit from chemotherapy regardless of genomic MammaPrint risk group. Therefore, the MammaPrint

If a patient has HR+, HER2-negative, node-positive breast cancer, the MammaPrint assay may be used in patients with 1–3 positive nodes and a high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy. However, such patients should be informed that a benefit from chemotherapy cannot be excluded, particularly in patients with greater

The clinician should not use the MammaPrint assay to guide decisions on adjuvant systemic therapy in patients with HR+, HER2-negative, node-positive breast cancer at low clinical risk, nor any patient with HER2-positive or triple-negative breast cancer, because of the lack of

The PAM50 Breast Cancer Intrinsic Classifier™ assay (ARUP Laboratories, Salt Lake City, UT) is a standardized test measuring 50 classifier genes and five control genes, amenable to assay by techniques such as quantitative real-time reverse transcriptase PCR [19]. It was originally developed in a microarray-based cohort of node-negative, untreated breast cancer patients. It

appear to benefit from chemotherapy even with a genomic high-risk cancer.

were recommended to receive 7 years of hormonal therapy.

assay does not have clinical utility in such patients.

than one involved lymph node.

2.3. PAM-50: PROSIGNA

definitive data in these populations [18].

In NSABP B-28 trial, RS was shown to be a statistically predictor of LRR, with 10-year cumulative incidence of LRR of 3.3, 7.2 and 12.2% in low, intermediate and high RS (P < 0.001) [9]. RS is a strongly predictive factor of LRR for HR+ breast cancer regardless of node status. Another study, PACS 01 trial, with a median of 7.7 years follow-up, showed that RS was a significant predictor of distant recurrence free interval survival, disease-free survival (DFS) and OS (P < 0.001) in HR+, node-positive patients treated with chemotherapy plus endocrine therapy [10].

The Southwest Oncology Group (SWOG)-8814 focused on exploring the benefit of therapy in patients with HR+, node-positive breast cancer. It enrolled postmenopausal women treated with chemotherapy or simple endocrine adjuvant therapy, of which 367 cases (40%) received an RS detection. RS had a definite predictive value (P = 0.016) for adjuvant treatment benefit over 5 years and was poorly predicted for treatment beyond 5 years (P = 0.87). High-risk patients receiving chemotherapy combined with endocrine therapy compared with simple endocrine therapy benefit significantly (P = 0.033). SWOG-8814 trial showed that the RS was also prognostic for TAM-treated patients with positive nodes and predicts significant benefit of chemotherapy [cyclophosphamide & adriamycin & fluorouracil (CAF)] in tumors with a high RS [11].

In a recent prospective phase III trial, West German Study Group Plan B, 348 patients (15.8%) with RS ≤ 11 had excellent 3-year survival even if they omitted chemotherapy. The 3-year DFS in patients with RS ≤ 11 was 98%, in which 41.1% had node-positive and 32.5% were grade 3 disease. These were the first prospective data to report clinical outcome when RS was used to make physical decision in patients with HR+ breast cancer regardless of lymph node invasion [12].

Rx for Positive Node, Endocrine Responsive Breast Cancer (RxPONDER) trial is an ongoing multicenter phase III trial revealed that patients with node positive breast cancer who had low to intermediate RS results could benefit from chemotherapy [13]. The trial also determined whether there is an optimal RS cutoff for these patients above which chemotherapy should be recommended in clinical practice. RxPONDER trial randomized patients with HR+, HER2 negative and 1–3 lymph nodes breast cancer with RS ≤ 25, to improve the risk of stratification in patients with low or intermediate RS.

## 2.2. MammaPrint

MammaPrint was first developed by the Netherlands Cancer Institute group. van't Veer et al. [14] used a gene-expression panel to detect 78 frozen tumor tissues from patients with pT1-2cN0 invasive breast carcinoma who had received standard treatment. Ribonucleic acid was isolated from fresh frozen tumor tissue to obtain complementary DNA. The gene-expression panel contains 70 genes related to early risk of metastasis, including tumor invasion, metastasis, interstitial invasion, and angiogenesis-related genes.

