Stage I-III breast cancer

Early Breast Cancer (Stage I-III Breast Cancer)

What every physician needs to know:

Breast cancer is the most common cancer in women in the developed world. It is expected that in 2017 an estimated 252,710 new cases of invasive breast cancer will be diagnosed in women in the US, along with 63,410 new cases of non-invasive (in situ) breast cancer. Unfortunately, it is estimated that there will be 40,610 deaths from the disease.

The estimate for men is less than 1% of cases for a total of 2470 cases.

Of note, although this is the most common cancer it is not the leading cause of cancer deaths in women, a distinction held by lung cancer. Recent studies suggest there has been a slight decrease in the incidence of breast cancer, which is coincident with the reporting of the women’s health data on the use of hormone replacement therapy (HRT) and the decreased use of these medications.

In the last 20 years there has been an improvement in the overall survival of breast cancer, which is credited to screening mammography resulting in earlier diagnosis as well as the increased use of adjuvant therapy and multidisciplinary care. Screening mammography has been shown in both clinical trials and in geographic studies to decrease mortality from breast cancer and has been widely available in the developed world for over 20 years. Controversy remains, however, over the appropriate age to begin screening, the frequency of screening, and whether a high-risk population can be defined.

Adjuvant systemic therapy is another factor that has had an impact on improving breast cancer survival in the last 30 years. Studies by the NSABP and others showed that administering systemic therapy to women with early breast cancer in the form of chemotherapy or endocrine therapy could decrease the risk of recurrent, metastatic disease.

Over the years, recommendations have changed, with both the types of treatment and the patient population undergoing modifications as new evidence becomes available. Although initially the use of therapy was based on anatomical factors such as size and lymph node involvement, in the last decade studies have suggested that biological factors may have more importance in determining both the risk of recurrence and the responsiveness to therapy.

Adjuvant radiation has also been shown to decrease both local recurrence and have an effect on survival. New techniques have been developed to decrease toxicity. Recently, a number of studies have suggested that radiation to nodal areas may be of benefit. Similar to the risk of systemic recurrence it appears that the risk of local recurrence may be related to biological variables.

To ascertain the risk of breast cancer recurring as well as the appropriate treatment for early breast cancer, a number of factors are considered. A prognostic factor is a factor that estimates the risk of the cancer recurring and may include features such as tumor size, nodal involvement, grade, estrogen receptor status and whether HER2 is overexpressed. A predictive factor relates to how the cancer will respond to various treatments such as endocrine therapy or anti-HER2 treatment.

There have been extensive publications on models which may be used to give a more objective estimate of prognosis. As well, recent laboratory tests have been developed to estimate responsiveness to treatment. When a new breast cancer patient is assessed, these factors are discussed with her prior to finalizing a treatment recommendation.

Breast cancer care requires a multidisciplinary approach for the diagnosis, treatment and follow-up care.

Are you sure your patient has early breast cancer? What should you expect to find?

Diagnosing early breast cancer

Breast cancer may present with signs and symptoms or may present asymptomatically as a mammographic finding. Depending on the use of screening mammography, the incidence of palpable versus nonpalpable cancers will vary. Approximately 50% of cancers in most of the US present as palpable masses. Most patients with early breast cancer are asymptomatic other than a possible mass.

Mammography and diagnostic imaging presentation:

On mammography a cancer often appears as a cluster of calcifications or as an architectural distortion.
Cancers that are diagnosed between regular screening mammography are known as interval cancers.
With good mammographic screening, approximately 85% of breast cancers in post-menopausal women and 75% of cancers in women 40 -50 will be diagnosed by mammography.
If a screening mammogram suggests changes that may be malignant, diagnostic mammograms are done which provide further views of the breast. These may include magnification views.
Ultrasound may be used to assess if a mass or abnormality is cystic or solid. Lesions that look like simple cysts are rarely malignant. Complex cysts or solid lesions require further diagnosis.
If a lesion looks like a typical fibroadenoma (a benign lesion often seen in young women), this may simply be followed with a repeat ultrasound and mammogram in a few months’ time. Any other solid lesions should be considered for biopsy.
Magnetic Resonance Imaging (MRI) is increasingly used. Although the sensitivity of MRI is very high, ranging from 80-100%, the specificity is less with reports of a range of 37-97%. This may be due to differences in imaging protocols, skill of the radiologist, or diagnostic criteria. Poor specificity may lead to unnecessary biopsies of benign lesions. MRI has been compared to mammograms and ultrasounds and is recommended in women with a high risk of breast cancer such as BRCA mutation carriers, as well as in cases where other imaging such as mammogram and ultrasound are not conclusive. Its use as a widespread screening tool for women with an average risk of breast cancer has not been established.
Many other techniques for diagnosing breast cancer are also being tested and may be helpful but most have not been approved for screening at this time. Tomosynthesis is a special kind of mammogram that produces a 3-dimensional image of the breast by using several low-dose x-rays taken at different angles in a circular arc around the breast. The resulting imaging data provide more resolution than a standard mammogram. The radiation dose for the tomosynthesis is similar to that of a standard mammogram. Although the FDA has approved tomosynthesis mammography, it is used variably as a standard screening modality.
An abnormality shown on mammography, MRI or ultrasound that is suspicious of cancer should be biopsied with a core biopsy which can establish the diagnosis and give further information that is necessary for treatment planning.
If the biopsy is negative, follow-up to ensure stability of the abnormality seen is essential.

Presentation with physical changes rather than screening mammography changes:

Patients may present with a mass and any new mass should be examined and assessed carefully as there is no one criteria that can confirm a benign lesion.
Although we speak of a mass, cancer may also present as a change in the breast such as a new thickening, redness, swelling, heat or a rash. Any change in the breast should be considered as possibly suspicious.
If the patient is premenopausal there may be breast changes related to her menstrual cycle and a re-examination at a different time in her cycle may be indicated.
Nodal areas should be examined. This should include the axilla as well as the supra- and infra-clavicular areas.
Changes in the breast such as swelling, heat, redness, a rash or other skin lesions may suggest inflammatory breast cancer, which is a rare but very aggressive form of breast cancer. This is often wrongly diagnosed initially as mastitis which should not occur except in a lactating woman. Any new rash or redness of the breast should be investigated.
Any persistent or new mass should be considered for imaging, which should include bilateral mammography and a unilateral ultrasound at the minimum, and may also include an MRI. Dependent on the imaging, core biopsies can be done.
Follow-up of any mass, including cystic lesions which are drained, is essential. If the mass recurs or persists, further diagnostic procedures should be considered.
Core biopsies are usually performed by radiologists under image guidance. Radiology centers that specialize in breast imaging should be used if at all possible as this may accelerate the diagnosis, and avoid unnecessary duplicate imaging.

Types of early breast cancer

Breast cancer is not one disease but includes a number of types of cancer. In the past, histology was considered as the classification but more recently molecular or genetic factors have replaced older definitions.

New techniques for assessing tumors, such as deep sequencing, are being done and suggesting further typing of the disease. However at this time, these newer classifications have not entered our clinical arena. We will present both the older classification as a reference as well as the current definitions of breast cancer, which are evolving rapidly.

Breast cancers are commonly sensitive to hormones. Approximately 70% of breast cancers are found to have estrogen and/or progesterone receptors. HER2 (Human Epidermal Growth Factor Receptor 2, erbB2, HER2/neu) was initially described in the 1980s and was shown to be associated with a more aggressive form of breast cancer. Various series have suggested that 15-20% of breast cancers over-express HER2, with half of these also expressing estrogen receptors.

