Clinical Prognosis and Staging of Breast Cancer

Introduction

An estimated 281,550 women were diagnosed with invasive breast cancer and 49,290 women were diagnosed with in situ cancer in 2021 in the United States. One in eight women are expected to be diagnosed with breast cancer as compared to one in 833 men. It is estimated that 43,600 women in the United States succumbed to breast cancer in 2021. The overall mortality rate has declined 1% per year based on the most recent available data from 2013 to 2018. For individual patients these statistics are irrelevant. Patients like to know their individual prognosis. They would like to know their best therapeutic option. Prognostic factors predict disease-free and overall survival (DFS and OS). Many of the factors related to prognosis depend on the tumor, including the stage of the cancer at the time of the diagnosis, the hormonal status, and the presence or absence of human epidermal growth factor receptor-2 (HER2) amplification. Other factors are patient-dependent such as age, menopausal status, and other comorbidities. One of the most important prognostic indicators has been the stage of the cancer at the time of the diagnosis. Although the stage predicts the overall 5-year survival, it does not provide information about the treatment option. The 8th edition of the American Joint Committee on Cancer (AJCC) staging system considered this factor. The authors have emphasized that several biomarkers should be documented at the time of initial diagnosis. Some of these biomarkers have been studied for many decades, and their validity and role in the selection of treatments are well established. Others have been proven important just during the last decade. These biomarkers include hormone receptor status (estrogen receptor [ER] and progesterone receptor [PR], HER2, a marker of proliferation [such as Ki67 or a mitotic count]). Newer biomarkers include genomic prognostic panels (such as OncotypeDx, Mamma-Print, EndoPredict, PAM 50 [Prosigna], Breast Cancer Index, etc.).

This chapter intends to provide information about original anatomic stage of breast cancer with a strong emphasis on the impact of nodal status on the ultimate prognosis, as well as recently established AJCC prognostic stage groups. The difference in the subgrouping will be highlighted. The 8th edition of the AJCC staging system has primarily used data from the National Cancer Database (NCDB). These data are based on analysis of 334,243 women diagnosed from 2010 to 2012. Additionally this chapter will provide information on patient-related factors such as age, race, pregnancy, sociological factor, histologic type, and gender. In addition, the impact of type of metastases on the ultimate prognosis will be discussed. Finally, we intend to highlight the role of the multidisciplinary approach to breast cancer treatment.

Anatomic Stage Groups

The staging system for breast carcinoma applies to both invasive carcinoma and ductal carcinoma in situ. Lobular neoplasia/lobular carcinoma in situ is not included in this staging system. Clinical stage (c) is established using information prior to surgery or neoadjuvant therapy. Pathological stage (p) is based on information obtained following surgery. AJCC published the first staging manual in 1959. AJCC has published an additional seven editions to incorporate advances in science and our understanding in cancer progression and the natural history of various tumors. The initial edition concentrated primarily on the anatomical stage of the cancer. Although some further clarifications have been made to this system, the original concept has remained intact in the current AJCC anatomic stage groups of breast cancer. This system uses three anatomical parameters to classify cancer: tumor size (T), regional lymph node status (N), and presence or absence of distant metastases (M). This classification is globally used when no other prognostic indicators or biomarkers are available. In the AJCC anatomic stage groups, T reflects the largest contiguous mass (primary site). If multiple foci of invasive cancers are noted, only the largest size is included in the staging. Both radiologists and pathologists should provide the number of invasive foci and indicate the size range.