The MINDACT study was a randomized trial that included 6693 women with histologically proven operable N0/N1 invasive breast cancer without distant metastases [15]. Patients were recruited from 2007 to 2011. Initially, only patients without regional lymph node metastasis were enrolled. The study was amended to include patients with 1–3+ nodes in 2009. MammaPrint assay was used to determine participant's genomic risk and a modified version of Adjuvant! Online (version 8.0 with HER2 status) was used to determine clinical risk [16, 17]. Patients with both low clinical and low genomic risk were not treated with adjuvant chemotherapy; on the other hand, patients with high clinical and high genomic risk received adjuvant chemotherapy. The patients with discordant clinical and genomic risk results (high/low or low/ high) were randomized to receive chemotherapy or not to receive chemotherapy. All patients were recommended to receive 7 years of hormonal therapy.

Patients at low clinical risk but high genomic risk who received chemotherapy had a 5-year distant metastasis free survival of 95.8% compared with 95.0% among those who did not receive chemotherapy. The adjusted hazard ratio for distant metastasis or death with chemotherapy versus no chemotherapy in this group was 1.17 (P = 0.66). Thus, a chemotherapy benefit is unlikely in women with tumors at low clinical risk regardless of genomic subtype. If a patient has ER/PgR-positive, HER2-negative, node negative, breast cancer, the MammaPrint (Agendia) assay should not be used in those with low clinical risk per MINDACT categorization to inform decisions on withholding adjuvant systemic chemotherapy because women in the low clinical risk category had excellent outcomes and did not appear to benefit from chemotherapy even with a genomic high-risk cancer.

If a patient has HR+, HER2-negative, node-negative breast cancer, the MammaPrint assay may be used in those with high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy due to its ability to identify a good-prognosis population with potentially limited chemotherapy benefit. Women in the low clinical risk category did not benefit from chemotherapy regardless of genomic MammaPrint risk group. Therefore, the MammaPrint assay does not have clinical utility in such patients.

If a patient has HR+, HER2-negative, node-positive breast cancer, the MammaPrint assay may be used in patients with 1–3 positive nodes and a high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy. However, such patients should be informed that a benefit from chemotherapy cannot be excluded, particularly in patients with greater than one involved lymph node.

The clinician should not use the MammaPrint assay to guide decisions on adjuvant systemic therapy in patients with HR+, HER2-negative, node-positive breast cancer at low clinical risk, nor any patient with HER2-positive or triple-negative breast cancer, because of the lack of definitive data in these populations [18].

#### 2.3. PAM-50: PROSIGNA

In ECOG E2197, the predictive utility of RS on loco-regional recurrence (LRR) was evaluated in 388 patients with N0-N1 involvement and treated with breast conserving surgery, chemoendocrine therapy and breast irradiation. The 10-year rates of LRR for HR+ tumors were

In NSABP B-28 trial, RS was shown to be a statistically predictor of LRR, with 10-year cumulative incidence of LRR of 3.3, 7.2 and 12.2% in low, intermediate and high RS (P < 0.001) [9]. RS is a strongly predictive factor of LRR for HR+ breast cancer regardless of node status. Another study, PACS 01 trial, with a median of 7.7 years follow-up, showed that RS was a significant predictor of distant recurrence free interval survival, disease-free survival (DFS) and OS (P < 0.001) in HR+, node-positive patients treated with chemotherapy plus

The Southwest Oncology Group (SWOG)-8814 focused on exploring the benefit of therapy in patients with HR+, node-positive breast cancer. It enrolled postmenopausal women treated with chemotherapy or simple endocrine adjuvant therapy, of which 367 cases (40%) received an RS detection. RS had a definite predictive value (P = 0.016) for adjuvant treatment benefit over 5 years and was poorly predicted for treatment beyond 5 years (P = 0.87). High-risk patients receiving chemotherapy combined with endocrine therapy compared with simple endocrine therapy benefit significantly (P = 0.033). SWOG-8814 trial showed that the RS was also prognostic for TAM-treated patients with positive nodes and predicts significant benefit of chemotherapy [cyclophosphamide & adriamycin & fluorouracil (CAF)] in tumors with a