Approximately 15% of breast cancers do not express estrogen or progesterone receptors and are HER2 normal. These cancers have been classified as “triple negative breast cancer” (TNBC), by virtue of what they do not express. This term is somewhat confusing as it suggests a homogenous group and it is clear that there are a number of different kinds of TNBC with different behaviors. The most common TNBC is the basal-like breast cancer which is defined below.

Histological subtypes:

The most common types of breast cancer by histology are the following:

Infiltrating ductal – also known as mammary carcinoma. This accounts for approximately 65% of breast cancers.
Lobular breast cancer – in most series these are about 15% of breast cancers. The classic lobular cancers are almost uniformly estrogen sensitive, but this may not be true for pleomorphic lobular cancers.
Tubular cancers – these are low-grade, hormone-sensitive cancers.
Medullary cancers – this term has been used for a number of years and is fraught with variations. These are generally high grade TNBC, but may have a better prognosis than other TNBC.
Mucinous cancers – these are estrogen-sensitive and may be large but are usually low-grade and rarely involve lymph nodes.

There are a number of other much less common histological varieties including metaplastic, adeno-cystic, micropapillary, colloid, adenosquamous, as well as sarcomas and lymphomas of the breast. A full review of these subtypes is beyond this chapter but treatment decisions are often made on grade, estrogen and progesterone receptor status, HER2 expression and the studies that are available in the literature. Rare types of cancer should be reviewed by an expert breast pathologist to confirm the histology as this may affect treatment recommendations.

Intrinsic breast cancer subtypes:

In 2000, a seminal publication by Perou et al used gene expression profiling and hierarchical clustering to describe subtypes of breast cancer. This has revolutionized the breast cancer world. These subtypes take into account prognostic variables for breast cancer and have been validated on a number of series. The initial classification suggested 4 types: the luminal types with expression of cytokeratin 8 and 18, the basal subtype with cytokeratins 5 and 17, the HER2 subtype with amplification of HER2, and normal.

Since the initial publication, clinical modifications of the system have been developed to help determine both prognostic and predictive factors for individual tumors. It is clear that this classification will be replaced as we learn more about the differences of breast cancers within these groups and their responses to therapies. Currently we generally use the following subtypes:

Luminal A- these cancers are estrogen and progesterone positive and HER2 normal. They are low grade and associated with the best prognosis.
Luminal B- these cancers are estrogen positive but may be progesterone low or negative. They have a higher grade as determined by measures of proliferation such as Ki67. The prognosis of these tumors is less good than luminal A.
Luminal HER2 – these cancers are often included in the luminal B category but for treatment purposes are really separate. They are estrogen positive and may be progesterone positive, low or negative. They overexpress HER2.
HER2- these cancers overexpress HER2, are generally high grade, and have negative estrogen and progesterone receptors.
Basal- these cancers are generally high grade and are estrogen and progesterone negative and HER2 normal. Other features include a high Ki67, and CK5/6 or EGFR positivity. Very rarely basal like cancers may be estrogen positive.
Claudin-low – this is a small group of cancers recently identified that have a low level of claudin and a poor prognosis suggesting they are a distinct group.
Non basal triple negative – these cancers are estrogen and progesterone negative as well as HER2 normal but do not have overexpression of CK5/6 or EGFR and may have a slightly different prognosis or response than basal like cancer.

Which individuals are most at risk for developing breast cancer:

The risk of getting breast cancer appears to be linked to both inherited and environmental factors with the latter having the greater impact for the majority of women. There are a number of known risk factors for breast cancer and a number that are speculative; for most women one clear cause is usually not evident.

The incidence of breast cancer is different in developed versus developing nations and this has been well described with increasing rates of the disease as the country becomes more “westernized” in its life style. Of note, studies of immigrant women report that the risk of getting breast cancer appears to be linked to both place of birth as well as place of residence with the daughters of immigrants quickly assuming the risk associated with the country of residence.

Models for assessing the risk of getting breast cancer include the Gail Model which takes into account features such as age of menarche, age of first child birth, family history, history of prior breast biopsies and, age.

Women with an increased risk (Gail model > 1.67% at 5 year risk of getting breast cancer) are often included in recommendations for risk reduction strategies such as chemoprevention. Studies of tamoxifen, raloxifene and more recently the aromatase inhibitor exemestane, have all shown that the incidence of breast cancer can safely be reduced in women with an increased risk of developing breast cancer. Nevertheless, the uptake of chemoprevention has been minimal.

Strong risk factors (risk greater than 4 x normal)

Advancing age.
Female gender.
Previous breast cancer diagnosis.
BRCA mutations (known) or family history with pre-menopausal or bilateral breast cancer.
Increased breast density.

Moderate risk factors (risk between 2-4 x normal)

Over 30 years old at the birth of first child.
Past breast biopsy with any signs of cell abnormality or hyperplasia.
Post-menopausal obesity (high BMI).
Chest wall radiation. This poses a greater risk (considered a strong risk factor), if it occurred during the teen years.

Weak risk factor (risk between 1-2 x normal)

Early menarche (before age 12).
Late menopause (after age 54).
Family history of breast cancer if affected relatives were older or post-menopausal and not BRCA mutation carrier.
Alcohol – moderate to heavy alcohol consumption. This is controversial as some studies would suggest this is a moderate risk factor.
Prolonged hormone replacement therapy, particularly with both estrogen and progesterone.
Question of second hand smoke, smoking during teen years, exposure to other environmental carcinogens.

There are a number of other factors which appear to have less impact and are less frequently implicated. Some of these are genetic factors which have been less well characterized compared to BRCA mutations or are less frequent, such as mutations of p53, PTEN, ATM, CHEK2, PALB2, and CDH1.

There are also other environmental factors which are more controversial, including some environmental toxins, shift work, and racial factors. For example, African Americans have a lower incidence than Caucasians of getting breast cancer although when they do get breast cancer their risk of TNBC is greater, resulting in higher mortality after diagnosis.

Male breast cancer, which accounts for less than 1% of cases, may be related to BRCA2 mutations, radiation to the chest wall, Klinefelter syndrome or unknown environmental factors.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e, stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

Obtaining a tissue diagnosis

As already stated, whether a cancer is diagnosed by screening mammogram or by physical examination, a tissue diagnosis is necessary. This is now usually a radiologically guided biopsy done by ultrasound or mammogram and very occasionally with MRI. Multiple cores are usually taken. In some centers they are all used for diagnosis but in others some are flash frozen for tumor banking.

The tissue is assessed for a diagnosis of malignancy and the following parameters should be reported:

Is it cancer?
Is it invasive or in situ cancer, or both?
Grade
Histological type
Extent of involvement of the core
Lymphatic or vascular invasion may be noted but may be difficult to assess
Estrogen and progesterone receptor status
HER2 expression
Ki67 is often also reported as another assessment of proliferation

There has been discussion about the role of markers such as estrogen and HER2 with the core biopsy, but by getting this information early, a decision about systemic therapy can often be made, including possible neoadjuvant therapy (treatment before surgery). There is also some evidence suggesting that markers that are assessed on a core biopsy may be more reliable than on a final surgical specimen due to how specimens are processed by pathology labs.

Estrogen receptor status should be obtained on all in situ and invasive cancers. Progesterone and HER2 status are usually only done on invasive cancers. The American Society of Clinical Oncology (ASCO) and the College of American Pathologists have both developed guidelines for the standard testing of markers and quality control programs are available and widely used.

