the new treatment paradigm for early stage breast cancer · 2016-08-08 · most of the nearly 5,000...

1Breast Cancer Therapy | www.smgebooks.comCopyright Citrin DL.This book chapter is open access distributed under the Creative Commons Attribution 4.0 International License, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited.

Gr upSMThe New Treatment Paradigm for Early

Stage Breast Cancer

ABSTRACTRecent advances in imaging technology and in our understanding of the molecular biology of

breast cancer have led to a change in the treatment of patients with early stage disease. While the goal of surgery remains the removal of all evident disease within the breast and regional (axillary) nodes, the role of additional drug therapy has undergone significant changes.

Traditionally, the most important prognostic variable in patients with newly diagnosed breast cancer has been the stage of the disease, defined as the size of the primary tumor in the breast and the extent of involvement of regional (axillary) lymph nodes. Treatment was also largely determined by these anatomical factors, where surgical removal of all evident disease was the primary goal of treatment. This is usually followed by post-operative (adjuvant) drug therapy given to suppress or eradicate occult micro-metastatic disease to prevent late recurrence and increase overall cure rates.

Dennis L Citrin1,2*1Cancer Treatment Centers of America at Midwestern Regional Medical Center, USA2Department of Medicine, Rosalind Franklin University of Medicine and Science, USA

*Corresponding author: Dennis L Citrin, Department of Medical Oncology, Midwestern Regional Medical Center, 2520 Elisha Avenue, Zion Illinois 60099 USA, Tel 847 731 5892; Fax 847 731 1058; Email: [email protected]

Published Date: June 15, 2016


Important biological differences between breast cancers, identified by the presence of estrogen and progesterone receptors, and more recently human epidermal growth factor receptor 2 (HER2/neu), has led to more specific and effective adjuvant treatments (endocrine therapy and HER2 directed drugs respectively).

The recent introduction of tumor genomic testing, which allows accurate characterization of the molecular subtype of breast cancer, has further improved our ability to more accurately define the prognosis for each patient. As a result, we can now safely avoid adjuvant chemotherapy in patients with good prognosis tumors without reducing the probability of cure, while providing a compelling rationale for more aggressive systemic treatment in patients with high-risk tumors.

In addition to prognostic information, genomic testing also provides important predictive information, by identifying those tumor molecular sub-types where pre-operative (neo-adjuvant) therapy is most likely to be effective and which drugs are likely to be most effective. Additionally, advances in imaging technology, in particular ultrasound and Magnetic Resonance Imaging (MRI) permit more accurate diagnosis and measurement of tumor response to systemic treatment.

Because of these advances, there is now an alternative treatment paradigm for many patients with newly diagnosed breast cancer. Identification of tumor biology and molecular sub-typing combined with accurate pre-treatment tumor staging can provide a more precise and effective treatment plan (tailored to the characteristics of the individual patient and her tumor), than the conventional approach of breast surgery dictated primarily by anatomic factors followed by adjuvant drug therapy.

Keywords: Tumor staging; Tumor biology; Genomic testing; Adjuvant therapy; Neo-adjuvant therapy

Abbreviations: DMFS: Distant Metastases Free Survival; HER2/neu or HER2: Human Epidermal Growth Factor Receptor 2; IHC: Immuno-Histochemical Staining; FISH: Fluorescent in Situ Hybridization; pCR: Pathologic Complete Response

INTRODUCTION Most of the nearly 5,000 women newly diagnosed with invasive breast cancer every week

in the United States have potentially curable early stage disease. Over the past several decades, curative treatment of the patient with early stage breast cancer has increasingly involved the use of multiple treatment modalities [1]. To achieve cure, all evident disease in the breast must be surgically removed. Additionally, the regional (axillary) lymph nodes are sampled. Post-operative radiation treatment is indicated when partial mastectomy (breast conserving surgery) is chosen, or after mastectomy if there is significant metastatic involvement of axillary nodes [2].

In addition to the local treatment modalities of surgery and radiation, most patients with early stage breast cancer also receive some form of adjuvant drug treatment. Adjuvant therapy is defined as drug treatment given after surgical removal of the primary tumor. Such therapy is


designed to kill or suppress occult micro-metastases, thus increasing the probability of long-term metastasis free survival [1].