The maximum size of the tumor is the largest contiguous dimension of the tumor. Satellite nodules or intense fibrosis following neoadjuvant chemotherapy are not included in this measurement. The American College of Radiology (ACR) requires that all imaging reports follow the same guideline and contain at least the largest continuous dimension. They recommend including any evidence of calcification or architectural distortion. The size of the in situ component does not influence the T stage. The ultimate size of the tumor influences the therapeutic options, and it is recommended to estimate the size of the tumor based on imaging studies, gross findings, and microscopic findings. Several studies suggest that imaging studies using MRI provide more accurate measurements of tumor size. Histopathologic determination of the size remains the gold standard for measuring the ultimate size of the tumor. A recent study also suggests that the density of the breast does not necessarily influence the tumor measurement determined by imaging studies. This study also emphasizes that discrepancies between imaging-assessed size and pathologic size are not uncommon.

The designation N reflects the regional lymph node (LN) classification, including ipsilateral axillary lymph nodes, interpectoral lymph node/nodes, and internal mammary nodes. Prognosis of the breast cancer remains dependent on lymph node status. A recent study suggests that positive LN is an epiphenomenon of the onset of and chronometer for the duration of tumor cell dissemination from growing breast cancers. Metastatic tumors are initiated parallel to LNs by primary tumors and are not necessarily caused by positive LNs.

AJCC does not require imaging studies to categorize lymph nodes as cN0, even in patients with prior lymph node removal. The category sentinel is used only with pathologic stage and only if fewer than six lymph nodes are evaluated. If fewer than 200 cells are noted within the sentinel lymph node, the patient is staged as N0i. This indicates the presence of isolated tumor cells (ITCs) and does not alter the nodal stage at the present time. Most clinical teams agree that molecular testing in sentinel lymph nodes is not recommended. Nodes with ITCs are excluded from positive lymph nodes, but their number should be reflected in the report. The scientific community is not in complete agreement of how ITCs ultimately impact the long-term prognosis; however, there is a general agreement that these patients do not require complete axillary dissection. Lymph nodes with metastatic tumor load greater than 200 cells and less than 2 mm are classified as N1mic. These patients do not require axillary dissection. Ten-year DFS of N1mic breast cancer patients with no additional surgery has been reported at 76.8% as compared to those with axillary dissection at 74.9% ( P = ns). Patients with one to three positive lymph nodes (level I/II) are classified as pN1a; patients with four to nine lymph nodes are classified as pN2; and patients with 10 or more positive lymph nodes are classified as pN3a. Patients with histologically confirmed metastases to the internal mammary nodes detected by sentinel lymph node identification, not imaging studies, are classified as pN1(sn). Histologic evidence of metastases in ipsilateral supraclavicular lymph node(s) is classified as pN3c.

Other nodal-related factors that alter the prognosis include size of the involved lymph node and presence of extranodal extension (ENE). The size of positive LN/LNs plays an important role in the ultimate prognosis. On multivariable analysis, large (≥2 cm) LN size was significantly associated with worsened breast cancer–specific survival (64.8%) after 109 months’ follow-up. The cancer protocol template endorsed by the College of American Pathologists (CAP) recommends including the size of the largest lymph node metastasis. ENE has a negative effect on the prognosis. Studies have shown that patients with ENE of sentinel lymph nodes are more likely to have additional positive lymph nodes, and some studies recommend complete axillary dissection in this group of patients. The cutoff value is currently set at 2 mm or less; however, this value has not been validated.

The designation M refers to the presence of metastasis. If a patient presents with M1 disease prior to neoadjuvant treatment, the stage is IV and remains IV regardless of the response to the neoadjuvant therapy.

A patient can be classified as M0 in absence of any imaging studies if the finding correlates with the T and N classification and the patient does not show any elevated liver enzymes or suspicious findings on physical or clinical history. Most experts agree that no staging is required in asymptomatic patients with T1–2 N0 breast cancers. They recommend staging with imaging studies for stage III (clinical or pathologic) cancers. Metastatic breast cancer (MBC) is considered incurable; however, some patients present with a single metastatic lesion (oligometastatic breast cancer). These patients seem to have a better prognosis and can be treated with a goal of achieving complete remission. Oligometastatic tumors are a very small fraction of all MBCs. These tumors are characterized by the presence of solitary or a few detectable metastatic lesions that are usually limited to a single organ. These patients can be treated using a multidisciplinary approach with a potential curative goal, as long as the patients are young and show good performance status. The current data remain limited in these patients. Prospective international randomized trials are necessary for further confirmation.