The use of other tests such as Mammoprint, PAM50/Nanostring and Oncotype Recurrence Score may or may not be appropriate on a core biopsy and have been considered more with the surgical specimen. These tests may be similar but may not sort cancers into the exact same groups.

Oncotype DX testing will be described below and is currently done on the final specimen when the nodal status is known, although its use in the neoadjuvant setting has been studied. Clearly the way of the future will be for some kind of molecular testing, which will replace our current histology and immunohistochemistry, and will likely be performed at the time of initial diagnosis. However, we will need to first validate a technology and then make it readily available and affordable for clinical use.

Imaging studies

A single standard for the clinical staging of breast cancer does not exist. In general, clinical staging should reflect the risk of finding cancer that has spread to locoregional or distant sites. Therefore, the appropriate testing for a small low grade cancer may be only standard pre-operative blood tests, while a woman with a larger high grade cancer may benefit from more extensive imaging.

Some subtypes of breast cancer, such as HER2-positive, may have a higher risk of spread at the time of diagnosis and therefore may be more appropriate for presurgical staging.

MRI of breasts

The role of MRI in the staging of breast cancer is controversial. Reports show that pre-surgical MRI of the breasts more readily diagnose multifocal cancers and the extent of the local disease, enabling better surgical planning. Thus some centers are routinely performing MRIs prior to surgery.

At this time, however, there is no evidence of an impact on survival, although it may decrease local recurrences and repeat surgical procedures for involved margins. The use of MRI may be predicated by the type of cancer, age of the patient, density of the breast, quality of the imaging, and individual practices. MRI may have more impact on younger women or more diffuse cancers.

PET/CT scans

Although PET scans may be helpful in staging high grade cancers, their role is less clear in lower grade breast cancers and in particular in lobular cancers (which rarely show enhancement). At this time they are not standardly recommended for staging in most cases. Their sensitivity for showing nodal metastases varies and they cannot at this time replace surgical exploration with a sentinel node biopsy.

However, for patients with a significant risk of distant disease and a higher grade cancer they may be an optimal staging study, particularly if the primary tumor is still in place and takes up tracer clearly. They may also be able to replace multiple imaging procedures for those cases.

Bone scans

Bone scans have been recommended for years in breast cancer patients with Stages II and III cancer as the bones are the most common site of advanced disease. Their role in addition to PET/CT is not clear. However, in patients with Stage II and above cancers, especially low grade and lobular cancers and in patients with symptoms that may be indicative of spread to the bones, they should be considered.

Assessment of patient fitness for therapy

An assessment of any cancer patient must include a good history and physical examination to consider other health issues. We often become focused on the risk of the breast cancer without taking into account the other conditions a patient may have, which may affect her individual mortality. This should be considered when assessing an early breast cancer prior to recommending therapy and appropriate tests or consultations for other medical conditions should be done.

In addition, there are specific treatments that may not be appropriate for patients with other conditions and again specific testing should be done. When cardiotoxic agents are being considered, an evaluation of the left ventricular function by echocardiogram or nuclear gated scanning (MUGA) should be done.

If the treatments are being given to persons with pulmonary compromise, full pulmonary function tests should be performed. In patients with evidence of connective tissue or neurological disease, special assessments should be made prior to adjuvant treatment recommendations.

Staging

Staging is a measure of how much cancer there is and is usually done rather crudely. At this time we do not have sensitive techniques for determining the exact spread of micrometastatic cells. The TNM classification is used internationally and is frequently updated; this chapter uses version 2.2011. Many oncologists are suggesting that biological factors may be more important than our older anatomical staging system but it still appears that the bulk of disease and its spread have prognostic implications. (Table I)

Staging of breast cancer has been further complicated by the assessment of nodes by not just standard histology with H&E, but also by immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR). Also, sentinel node biopsies have been widely introduced and the role of completion axillary dissection is now being questioned and in many cases eliminated. Thus the full status of the axilla may or may not be known for an individual woman.

Pathology’s now report if they see isolated tumor cells (ITC) in the lymph nodes, which are small clusters of cells not greater than 0.2 mm, single tumor cells or a cluster of fewer than 200 cells in a single histological cross section. These nodes are not included as positive nodes although they are included in the denominator of total number of nodes. Studies suggest that the presence of ITCs is not associated with a poorer outcome, but this is still being debated. Additionally, recent studies have suggested that circulating tumor DNA (ctDNA) may be a technique that can detect cancer and specific mutations by a simple blood test. More studies are necessary prior to our widespread use of this as part of standard screening but there is increasing evidence that the presence of ctDNA may either be a bad prognostic sign or may in some cases predict response to some treatments in the advanced setting.

What should the initial definitive therapy for the cancer be?

Surgery remains the primary treatment of breast cancer. Surgical practices have evolved from the Halsted theory that the tumor spread in a contiguous manner and thus removal of the breast and axillary nodes en bloc was important for cure to the Fisher theory of the metastatic potential of all, even the smallest breast cancer, by invasion of the lymphatic or hematologic system. Our current treatment of breast cancer takes into account both theories as they both contribute to our understanding.

The primary surgery is removal of the tumor and surrounding tissue to ensure clear margins. This may be done by breast conserving surgery such as a lumpectomy, partial mastectomy or quadrantectomy, or by removal of the entire breast with a mastectomy. The studies which led to the understanding that a mastectomy was not necessary and that breast conserving surgery with radiation led to similar outcomes were ground breaking, and a clear advance for women who no longer had to have a radical amputation.

Of interest, in the last decade the rate of mastectomies has increased again, for reasons that are not completely clear. Explanations for an increased rate of mastectomies include more recognition of BRCA1 and BRCA2 carriers for whom mastectomy may be preferable, the increased role of immediate reconstruction, the increased concern about radiation in young women, as well as other less obvious reasons.

There is concern that many women are opting for mastectomies without understanding their real risks of relapse, including systemic relapse and the lack of overall survival advantage for mastectomy.

Types of breast surgery

Mastectomy

Matectomy is the removal of the breast. This is most often a modified radical mastectomy. Indications for mastectomy include

large tumor (usually over 5 cm although this may vary with breast size).
multicentric disease (involving more than one quadrant).
inability to obtain clear surgical margins.
occasionally tumor location that may compromise a cosmetic result.
situations where radiation is contraindicated, including connective tissue disorders such as scleroderma or prior radiation to the breast and chest wall.

Patients with BRCA mutations will significantly decrease their risk of a new breast cancer and often choose to have a mastectomy, but this is choice. The older radical mastectomy which also removed the pectoralis muscles is no longer done except in rare extraordinary circumstances where there is gross invasion of the muscle and no other option.

Mastectomies may be skin sparing, especially when immediate reconstruction is being done, and these do require removal of as much breast tissue as possible and thin flaps to decrease the risk of recurrence. Recently nipple sparing mastectomies have been done according to standards including avoiding them with multifocal disease near the area and checking the nipple for malignancy and have not reported increased local recurrences. Subcutaneous mastectomies are not recommended as oncological surgeries.

Breast conserving surgery

Partial mastectomy refers to removal of the tumor and the tissue around it. Studies show a similar risk of recurrence for partial mastectomy plus radiation to the breast and for mastectomy in terms of local and overall relapse rates. Partial mastectomies may not be suitable for the reasons stated above and in cases where radiation is contraindicated. Lumpectomy is a term used synonymously often with partial mastectomy. A quadrantectomy is a partial mastectomy where the entire quadrant is removed.