The choice of adjuvant drug treatment for any individual patient is determined by two factors: overall prognosis and the biological type of breast cancer. We will discuss both of these factors and how they may impact both the choice of adjuvant therapy and its sequencing in the overall treatment plan.

CONVENTIONAL PROGNOSTIC FACTORS IN EARLY BREAST CANCER

Broadly speaking, patients with tumors, which carry a poorer prognosis, require more aggressive adjuvant therapy.

Prognosis for the individual patient has traditionally been determined by anatomic factors, which define the stage of the disease. These are the size of the primary tumor in the breast and the number of axillary nodes involved by metastatic disease [3,4]. Additional relevant prognostic factors include biologic factors such as the grade of the tumor, and the estrogen and progesterone receptor and HER2 status, identified by Immuno-Histochemical Staining (IHC) or Fluorescent in Situ Hybridization (FISH) [5-7].The inter-action between anatomic and biologic prognostic factors determines the prognosis for each patient with early stage breast cancer. The presence of one or more negative prognostic factor, which includes larger tumors, higher number of axillary nodes involved by metastatic disease, high tumor grade, negative estrogen receptor status and positive HER2 status are considered an indication for adjuvant chemotherapy [8].

The interaction between anatomic and biologic factors has formed the basis for computer algorithms such as Adjuvantonline.com, which provide a useful clinical guide for clinicians to determine the need for adjuvant therapy and the anticipated benefit of such therapy in any individual patient [9].

ADJUVANT THERAPYThere are three basic types of systemic therapy used in the adjuvant setting, depending on the

biologic type of breast cancer. Cytotoxic chemotherapy was the first systemic therapy used in the adjuvant setting. It is employed in most patients although as we will discuss later in this chapter, recent advances in molecular sub-typing suggest that some patients may derive little benefit from chemotherapy. Additionally, patients with estrogen receptor positive disease are treated with endocrine therapy, designed to reduce estrogenic stimulation of tumor growth to a minimum. HER2 positive tumors are treated with HER2 targeted therapy.

In general, adjuvant chemotherapy is given for approximately four to six months after surgical removal of the primary tumor [10], while endocrine therapy is prescribed for ten years [11]. Her2 targeted therapy is generally prescribed for twelve months [12].


Numerous studies in many thousands of women have shown that post-operative adjuvant drug treatment successfully prevents late recurrence of disease, and therefore increases overall cure rates [1].

Adjuvant chemotherapy is, however associated with long-term risks, the most serious of which include congestive heart failure [13] and acute leukemia [14]. These serious late toxicities are rare, but are seen most frequently in patients treated with Anthracycline drugs. Less severe long term side effects include peripheral neuropathy and loss of cognitive function. Although serious long-term side effects are relatively rare, a careful risk benefit analysis should be employed before the decision to recommend adjuvant chemotherapy is made.

NEO-ADJUVANT THERAPYFollowing the demonstration that adjuvant therapy could successfully reduce breast cancer

death rates, the concept of neo-adjuvant or pre-operative drug treatment was introduced [15]. Neo-adjuvant therapy is defined as the use of pre-operative systemic therapy to reduce the size of the primary tumor (and any involvement of axillary nodes) prior to definitive surgical treatment.

When neo-adjuvant chemotherapy has been most effective, totally destroying the tumor with no evidence of residual invasive disease in the resected breast and lymph nodes after pre-operative drug treatment (pathologic complete response (pCR), the long-term prognosis is excellent [16-18].

Although adjuvant and neo-adjuvant chemotherapy produce similar cure rates [15], neo-adjuvant therapy has several potential advantages however, when compared with the traditional approach of surgery followed by adjuvant chemotherapy.

When used in appropriate patients, neo-adjuvant therapy can significantly reduce the size of the primary tumor and lymph nodemetastases, increasing the probability that more limited, breast-conserving surgery can be performed.

An additional advantage of neo-adjuvant therapy compared with adjuvant therapy is that it provides the ability to monitor the effectiveness of the chemotherapy regimen chosen while treatment is being given prior to surgery, as the tumor remains in situ.