In a recent prospective phase III trial, West German Study Group Plan B, 348 patients (15.8%) with RS ≤ 11 had excellent 3-year survival even if they omitted chemotherapy. The 3-year DFS in patients with RS ≤ 11 was 98%, in which 41.1% had node-positive and 32.5% were grade 3 disease. These were the first prospective data to report clinical outcome when RS was used to make physical decision in patients with HR+ breast cancer regardless of lymph node

Rx for Positive Node, Endocrine Responsive Breast Cancer (RxPONDER) trial is an ongoing multicenter phase III trial revealed that patients with node positive breast cancer who had low to intermediate RS results could benefit from chemotherapy [13]. The trial also determined whether there is an optimal RS cutoff for these patients above which chemotherapy should be recommended in clinical practice. RxPONDER trial randomized patients with HR+, HER2 negative and 1–3 lymph nodes breast cancer with RS ≤ 25, to improve the risk of stratification

MammaPrint was first developed by the Netherlands Cancer Institute group. van't Veer et al. [14] used a gene-expression panel to detect 78 frozen tumor tissues from patients with pT1-2cN0 invasive breast carcinoma who had received standard treatment. Ribonucleic acid was isolated from fresh frozen tumor tissue to obtain complementary DNA. The gene-expression panel contains 70 genes related to early risk of metastasis, including tumor invasion, metastasis,

shown to be 3.8, 5.1 and 12.0% for low, intermediate and high risk of RS (P = 0.12) [8].

endocrine therapy [10].

126 Breast Cancer and Surgery

high RS [11].

invasion [12].

2.2. MammaPrint

in patients with low or intermediate RS.

interstitial invasion, and angiogenesis-related genes.

The PAM50 Breast Cancer Intrinsic Classifier™ assay (ARUP Laboratories, Salt Lake City, UT) is a standardized test measuring 50 classifier genes and five control genes, amenable to assay by techniques such as quantitative real-time reverse transcriptase PCR [19]. It was originally developed in a microarray-based cohort of node-negative, untreated breast cancer patients. It accurately identifies the major intrinsic biological subtypes of breast cancer commonly known as luminal A, luminal B, HER2 enriched, and basal-like [20] and predicts the risk of recurrence (ROR) at 10 years. Tumors that are named as luminal A in PAM50 intrinsic subtype indicate usually very good prognosis with only adjuvant endocrine therapy, whereas luminal B subtypes have increased risk of recurrence without adjuvant chemotherapy.

2.4. EndoPredict

ranges between 0 and 15 after scaling [25].

common clinical parameters.

scores improves their prognostic ability.

The EndoPredict (EP) assay combines the expression of three proliferative and five ERsignaling/differentiation-associated genes and is normalized by three housekeeping genes [24]. EP may be measured in formalin-fixed, paraffin-embedded tissue sections by quantitative real-time polymerase chain reaction in decentralized laboratories and provides a score that

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EPclin was derived from EP by incorporating nodal status and tumor size to create an integrated diagnostic algorithm for clinical decisions [24]. Both EP and EPclin were trained on a cohort of 964 patients with ER+, HER2-negative carcinomas treated with adjuvant endocrine therapy only. Thresholds for EP and EPclin to differentiate between patients at low or high risk corresponding to a 10% probability of distant recurrence at 10 years were set at 5 and 3.3, respectively. Patients with an EP score < 5 (EPclin score < 3.3) were classified as low risk for distance recurrence, whereas patients with an EP score ≥5 (EPclin score ≥3.3) were stratified as high risk. Both EP and EPclin were shown to be prognostic for early and late distant recurrence in the ABCSG-6 and ABCSG-8 trials involving patients with ER+/HER2-negative breast cancer treated with adjuvant endocrine therapy only [26]. EndoPredict provides prognostic informa-