The approach to the axilla is much more controversial. The initial treatment according to Halstedian theory recommended complete removal of the axillary nodes in levels 1, 2 and 3. Some operations included triple nodal sampling and included the internal mammary nodes.

The recognition of the morbidity of radical surgery to the axilla in terms of pain, decreased range of motion and lymphedema, led to less exploration of the axilla with initial removal of only levels 1 and 2 and more recently sentinel node dissection. (SLND). For years there was debate about whether axillary surgery was therapeutic or simply diagnostic.

The pathology of sentinel lymph nodes is also evolving. Initially as well as standard H&E, IHC and /or RT-PCR techniques were recommended. Phenomena such as isolated tumor cells were recognized. Increasingly sophisticated pathology to look at nodes is becoming less in vogue as it does not appear that there is a prognostic impact of these cells. This may however change as we determine whether ITCs do correlate with outcomes related to other factors with tumor biology.

Types of axillary surgery

Axillary node dissection (ALND)

This refers to an exploration of the axilla. With a modified radical mastectomy this can be done with one incision but with a partial mastectomy a separate incision is required. Usually block removal of the axillary contents of level 1 and part of level 2 is done as well as removal of any suspicious nodes.

Sentinel lymph node dissection (SLND)

With the understanding of the morbidity of ALND, this approach was developed and has become standard. By injecting blue dye and/or radionucleotide tracer into the tumor, and then using a probe in the operating room, the surgeon is able to detect the first node to drain the tumor (the sentinel node) and remove it as well as other nodes in the vicinity.

This has improved the understanding of the lymph drainage of tumors, decreased the number of nodes needing to be removed, and decreased unnecessary axillary surgery. The surgeon must be trained and understand which tumors are not suitable for SLND and stringent guidelines have been developed to ensure a low false negative rate for most procedures. Generally if there are palpable nodes, there is a greater risk of a false negative SLN biopsy.

As well, the procedure may have less accuracy if there has been prior surgery to the breast and axilla. With negative SLND, the elimination of ALND has been easy. The role of SLND procedures alone in the presence of positive nodes is less clear. Recent studies including one reported by the American College of Surgical Oncology Group (ACOSOG) suggest that with minimal disease in up to three sentinel nodes, further axillary surgery may be unnecessary.

SLND is also often done prior to neoadjuvant chemotherapy. Studies have suggested that if SLND is done after neoadjuvant chemotherapy it may still be representative of primary staging, but this may vary with breast cancer subtype.

Reconstructive surgery

Breast reconstruction has also changed over the years with new techniques and an increased emphasis on immediate reconstruction at the time of the primary surgery. Although delayed reconstruction is also frequently done for women who have had a mastectomy, many centers have a good coordination of surgical services to allow women to have the cosmetic surgery done at the time of the mastectomy.

The oncological care should not be compromised and this often requires a multidisciplinary team including the medical and radiation oncologist to develop the best plan for the woman. Radiation after reconstruction is done in many centers but the type of reconstruction and the timing of it may need to be modified if radiation is indicated.

There are a number of kinds of reconstruction, including tissue expanders/implants, autologous tissue options and a number of new techniques and products. A full description is beyond the scope of this chapter. The choice of surgical procedure is often related to the desired breast size, treatment of the cancer such as the need for radiation, patient’s medical history and lifestyle as well as the patient and surgeon’s preferences.

What other therapies are helpful for reducing complications?

Adjuvant and neoadjuvant systemic therapy of breast cancer

Adjuvant therapy for breast cancer was initially introduced in the 1970s for pre-menopausal women and since that time the indications for treatment and the types of treatment have expanded considerably with a clear improvement in survival with our increased understanding of who to treat and what to recommend.

The Early Breast Cancer Trialists’ Cooperative Group (EBCTCG) has consistently shown benefit for adjuvant systemic treatment with serial meta analyses of international trials. As discussed above there are a variety of prognostic and predictive factors that are considered prior to making a recommendation for systemic therapy, and these include the stage, breast cancer subtype (including estrogen and progesterone receptor status and HER2 expression), as well as the age and comorbidities of the patient. Finally the patient’s individual beliefs often also play a role in the treatment recommendations for adjuvant treatment.

Both endocrine and cytotoxic therapies are used as well as anti HER2 therapies. The role of other targeted therapies in early breast cancer, such as antiangiogenic agents like bevacizumab are being tested in both adjuvant and neoadjuvant settings but have not yet been shown to have value in the adjuvant setting and are not approved by any regulatory bodies.

There are many diverse opinions about the relative benefit of various therapies and which protocol is most efficacious. Unfortunately, many of these disputes cannot be solved by the current body of knowledge. The EBCTCG’s most recent update confirms a benefit for endocrine therapy with tamoxifen, aromatase inhibitors and oophorectomy all having efficacy in specific groups.

As well, a benefit from chemotherapy overall is reported with an advantage for poly chemotherapy and the addition of taxanes. They report an advantage for radiation therapy. These findings are based on thousands of women and the challenge for the clinician is taking this information and marrying it with our increased understanding of the variable response to treatments of different subtypes to make individual treatment recommendations.

Neoadjuvant systemic therapy is administered for both locally advanced breast cancer (LABC) and less advanced stages. For LABC it is necessary to downstage the primary tumor and facilitate surgery as well as to decrease systemic risk. Numerous studies have been done in this group of patients.

Pathological complete response (pCR) has been used as the endpoint for assessing various systemic protocols. The definition of pCR has varied, with some groups defining it as the absence of all invasive and in situ cancer in both breast and nodes while others define it in breast only or do not require a lack of in situ cancer. Recently, studies have tended to use a lack of invasive cancer in breast and lymph nodes as the accepted definition. The varying definitions have made comparisons of different studies difficult. pCR is seen more often in highly proliferative tumors such as TNBC or HER2 positive cancers and rarely in ER+ tumors after standard chemotherapy.

Endocrine therapy has also been given in the neoadjuvant setting usually for up to 6 months prior to surgery and is rarely associated with pCR but often very effective. Markers of response such as a pre therapy and 1-2 week Ki67 have been used in some studies to test efficacy of the treatment, and this has been shown to be a good marker of activity in both cytotoxic and endocrine therapy.

Neoadjuvant therapy is also used in lower stages of disease. The NSABP B18 study randomized women to either standard adjuvant therapy with 4 cycles of AC chemotherapy or to the same chemotherapy prior to surgery and did not show any statistically different outcomes suggesting that neoadjuvant therapy is safe. This has been confirmed by many other groups. It may be that certain subtypes of breast cancer benefit more than others, including triple negative or HER2 overexpressing cancers.

In addition, a patient receiving neoadjuvant therapy either with LABC or low stage disease should be followed closely. If the tumor is not responding, other local measures may need to be instituted quickly rather than continuation of the systemic protocol. Neoadjuvant therapy may be of value in patients who need time to decide on their surgical treatment, such as patients who are being tested for BRCA mutations, as chemotherapy can proceed prior to receiving genetic results.

Adjuvant endocrine therapy

All invasive cancers should be assessed for estrogen and progesterone receptor status. Patients with endocrine sensitive tumors should be considered for hormone treatment regardless of their stage, age or whether they are also receiving chemotherapy as endocrine treatment has been consistently shown to decrease local, regional and distant recurrence as well as the development of contralateral breast cancer.