By measuring the tumor and involved nodes clinically and radiologically throughout the course of treatment, the oncologist can determine how effective the chosen regimen is in down-staging the disease.

In contrast, the efficacy of adjuvant therapy can only be determined after long-term follow-up, and is confirmed by a significant reduction in the incidence of late treatment failure. As such, trials of adjuvant therapy by their very nature take many years, if not decades to be fully evaluated.

Neo-adjuvant therapy offers a unique opportunity to study the efficacy of drug therapy in vivo. The treating oncologist can quickly confirm that the disease is indeed responding to therapy or cross over to a different regimen if there is minimal or no response to the first regimen chosen.


The ability of neo-adjuvant therapy to broaden and improve the treatment options for patients with early breast cancer has emphasized the importance of accurate definition of the biologic type of breast cancer.

Up till recently, definition of the biologic differences between various breasts cancers relied on Immuno-Histochemical Staining (IHC) or Fluorescent in Situ Hybridization (FISH) [5-7].These conventional prognostic biologic factors have recently been supplemented by gene expression profiling (tumor genomics).

CLASSIFICATION OF BREAST CANCER BASED ON TUMOR GENOMICS

In contrast with traditional sub-typing (IHC or FISH) which interrogate cell surface characteristics; molecular sub-typing identifies the downstream pathway genes, which are driving the tumor’s growth.

Perou was the first to show that breast cancers could be classified into different molecular subtypes based on different gene expression profiles [19]. Since then numerous groups have reported similar assays [20-24].The results of genomic testing demonstrate that breast cancer is not a homogeneous disease. Four major molecular subtypes have been identified, each with different clinical and pathological characteristics. These are Luminal-A, Luminal-B, Basal-like or HER2 positive.

There are marked differences in long-term outcome (prognosis), and response to neo-adjuvant chemotherapy with each molecular sub-type. These differences have profound clinical implications.

PROGNOSTIC SIGNIFICANCE OF MOLECULAR SUB-TYPEEarly stage tumors identified by genomic testing as Luminal A have an excellent prognosis,

with such a low risk of distant recurrence that adjuvant chemotherapy can be safely avoided [25]. In a major prospective study of 427 patients, the Mamma Print 70-gene signature identified Low Risk patients, the majority of whom received no chemotherapy, and 97% of those patients remained disease free at 5 years [26]. In contrast, Luminal B, HER2-type and Basal-like tumors are associated with a high risk of disease recurrence, and more aggressive adjuvant or neo-adjuvant chemotherapy is generally indicated [20-24,27,28].

It appears that the results of genomic testing area more accurate indicator of prognosis than conventional clinical and pathological factors. A recently published international prospective study of 6693 patients (Microarray In Node negative and 1-3 positive lymph node Disease May Avoid Chemotherapy, MINDACT) compared the use of traditional clinical–pathological prognostic factors (using Adjuvant Online), and the 70-gene profile (Mamma Print) in determining the need for adjuvant therapy [29].


In this study, if both methods classified the patient’s risk of relapse as low, no adjuvant chemotherapy was given. Patients classified by both methods with high risk of relapse received chemotherapy. Where clinical–pathological and genomic prognostic factors were discordant, the patient was randomized to using either the clinico-pathologic result or the genomic result to determine the need for adjuvant chemotherapy or no chemotherapy.

Among the 3,356 patients enrolled in the MINDACT trial who were categorized as having a high risk of breast cancer recurrence based on clinical and conventional pathological criteria, treatment based on Mamma Print results reduced the prescription of chemotherapy by 46% (1550 pts), who were in fact low risk by genomic testing. Five-year distant metastasis–free survival in these patients was in excess of 94 percent, whether they received chemotherapy or not.

The authors concluded that based on the MINDACT data, if a decision to withhold chemotherapy was based on only clinical low risk status, 3337 patients would not receive chemotherapy. In contrast if a decision to withhold chemotherapy was based on genomic status only, 4295 patients would not receive chemotherapy. An additional 958 patients (14%) of all patients enrolled in the MINDACT trial could therefore safely avoid chemotherapy by using the 70-gene signature Mamma Print signature to assess risk compared with using traditional clinical assessments.