The discussion about the prognosis of patients with metastatic cancers will continue at the end of this chapter.

AJCC Prognostic Stage Groups

AJCC in their 8th edition have strongly considered the other prognostic indicators. The prognostic factors include grade, tumor biomarkers such as hormonal status, estrogen (ER), progesterone (PR), HER2-neu, and proliferation index. Gene expression profiles (GEPs) have also been considered. This new prognostic staging reflects the results of numerous studies and data evaluations by many previously conducted studies, as well as the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute.

Plichta and colleagues have recently compared the stage of almost half million women with breast cancer stage I to III. They used the 8th edition of AJCC as compared to 7th edition. They found that this prognostic staging better refines and estimates the OS. They believe using this prognostic staging will help the clinical team to provide better care and treatment options for the patient. This prognostic staging has given strong consideration to the result of the ancillary tests and the grade of the tumor. Fig. 26.1 shows the comparison of the staging using the 7th edition versus the 8th edition. Many tumors have been downstaged, while others are upstaged. Fig. 26.1 shows that this prognostic stage is superior to staging based on the 7th edition, and better correlates with the probability of survival. In addition, it shows how using presence of hormonal receptor will influence the probability of survival ( Fig. 26.2 ). As Fig. 26.3 shows, age also plays an important role in prognosis. Both of these factors, as well as tumor grade, will be revisited in the following sections.

AJCC has also included in their prognostic staging group the OncotypeDX score. In 2002 scientists in the Netherlands reported that GEP could predict outcome of breast cancer. This finding was used to develop a more simple and robust real-time reverse transcriptase polymerase chain reaction (RT-PCR) test that could be applied to formalin-fixed paraffin-embedded tissue. The OncotypeDX is a RT-PCR–based gene profiling test initially introduced for patients with node-negative, receptor-positive breast cancers. This test would categorize patients as having a recurrence score (RS) that was low, intermediate, or high. The RS is also predictive of OS and is felt to be independent of tumor size and patient age ( P < 0.001). This test has been validated by multiple studies. In addition, it can predict which patients will benefit from chemotherapy. This test has been not been formally approved by the US Food and Drug Administration (FDA) but is a Clinical Laboratory Improvement Amendments (CLIA)-approved test. By incorporating gene expression, AJCC committee members have acknowledged that both the Breast Cancer Guideline Committee of the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology suggested the use of gene expression array to determine prognosis in ER-positive breast cancer patients. The 8th edition of AJCC considers all T1, ER-positive, HER2-negative, N0, M0 cancers with a OncotypeDX score of less than 11 as stage IA, regardless of the tumor grade. The authors of the AJCC staging manual acknowledge that most cancer deaths are not in developed countries, and anatomic staging cannot be ignored. By establishing the new prognostic staging, the authors intended to create a staging manual that is relevant for the present and adaptable to the future, but will remain anchored to the past.

Molecular Testing and Clinical Prognosis

During the last 15 years, many investigators throughout the world have tried to identify which breast cancer patients would definitely benefit from adjuvant chemotherapy. Many studies have shown that chemotherapy is beneficial to only a select group of breast cancer patients. The psychological, social, and financial cost to patients and society is tremendous. Many trials have been completed and others are being conducted on these molecular tests. The chapter on molecular prognosis has extensively discussed many of these trials. As previously indicated, the 8th edition of AJCC staging system has incorporated the molecular test results (the result of OncotypeDX) in their prognostic clinical stage.