The only exception may be some very small cancers with otherwise favorable features that have a very low risk of recurrence where the benefit of endocrine therapy may be minimal and must be balanced with the risk to the specific patient.

At this time there are no clear markers of resistance to endocrine therapy in tumors that are estrogen receptor positive although studies have suggested a higher risk of recurrence tumors that are also HER2 positive, that have lower levels of endocrine expression or that only in either estrogen or progesterone receptors with expression and are negative for the other receptor.

Due to the differences in the endocrine axis, hormonal therapy recommendations depend on the menopausal status of the woman. This may be difficult to determine, especially in women who have had a chemotherapy-induced menopause and in cases where there is any doubt it should be assumed that the woman is pre-menopausal until otherwise proven as giving an ineffective treatment will be avoided. FSH and estrodiel can be measured but are known to fluctuate and therefore must be measured over time to have any credibility.

Pre-menopausal women

Tamoxifen has been the mainstay of treatment and has been consistently shown to be effective in decreasing the odds of recurrence by 39% and the annual odds of death by 31%. Standard treatment is for 5 years. Recent data however has questioned if it is the only and optimal effective treatment.

Oophorectomy has also been studied and in the EBCTCG meta analysis is equivalent to tamoxifen. The numbers however are small. As well, some studies have suggested that the impact of oophorectomy may vary with age; women younger than 40 may have more benefit than those older. Tamoxifen is generally begun after chemotherapy.

The SOFT trial assessed the benefit of adding ovarian suppression to tamoxifen. It demonstrated a non-significant benefit for the dual therapy. As well, the SOFT data was combined with the data from the TEXT study. This combined analysis compared ovarian suppression with tamoxifen to ovarian suppression plus exemestane, an aromatase inhbitor. There was a statistically significant benefit for the aromatase inhibitor in terms of progression-free survival, but not for overall survival. In woman < 35 years of age who had high risk cancers requiring chemotherapy, the AI plus ovarian suppression was superior. In other premenopausal women no significant difference was seen with the three regimens. Toxicity becomes an issue.

As well, although there were not large differences reported in toxicity, there are concerns about the tolerance of this therapy in premenopausal women who are not on a clinical trial. Thus the results should be considered in the treatment of premenopausal women balancing their risk of recurrence with the toxicity of the treatment. Women younger than 35 enrolled in the SOFT trial had inferior outcomes compared with older women. There was also the suggestion from this trial that these young women may benefit from the addition of chemotherapy to hormonal therapy. Further analysis and additional studies are needed to confirm this finding.

The ABCSG-12 trial randomized pre-menopausal women who were not receiving chemotherapy to either tamoxifen or anastrazole with ovarian suppression. In contrast to the SOFT/TEXT analysis, this study did not show any difference in the two agents in this group of women. The ABCSG-12 study also had a second randomization to zolendronic acid or placebo and did show a disease-free survival benefit for the addition of the bisphosphanate at a dose of 4 mg every 6 months for 5 years.

Although these findings generated considerable initial interest, another trial did not show benefit for the addition of zolendronic acid, albeit at a different dose. Thus, we await other data prior to standard administration of this drug in premenopausal women.

The active metabolite of tamoxifen is endoxifen which depends on cyp2D6. There is literature regarding the impact of other drugs on the utility of tamoxifen. Currently, routine measurement of endoxifen and/or cyp2D6 are not recommended at this time.

The usual recommendations are for women on tamoxifen to avoid if possible other drugs which are strong metabolites of cyp2D6. The major culprits for the breast cancer population are fluoxetine (Prozac), paroxetine (Paxil) and buproprion (Wellbutrin).

Post-menopausal women

Tamoxifen was the mainstay of hormonal treatment in older women as well but has recently been extensively compared to aromatase inhibitors (AI). The most recent ASCO guidelines now recommend the use of AIs in the treatment of endocrine sensitive tumors. Studies have shown a benefit for upfront AI use for 5 years, for the introduction of AIs after 2-3 years of tamoxifen and after 5 years of tamoxifen.

The Breast International Group (BIG) 1-98 study also showed that upfront letozole followed by tamoxifen resulted in a more favorable outcome compared to 5 years of tamoxifen alone. Which strategy is used may depend on the true menopausal status of a women (for example someone who is newly menopausal may receive 2-3 years of tamoxifen to ensure her hormonal status, followed by an AI), her risk of relapse (someone with a high risk of relapse may benefit from upfront AI), her other medical conditions and also her tolerance of the drugs.

The three licensed AIs (anastazole, letrozole, and exemestane) have all been shown to have similar benefit. Anastrazole and letrozole are non-steroidal AIs while exemestane is a steroidal aromatase inactivator. Clinically all three agents have a significant effect on estrogen levels and similar toxicity profiles.

The MA27 study randomized post-menopausal women to either anastrozole or exemestane and did not show a difference in outcome in terms of recurrence. There was a slightly different side effect profile although the incidence of toxicities was similar. The FACE trial has randomized early breast cancer patients to either letrozole or anastrozole and results are pending.

At this time there are no good criteria for choosing one AI over another from the reported literature. In clinical practice one finds that some women tolerate one drug over another and giving drug holidays and switching medications may improve compliance. ASCO guidelines do recommend the use of an AI at some point in the treatment of a post menopausal woman.

Studies are being done to look at extended adjuvant therapy with AIs. The MA17 study showed that after 4.5–6 years of tamoxifen, letrozole was superior to placebo in both node-negative and node-positive women with a survival benefit seen in node-positive women.

The ATLAS and ATTOM studies showed long-term tamoxifen (more than 5 years) was also effective in decreasing recurrence. Studies such as B42, MA17R and SOLE are looking at extending AI use for more than 5 years and will report on both efficacy and toxicity.

Other studies such as MA17R or NSABP B42 studied more than 5 years of an AI and showed that although there was a benefit (which was significant in MA17R) the major advantage to longer AI was in decreasing contralateral breast cancer. The use of longer therapy should therefore be based on the individual risk of both systemic, local and contralateral disease.

Studies of bisphosphanates in the adjuvant setting in addition to standard therapy have not been consistent but a meta-analysis suggested that there was a benefit for post menopausal women. This analysis did not show a difference between the use of oral versus intravenous bisphosphanates. The results of a large adjuvant study that randomized between the addition of denosumab, an antibody to RANK ligand, versus placebo in addition to standard adjuvant treatment have not yet been reported.

Chemotherapy

Chemotherapy has been used for the treatment of breast cancer in the adjuvant setting for over 30 years and there is little doubt that along with endocrine therapy, it has contributed to the improvements in survival reported since that time. Initial treatment was limited to pre-menopausal women with nodal involvement but the use of chemotherapy has expanded and now contracted as we learn about both risk and response.

Nodal involvement alone is no longer considered an indication for chemotherapy. The Oxford Overview (EBCTCG) does suggest that all tumors do have some benefit from chemotherapy but it is clear that the magnitude of that benefit may be small for some low grade tumors. For example, a luminal A tumor which is grade 1, highly ER and PR positive, HER2 negative and involves two nodes minimally may have a risk of relapse but the addition of chemotherapy to endocrine therapy may only add 1-2% decrease in recurrence, while adding significant toxicity.