The MINDACT results have major clinical significance, as many patients with early stage breast cancer who are currently treated with adjuvant chemotherapy may in fact be safely spared chemotherapy, with its associated risks if genomic testing confirms the tumor is in fact low risk [29].

PREDICTIVE SIGNIFICANCE OF MOLECULAR SUB-TYPEIn addition to providing prognostic information, gene expression profiles can also predict

how likely an individual tumor is to respond to neo-adjuvant (pre-operative) chemotherapy. As described above, Pathologic Complete Response (pCR) following neo-adjuvant therapy is an indication of significant responsiveness to therapy, and is associated with an improved cure rate [16-18].

A recent study of 437 patients in four neo-adjuvant chemotherapy trials, using an 80 gene assay for molecular sub-typing (BluePrint), showed better determination of responsiveness to chemotherapy than IHC/FISH, with better correlation with long-term outcomes [30].

Luminal A-type tumorshave a low pCR rate when treated with neo-adjuvant) chemotherapy. In contrast, HER2 positive and Basal-type tumors are highly sensitive to chemotherapy, with a high pCR rate and improved distant metastasis free survival following neo-adjuvant treatment. Luminal B-type tumors have a higher pCR rate than Luminal A-type tumors, but significantly lower than HER2 positive and Basal-type tumors (Table 1) [8,30,31].


Table 1: Prognosis and Chemotherapy Sensitivity ofDifferent Molecular Sub-Types.

[Ref 30]

Specific molecular sub-types appear to respond to different chemotherapy regimens. HER2 positive tumors are Anthracycline sensitive [32], while Basal-type tumors are sensitive to Platinum compounds [33].Ongoing research will better define appropriate regimens for each sub-type.

In that context, the I-SPY 2 trial (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis) uses a unique adaptive design to match experimental therapies with the results of genomic testing [34]. The goal of the trial is to improve our ability to quickly identify effective (and ineffective) neo-adjuvant drug treatment in the individual patient, thus avoid exposing patients to drugs that offer them little benefit.

I-SPY-2 trial uses pCR as the primary endpoint and focuses on women with higher risk molecular subsets of breast cancer. The study is designed to screen new agents in combination with chemotherapy. The goal is to test these novel agents for their ability to improve pCR rates for subsets of breast cancer defined by both standard and molecular markers. Several promising drug regimens have already been identified by I-SPY [35,36].

An important component of the I-SPY trialis the use of sensitive serial imaging studies. Change in tumor volume measured by serial Magnetic Resonance Imaging (MRI) is the imaging method that best predicts pCR [37]. Serial MRIs provide a noninvasive measure of response to therapy, providing information that cannot otherwise be obtained without surgical resection. An example of the documentation of clinical response to neo-adjuvant therapy byserial MRI examinations is shown below (Figures 1, 2).

Molecular sub-type Chemosensitivity (pCR/total,n/N(%) Prognosis (5 yr DMFS)Benefit from Chemo

5 yr DMFS (pCR)5yr DMFS (RD)

Luminal A-type 5/90 (6%) 93%75% pCR94%RD(P=.216)

Luminal B-type 16/154(10%) 74%85%pCR72%RD(P=.216)

HER2-type 33/70(47%)` 77%91%pCR64%RD(P=.019)

Basal-type 45/123(37%) 68%91%pCR54%RD(P<.000)


Figure 1: 45 year-old woman presented with a 10 cm mass in right breast and 6 cm right axillary node. Core needle revealed triple negative (Basal-Type) cancer. Patient desired breast-

conserving surgery.

Figure 2: After 4 treatments with neo-adjuvant chemotherapy, there was major improvement on physical examination and repeat MRI. Patient had breast-conserving surgery with contra-

lateral breast reduction. All resected tissue from breast and axilla was scar tissue with no residual cancer (pCR). Patient had two additional cycles of post-operative chemotherapy

followed by radiation and remains cancer-free four years later.