OncotypeDX, otherwise known as the 21-gene assay (Recurrence Score Assay) is performed on ER-positive HER2-negative breast cancers. The test is performed on paraffin-embedded formalin-fixed tissue. The initial studies were all performed on low-stage, predominantly lymph node–negative breast cancers. This assay is based on RT-PCR. The assay not only guides treatment options, especially in early-stage breast cancers, but also can provide prognosis. The RS yields a continuous numeric variable on a scale of 0 to 100. Based on the results of National Surgical Adjuvant Breast and Bowel Project (NSABP) B20, patients are stratified into low risk (RS ≤0–17), intermediate risk (RS 18–30), and high risk (RS ≥31). Multiple studies have shown that patients with a low RS of 0–17 will not benefit from chemotherapy. The patient with a low score has an excellent prognosis with endocrine therapy alone. It is important to keep in mind that the majority of patients enrolled in various trials involving OncotypeDX were postmenopausal. At least in one study with a medium follow-up of 46 months, the absolute risk of distant metastases among patients with a RS of 11–17 who were <40 years old was 7.1% (3 out of 42 patients) versus 0.2% among patients ≥40 years old (2 of 854 patients). Those with a RS >31 are considered to be high-risk. The majority of these patients receive adjuvant chemotherapy. Overall, the use of chemotherapy has declined considerably in patients with early-stage ER+, HER2− breast cancer.

For many decades, the scientific community has considered lymph node status as an important prognostic marker. Almost all patients with positive lymph node status used to receive adjuvant chemotherapy; however, recent studies show that patients with ER+/HER2− cancers with limited positive lymph nodes (one to three positive nodes) and low RS may not benefit from additional chemotherapy. Postmenopausal breast cancer patients with positive lymph nodes have a good prognosis if their tumors show a low RS. In a Southwest Oncology Group (SWOG) study, investigators have shown that postmenopausal patients with a RS <18 had no benefit from additional chemotherapy even in presence of positive lymph nodes. This study has been validated by another larger study performed in postmenopausal women.

Another molecular test used worldwide to select breast cancer patients with low risk of developing metastases is MammaPrint. This test is based on 70-gene expression signature and is FDA-approved. The largest clinical trial using this test is the I-SPY2 neoadjuvant trial (NCT01042379). The population is categorized into eight groups based on defined biomarkers (ER/PR/HER2) and MammaPrint. Previous studies have shown that a high genomic risk is associated with chemosensitivity. For this trial, patients are divided into high-risk (MP1) and ultra-high–risk (MP2) groups based on a higher cutoff point. Patients classified as MP2 had a greater sensitivity to neoadjuvant chemotherapy, because their pathologic complete response (pCR) was 44% compared to 24% pCR in MP1. MammaPrint has been incorporated in the 8th tumor, node, metastasis (TNM) edition along with OncotypeDX in order to downstage selected ER-positive, HER2-negative, node-negative tumors. The long-term result of MINDACT (a MammaPrint-based trial) is not yet available, but it might enable the clinical team to select the best duration for endocrine therapy. This test is not as widely used as OncotypeDX in the United States as it is in Europe; however, it might be proven very helpful and cost-effective in future.

EndoPredict (EPclin) is another RNA-based multigene assay that is based on expression assay of 12 genes: eight cancer-related genes (five ER signaling–associated genes and three proliferating genes), three reference genes, and one control gene for DNA contamination. The test integrates genomic and clinical information. The performance of EPclin is used for establishing 10-year distant free interval (DRFI) rate for those receiving adjuvant endocrine therapy alone compared to those with chemotherapy plus endocrine therapy. The authors believe EPclin is highly prognostic. This test is particularly helpful in node-positive women. High EP score can also predict chemotherapy benefit. This test is most useful in the intermediate risk group. Genomic testing appears to result in more consistent final decisions, across patients’ situations and across centers.

There are other GEP tests; however, they are less often ordered at this point, and they will not be covered in this section. GEPs offer new tools in shared decision-making regarding treatment. It remains important to consider patients’ perception and understanding of these tests. One must also make sure that vulnerable population are not marginalized by these tests.