Therefore, the oncologist and patient may decide to avoid chemotherapy. In contrast, an ER positive, PR negative, Grade 2 tumor with 2 nodes positive may have a higher risk of relapse, and therefore more absolute benefit from chemotherapy as well as responding better. This has complicated our treatment recommendations and there have been numerous attempts to develop objective measures to determine the benefit of adding chemotherapy.

One of these is the Oncotype DX recurrence score, which is a 21-gene RT-PCR based test, and was developed to predict the benefit of adding chemotherapy to hormone therapy in hormone sensitive early breast cancer. Test results are characterized as follows:

low (<18): endocrine therapy alone recommended.
18-31: treatment must be individualized based on the other features of the malignancy and the patient including age, comorbidities and patient choice.
> 31: chemotherapy added.

This test has been prospectively tested in North America in a large ECOG led study TAILORx of node negative patients. Results are pending. The RxPONDER trial has been opened by SWOG and will assess this test in node positive patients. The results of the lowest risk group in TAILORx who did not get chemotherapy have been published and show a very low relapse rate.

The BIG has conducted a large study, MINDACT, which tested a molecular assay, the Mammoprint, as well as assessing the computer risk assessment model, Adjuvantonline! This large study did show that for those tumors with a high genomic test the addition of chemotherapy was of benefit compared to those with a low genomic test. The genomic factors appeared to be more powerful than the clinical factors if they were discordant. This further confirmed the value of genomic testing in determining the value of chemotherapy. The Prosigna test also provides this kind of information.

There are a number of available chemotherapy regimens and there is not one optimal protocol for all patients. Tailoring to the patient in terms of her tumor, other health concerns and age may be appropriate. Studies have suggested:

Duration may be of importance, with at least 6 cycles generally recommended for node-positive cancers.
The benefit of taxanes may depend on breast cancer subtype.
The schedule of taxanes may be of importance particularly when used without antiHER2 therapy. Weekly paclitaxel appears to be superior to three weekly paclitaxel. Three weekly docetaxel appears to be superior to weekly docetaxel.
Anthracyclines have most efficacy in HER2-positive cancers.
Anti-HER2 therapy should be used in HER2 overexpressing tumors.

The risk of a cancer may be considered in the choice of regimen with the shorter (4 cycle) regimens often being recommended for the lower risk cancers.

Systemic adjuvant therapy recommendations

For endocrine-negative cancers, adjuvant therapy is recommended for node positive cancers and node negative cancers that are larger than 1 cm. For cancers that are 0.6-1 cm and/or have pN1mi-positive lymph nodes, adjuvant therapy may also be recommended, but benefit may be less pronounced. Chemotherapy is usually not recommended for tumors smaller than 0.5 cm or micro invasive and N0.

If the tumor is HER2-positive, the same recommendations apply but antiHER2 therapy with trastuzumab at this time is added to the chemotherapy regimen. The addition of pertuzumab, another antiHER2 therapy, has recently been reported and showed a benefit in node positive patients and in the neoadjuvant setting but less effect in low risk patients.

For endocrine sensitive tumors that are HER2 positive, the same recommendations apply, with the addition of endocrine therapy. There should also be discussion about the benefit of chemotherapy and trastuzumab in small node-negative cancers, but there is no high-level data to suggest less therapy at this time. The issue depends on the risk of recurrence of the tumor and the balance of toxicity of the treatment.

For endocrine sensitive tumors that are HER2-negative, the decision to add chemotherapy to endocrine therapy is based on the risk of recurrence. For tumors that have a high grade, are node positive and are large, or that have an Oncotype recurrence score of greater than 31 there may be a large benefit for the addition of chemotherapy. For tumors that have a lower risk of recurrence the benefit may be less and should be considered individually. This includes tumors with a smaller nodal or tumor bulk, lower grade or Oncotype recurrence score of 18-31.

Commonly used chemotherapy regimens in HER2 normal

Dose Dense AC/paclitaxel – Doxorubicin 60 mg/m² IV day 1, Cyclophosphamide 600 mg/m² IV day 1 cycled every 14 days for 4 cycles followed by paclitaxel 175 mg/m² IV over 3 hours day 1 every 14 days for 4 cycles with G-CSF support.
AC followed by paclitaxel – Doxorubicin 60 mg/m² IV day 1, Cyclophosphamide 600 mg/m² IV day 1 cycled every 14 days or every 21 days for 4 cycles followed by paclitaxel 80 mg/m² IV over 1 hour weekly for 12 weeks.
TAC – Docetaxel 75 mg/m² IV day 1, Doxorubucin 50 mg/m² IV day 1, Cyclophosphamide 500 mg/m² IV day 1 every 21 days for 6 cycles.
TC – Docetaxel 75 mg/m² IV day 1 and cyclophosphamide 600 mg/m² day 1 every 21 days for 4–6 cycles.
AC – Doxorubicin 60 mg/m² IV day 1, Cyclophosphamide 600 mg/m² IV day 1 cycled every 21 days for 4 cycles.
FEC100 followed by weekly paclitaxel – 5-Fluorouracil 500 mg/m² IV day 1, Epirubicin 100 mg/m² IV day 1, cyclophosphamide 500 mg/m² IV day 1 every 21 days x 4 cycles followed by paclitaxel 80 mg/m² IV every week for 12 weeks.
FEC/DOC – 5-Fluorouracil 500 mg/m² IV day 1, Epirubicin 100 mg/m² IV day 1, cyclophosphamide 500 mg/m² IV day 1 every 21 days x 3 cycles followed by docetaxel 100 mg/m² IV every 21 days x 3 cycles.
FEC/Paclitaxel – 5-Fluorouracil 500 mg/m² IV day 1, Epirubicin 100 mg/m² IV day 1, cyclophosphamide 500 mg/m² IV day 1 every 21 days x 4 cycles followed by 3 weeks of no treatment and then followed by paclitaxel 100 mg/m² IV every week for 8 cycles.
FEC 100 – 5-Fluorouracil 500 mg/m² IV day 1, Epirubicin 100 mg/m2 IV day 1, cyclophosphamide 500 mg/m² IV day 1 every 21 days x 6 cycles.
AC-followed by Docetaxel – Doxorubicin 60 mg/m² IV day 1, Cyclophosphamide 600 mg/m² IV day 1 cycled every 21 days for 4 cycles followed by docetaxel 100 mg/m² IV on days 1 every 21 days for 4 cycles.
CMF – cyclophosphamide 100 mg/m² po daily days 1-14, methotrexate 40 mg/m² days 1 and 8, 5-Fluorouracil 600 mg/m² IV days 1 and 8 cycled every 28 days for 6 cycles.

There are a number of other less commonly used chemotherapy protocols. Care should be taken to give growth factor support with filgrastrim appropriately. It is necessary in the dose dense regimens and is advised in all the regimens with higher doses of docetaxel to avoid febrile neutropenia and sepsis.

In triple negative cancers there have been a number of studies looking at the addition of carboplatin or cisplatin to standard regimens. A large German neoadjuvant study that used carboplatin suggested a benefit with an increased rate of pathological complete response. Other studies have suggested that the platinum agents are most effective in women who carry a BRCA mutation. Further studies are being done in the adjuvant setting to assess the role of platinums and particularly assess if there is a survival benefit and not just an improvement in pCR.