There are several prognostic multigene-based tests for managing breast cancer, but limited data comparing them in the same cohort. The prognostic performance of the EP test was compared with the research-based PAM50 non-standardized qRT-PCR assay in node-positive ER+ and HER2-negative breast cancer patients receiving adjuvant chemotherapy followed by endocrine therapy (ET) in the GEICAM/9906 trial [27]. EP and PAM50 ROR scores [based on subtype (ROR-S) and on subtype and proliferation (ROR-P)] were compared in 536 ER+/ HER2patients. Scores combined with clinical information were evaluated: ROR-T (ROR-S, tumor size), ROR-PT (ROR-P, tumor size), and EPclin (EP, tumor size, nodal status). Patients were assigned to risk categories according to prespecified cutoffs. ROR-S, ROR-P, and EP scores identified a low-risk group with a relative better outcome (10-year distant metastasisfree survival: ROR-S 87%; ROR-P 89%; EP 93%). No significant difference between tests was found. Predictors including clinical information showed superior prognostic performance compared to molecular scores alone (10-year MFS, low-risk group: ROR-T 88%; ROR-PT 92%; EPclin 100%). The EPclin-based risk stratification achieved a significantly improved prediction of MFS compared to ROR-T, but not ROR-PT. All signatures added prognostic information to

EPclin provided independent prognostic information beyond ROR-T and ROR-PT. ROR and EP can reliably predict risk of distant metastasis in node-positive ER+/HER2 negative breast cancer patients treated with chemotherapy and ET. Addition of clinical parameters into risk

Recently, in a secondary analysis of a randomized clinical trial, the prognostic value of six multigene signatures was compared in women with early ER+ breast cancer [28]. In this study, 774 postmenopausal women with ER+, HER2-negative disease, 591 had node-negative disease

tion beyond all common clinicopathological parameters and clinical guidelines.

Four versions of ROR exist in the research setting: ROR based on subtype information (ROR-S), ROR-S with proliferation (ROR-P), ROR-S with tumor size (ROR-T), and ROR-P with tumor size (ROR-PT) [20]. The minimum ROR score of all Luminal B scores was assigned as the lowrisk threshold for each model and the maximum ROR score of all Luminal A scores as the high-risk threshold [20]. Large validation studies (ATAC and ABCSG8) for the PAM50 assay were performed using the standardized version with pre-specified cutoffs based on actual survival outcomes (<10, 10–20, and > 20% risk of distant relapse at 10 years) and not subtype distribution [21].

The Prosigna Breast Cancer Prognostic Gene Signature Assay is an in vitro diagnostic assay, which is performed on the NanoString nCounter® Dx Analysis System using FFPE breast tumor tissue previously diagnosed as invasive breast carcinoma. The Prosigna Score is a numerical value on a 0–100 scale that correlates with the probability of distant recurrence within 10 years. The gene expression profile of a patient's tumor is compared with each of the four PAM50 prototypical molecular profiles to determine the degree of similarity. The results in combination with a proliferation score and tumor size produce an individualized Prosigna Score. This qualitative assay utilizes gene expression data, weighted together with clinical variables to generate a risk category and numerical score, to assess a patient's risk of distant recurrence of disease.

In node-negative patients, the 10-year distant recurrence-free survival (DRFS) rates were > 95% for the low-risk group, 90.4% for the intermediate-risk group, and < 85% for the high-risk group [22, 23]. In node-positive patients, the 10-year DRFS rates were 94.2% for the low-risk group and 75.8% for the high-risk group [22].

The Prosigna Breast Cancer Prognostic Gene Signature Assay is indicated in female breast cancer patients who have undergone surgery in conjunction with locoregional treatment consistent with standard of care, either as:


The assay should not be used for patients with four or more positive nodes.