It should also be noted that although Luminal A tumors have a low probability of significant response to neo-adjuvant chemotherapy, they are very sensitive to neo-adjuvant hormonal therapy. Neo-adjuvant hormone therapy is a therapeutic approach that has been used in a very limited way in the United States, although it has had wider application in Europe [38]. As molecular sub-typing is used more widely in clinical practice it is likely that neo-adjuvant hormone therapy will see wider use in the United States.

THE NEW TREATMENT PARADIGM Based largely on our increased understanding of the different biologic types of breast cancer

(defined by molecular sub-typing), we can now more accurately predict both the need for systemic chemotherapy and the probability of favorable response to pre- operative therapy. These facts form the basis for an entirely new treatment paradigm (Tables 2,3)

Table 2: Old Paradigm.

Table 3: New Paradigm.

1. Diagnosis by imaging and core biopsy: all elements of tumor size, nodal status, ER/PR/HER 2, and genomic profile

2. Refer to surgery, medical oncology and radiation BEFORE any treatment initiated.

3. Multi-disciplinary treatment conference

4. Primary treatment decision with all diagnostic elements available: depend on anatomic factors, assessment of risk of future relapse, and probability of response to systemic treatment.

5. If primary treatment chosen is drug treatment, re-assess clinically and radiologically after 3-6 months of treatment.

6. If primary treatment chosen is surgery, re-assess need for adjuvant drug treatment and radiation when definitive post-surgical pathology is available (as in 4-6 above)

As discussed earlier, treatment of the patient with early stage breast cancer has historically been dictated by the stage (anatomy) of the tumor. The patient with a breast lump was first referred to a surgeon for both biopsy and surgical treatment. The surgeon typically performed a simple or partial mastectomy with biopsy of the sentinel nodes. Following surgical treatment, additional radiation and drug treatment were prescribed, based on the anatomic and biologic factors described above.

This anatomically based approach has been largely replaced by a new paradigm, where the biology of the cancer is recognized to be of great importance. The old paradigm was based on the question, “What is the stage of the cancer?” However, the new paradigm asks the additional question, “What is the biologic type of cancer we are dealing with?”

1. Diagnosis by surgical excision or core biopsy

2. Primary treatment : surgical removal of all visible disease

3. Then refer to medical oncology and radiation for additional (adjuvant) treatment

4. Chemotherapy if high risk*

5. Other systemic therapy (endocrine, HER2 targeted) based on biologic type*

6. Radiation if breast conserving surgery and/or significant involvement of axillary lymph nodes.

* defined by stage (tumor size and nodal involvement), high grade, ER/PR negative or HER2 positive by IHC/FISH


Based on advances in genomic testing, clinicians can now readily identify the specific molecular sub-type of breast cancer they face. Based on all of the relevant information, anatomic and biologic, a specific treatment plan is developed, tailored to the individual patient and the characteristics of her disease.

Clinical staging information is obtained from imaging studies before surgery, and all of the important biologic information, including molecular sub-type can be obtained from a simple core needle biopsy of the tumor.

The combination of tumor stage and biologic sub-type provides valuable prognostic and predictive information that can be of major importance in determining not only what drug treatment(s) are most appropriate, but also the sequencing of treatment.

The new treatment paradigm may be simply stated: when tumor down-staging with neo-adjuvant drug treatment will significantly change the available surgical options and the biological type of cancer is predictive of an excellent response to drug treatment (HER2-type and Basal-type tumors), then pre-operative drug treatment should be the first treatment employed. Drug treatment should be continued until maximal benefit has been achieved. This generally does not require prolonged chemotherapy (beyond four cycles).

It is no longer appropriate to automatically send every newly diagnosed breast cancer patient to a surgeon for primary surgical treatment. Instead, every patient should meet with a surgeon and a medical oncologist prior to beginning any treatment.

Surgery, drug treatment and radiation remain the major treatment modalities, but the choice of which drug therapy, and the sequence of which treatment modality is primary, depend on the specific details of each patient’s individual disease.

There is no longer a one-size-fits-all approach to the patient with newly diagnosed breast cancer. The new treatment paradigm incorporates all available information, anatomic and biologic, to develop a highly individualized multi-disciplinary treatment plan for each patient newly diagnosed with early stage breast cancer.

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