Commonly used chemotherapy regimens in HER2 overexpressed tumors

Dose Dense AC/paclitaxel with trastuzumab – Doxorubicin 60 mg/m² IV day 1, Cyclophosphamide 600 mg/m² IV day 1 cycled every 14 days for 4 cycles followed by paclitaxel 175 mg/m² IV over 3 hours day 1 every 14 days for 4 cycles with G-CSF support. Trastuzumab 4 mg/kg IV is administered with the first dose of paclitaxel followed by 2 mg/kg IV weekly to complete 1 year of treatment. As an alternative, 6 mg/kg IV can be used at the completion of the paclitaxel and given every three weeks intravenously to complete 1 year of treatment.
AC followed by weekly paclitaxel with trastuzumab – Doxorubicin 60 mg/m² IV day 1, Cyclophosphamide 600 mg/m² IV day 1 cycled every 21 days for 4 cycles followed by paclitaxel 80 mg/m² IV over 1 hour weekly for 12 weeks with trastuzumab 4 mg/kg the first week of the paclitaxel followed by 2 mg/kg weekly to complete a year of treatment. After completion of the paclitaxel, an alternative would be 6 mg/kg every three weeks to complete one year of treatment
AC –followed by T with trastuzumab – Doxorubicin 60 mg/m² IV day 1, Cyclophosphamide 600 mg/m² IV day 1 cycled every 21 days for 4 cycles followed by paclitaxel 175 mg/m² IV over 3 hours day 1 every 21 days for 4 cycles– with the commencement of trastuzumab 4 mg/kg IV with the first dose of paclitaxel followed by 2 mg/kg IV weekly to complete 1 year of treatment. As an alternative, 6 mg/kg IV can be used at the completion of the paclitaxel and given to complete 1 year of treatment.
TCH – Docetaxel 75 mg/m² IV day 1, Carboplatin AUC 6 IV day 1, with trastuzumab 4 mg/kg week 1 followed by trastuzumab 2 mg/kg weekly for a year. An alternative is trastuzumab 8 mg/kg week one followed by trastuzumab 6 mg/kg every 3 weeks to complete one year.
Weekly paclitaxel x 12 weeks with trastuzumab, followed by trastuzumab to complete a year has been shown to be effective in lower risk node negative cancers.
The addition of pertuzumab at a dose of 840 mg cycle one and then 420 mg IV every three weeks to AC-paclitaxel trastuzumab or TCH was shown to decrease recurrence in node positive patients but is not yet approved and has not been shown to have a major survival impact.
In the neoadjuvant setting the addition of pertuzumab to the 4 cycles of taxane therapy with trastuzumab does improve progression free survival.

The HERA data also suggested that initiating trastuzumab after standard chemotherapy at a dose of 8 mg/kg IV and then 6 mg/kg IV every three weeks for one year was efficacious but is generally not recommended as there may be synergy by initiating the antiHER2 therapy during the taxane treatment.

Cardiac monitoring should be done prior to the initiation of the trastuzumab and every 12 weeks during therapy. The LVEF should be assessed by the same method throughout and a fall of over 15% or to below ULN or below 50% should precipitate further assessment of cardiac function. In some cases where there are no symptoms and the LVEF remains at a reasonable level, the trastuzumab can be continued as the risk of breast cancer recurrence may be more significant.

Myeloid growth factor support should be administered with protocols that are dose dense or when there is a significant risk of neutropenia such as treatment with docetaxel.

Biological therapies in early breast cancer

HER2

Other than endocrine therapy, the biological treatment with shown benefit in early breast cancer is anti-HER2 therapy. For the approximately 15-20% of tumors that overexpress HER2, chemotherapy with the anti-HER2 therapy trastuzumab has been indicated since the results of the large adjuvant studies were first reported in May 2005. These studies added trastuzumab to standard chemotherapy either during (NCCTG, NSABP, BCIRG, FinHER) or after (HERA) chemotherapy and all showed a decrease in recurrence, as well as a survival benefit.

One study BCIRG 005 also tested a novel non-anthracycline chemotherapy recipe, TCH (docetaxel, carboplatin, trastuzumab) and showed similar results to other active regimen in the study ACTH (adriamycin, cyclophosphamide, docetaxel, trastuzumab). Although shorter and longer regimens have been, and are being, tested, the standard therapy in most parts of the world is chemotherapy with concurrent trastuzumab during taxane treatment followed by single agent trastuzumab for a total duration of one year.

Other anti-HER2 therapies are being tested. A large study, ALLTO, has compared one year of trastuzumab to one year of lapatinib (and small molecule tyrosine kinase inhibitor) to a combination of the two therapies to sequential lapatinib and trastuzumab and did not show a benefit for the addition of lapatinib in any of the arms.

The AFFINITY study tested dual blockade of the HER2 receptor. This trial compared one year of trastuzumab with one year of the combination of trastuzumab and pertuzumab, an antibody that blocks the dimerization of HER2/HER3. This combination has been shown to be effective in the neoadjuvant setting. In the US, pertuzumab has been approved in the neoadjuvant setting in combination with trastuzumab and docetaxel. The results were more impressive in node positive than in node negative but were less than hoped for. At this time pertuzumab is not approved in the adjuvant setting.

In the ExteNET trial, neratinib (an oral irreversible tyrosine kinase inhibitor of HER1, HER2, and HER4) demonstrated a significant improvement in 2-year disease free survival for patients with early-stage HER2-overexpressing breast cancer (93.9% vs. 91.6%, HR 0.67, 95% CI 0.5 – 0.91). Patients received 240 mg neratinib by mouth for 12 months, after having completed a year of adjuvant trastuzumab therapy with the preceding year. Based on these data neratinib was granted approval in the US in May 2017. Common adverse events in patients receiving neratinib included diarrhea (antidiarrheal prophylaxis is recommended for at least 2 cycles), rash, nausea/vomiting, fatigue, and liver enzyme elevations.

Many other adjuvant studies and neoadjuvant studies are being done with these agents and others including TDM1 which conjugates trastuzumab with a cytotoxic DMI. At this time there is excitement that dual blockade and possibly these newer agents may provide further benefit. As well, subcutaneous trastuzumab has been tested and approved in many countries outside the US and provides a more convenient adjuvant therapy for women.

Antiangiogenic therapy

Antiangiogenic therapy has been tested in the adjuvant setting of triple negative breast cancer and was not shown to be effective. There are studies in the neoadjuvant setting suggesting a benefit but these are not validated and it is not standard therapy. As well, the BETH study tested the addition of an antiangiogenic agent, bevacuzumab, to trastuzumab in addition to standard chemotherapy and did not show a benefit in HER2-overexpressing breast cancer.

Others

There is also interest in blocking the insulin and insulin-like growth factor receptor pathways as there is evidence from epidemiologic and laboratory studies that suggest this pathway may impact breast cancer growth. A large adjuvant study, MA32, is being done to test the impact of metformin on breast cancer recurrence as it is not known if it has any effect and the toxicity in this group of women. Neoadjuvant studies of this and other agents are also being done. Finally, there are studies being done with other biological agents including mTOR inhibitors and drugs that inhibit the CDK pathway.

Although there is excitement, with early breast cancer it is necessary to be prudent prior to adopting new therapies as this is usually a curable situation. Certainly lessons from the past such as the premature widespread use of high-dose therapy and bone marrow transplantation prior to the completion of the relevant clinical trials should teach us to wait for proper randomized studies prior to assuming we have an improved therapy.

Radiation Therapy

Radiation is given to further decrease the risk of the cancer recurring locally but has also been shown in the most recent EBCTCG review to improve mortality. Radiation may be given to the breast only, or to breast and regional lymph nodes including the axillary, infraclavicular, supraclavicular and internal mammary nodes.

Post-mastectomy radiation

Post-mastectomy radiation is indicated if:

the tumor is greater than 5cm
margins are positive
there are involved nodes

Studies of post-mastectomy radiation have shown a survival benefit for node-positive patients. The field of the radiation may vary depending on the nodal status and other features of the tumor.

Radiation after breast conserving surgery

Breast radiation is given with breast conserving surgery. In this situation, nodal irradiation was standard when multiple (4 or more) nodes were involved. Recently the NCIC MA20 trial reported that nodal radiation was also of value in women after breast conserving surgery when 3 or fewer nodes were involved, or when there was high-risk node negative cancer. This study showed a decrease in regional recurrence and a trend towards improved survival. The impact of these studies with minimal nodal involvement such as Mi+ however is not known.

Most guidelines also recommend that internal mammary nodes be treated if they are clinically or pathologically involved and that this should be performed with CT planning of the radiation fields.

Studies have also shown that breast cancer subtype is associated with an increased risk of local recurrence with TNBC and HER2 breast cancers having a higher risk. Whether this will be true with contemporary chemotherapy and anti-HER2 therapy is not known.

Young women have an increased risk of recurrence and have been shown to benefit from a boost treatment to their surgical bed. Radiation is usually delivered after completion of chemotherapy but may be given during anti-HER2 therapy. Theoretical concerns have been cited to avoid radiation during tamoxifen with older reports of increased lung toxicity or decreased efficacy, but these have not been validated and many centers start the hormone therapy with tamoxifen or AI prior to radiation.

Accelerated partial radiation of the breast is being developed, but at this time, largely remains investigational in most centers. Generally it is thought that certain subtypes such as unifocal small, low-grade, estrogen-sensitive tumors (stage 1) in older women (age over 60 years) with no BRCA mutations may be safely treated with accelerated partial radiation in experienced centers but at this time it is not standard therapy.

Studies have been done in older women with low-risk hormone sensitive tumors eliminating radiation completely and have shown an increased local recurrence rate without radiation (1% with radiation versus 4% without radiation) but no impact on survival. Most centers continue to recommend radiation to fit older women. In less fit elderly cases, there may not be harm in with-holding radiation as long as the breast is watched for local recurrence.

There are a number of different radiation protocols that are accepted as standard with the treatment generally lasting from 16 days to 5 weeks, with additional days if there is a boost. Partial breast radiation has been developed using a variety of techniques, including to decrease the volume of breast that is irradiated and to accelerate the delivery of treatment.

A variety of techniques have been studied, including intraoperative radiation, multicatheter interstitial brachytherapy, balloon catheter brachytherapy, and conformal external beam radiation approaches. A recent report found that 4% of women may require a subsequent mastectomy after partial breast radiation compared to 2.2% of women with standard radiation, suggesting that the technique may need to be restricted to specific tumors that are low-risk and in women with a low-risk of complications from the procedure.

Toxicity of treatments

Toxicities of radiation therapy

The side effects depend on the fractionation, the size of the fields, the technique used and the tolerance of the individual but include:

skin toxicity (erythema, peeling, hyperpigmentation, ulceration)
fatigue
lymphedema
rarely cardiac and lung toxicity

Toxicity of hormonal therapy

Tamoxifen

Most common sides effect – hot flashes, vaginal discharge, endometrial cancer (risk of
Approximately 2/1000 for women taking 20mg for 5 years), risk of DVT (about 1% in the adjuvant setting but may be greater in women with other risks of DVT such as coagulopathies), other thrombotic events such as pulmonary embolus or cardiovascular event, weight gain.
Very rarely – nausea, vomiting, anorexia, muscle and joint aches which may be menopausal related, headache, depression, dizziness, skin rash, minimal alopecia, fatigue, facial hair, retinal changes, memory changes.
Tamoxifen does not render a pre-menopausal woman menopausal and therefore menses and/or ovulation can continue.

Aromatase inhibitors

Most common side effects – muscle and joint aches and pains which may be mild but may be debilitating and may be relieved with changing AI, increase in lipid and triglyceride levels may be seen, vaginal dryness and decreased libido, increase in osteopenia and osteoporosis.
Less common – nausea, headaches, swelling of hands, feet and lower legs with fluid retention, carpal tunnel syndrome, fatigue, hair thinning, skin rash, depression, weight gain, diarrhea, insomnia.

Ovarian Suppression

Menopausal symptoms result from LHRH agonists causing ovarian suppression which include hot flushes, vaginal dryness, decreased libido, bone loss.
Other sides effects are rare and may include pain where the needle was placed, increased bone pain, nausea, breast swelling, unexpected vaginal bleeding, appetite or bowel changes, tiredness, headaches, depression, dizziness and irritability.

Toxicities of chemotherapy

The side effects depend on the regimen used but include:

Common – alopecia, neutropenia and risk of sepsis, mucositis, fatigue, amenorrhea which may result in permanent menopause, anemia, nausea and vomiting, diarrhea, bloating, constipation, flu-like symptoms, joint aches and pains, fluid retention, myalgias and arthralgias, neuropathy, cardiotoxicity, memory loss and difficulties concentrating.
Many of the side effects can be controlled. Current antiemetics are usually effective for the regimens above but may need to be adjusted to the individual. Care should be given to avoiding long term side effects which may be avoided by adjusting doses or regimens if they appear during the treatment, such as cardiac toxicity or severe neurotoxicity.
Many women have minimal toxicity. Some studies have suggested that regular exercise during chemotherapy may be beneficial.

Toxicities of HER2 targeted therapies

Trastuzumab can cause cardiotoxicity and this should be monitored by clinical history as well as measurement of LVEF every 12 weeks. Risk factors include prior cardiac disease, hypertension, age, and the use of concurrent anthracyclines although these can sometimes be safely given. Some patients develop rash, fatigue, and diarrhea.
Lapatinib, which is being studied in early HER2 treatment also causes rash, diarrhea and a rise in liver enzymes.

Guidelines

There are a number of published guidelines for the treatment of early breast cancer that can be referenced. These include various ASCO guidelines that include a recent review of endocrine therapy for post-menopausal women.

The National Comprehensive Cancer Network (NCCN) guidelines are widely used and are a good reference that can be accessed online. The St Gallen Early Breast Cancer Guidelines are developed every 2 years and published providing an international perspective for the treatment of early breast cancer. Others including Cancer Care Ontario and the BC Cancer Agency also publish evidence based guidelines online. ESMO has also published guidelines including specific recommendations for young women.

What should you tell the patient and the family about prognosis?

The survival of patients with early breast cancer has improved remarkably. There have been recent studies showing rates worldwide; it appears that access to multidisciplinary care and standardized treatment guidelines have a major impact in the benefit that is being seen.

Below are recent survival rates based on stage. With the increasingly sophisticated pathology subtyping, survival by stage alone is a gross generalization but can sometimes be informative. These are the most recent statistics posted by the Surveillance Epidemiology and End Results (SEER) group.

5 year survival rate by stage:

Localized 98%
Regional (lymph node involvement) 84%
Distant 23%

Breast cancer specific survival rates may be slightly higher. All survival statistics are based on older results as they require time to mature and therefore may not reflect more recent results with the addition of targeted therapies such as trastuzumab. Results may improve considerably with longer follow-up and more contemporary treatment.

What if scenarios.

Pregnancy-associated breast cancer

If breast cancer is diagnosed during pregnancy or within one year of parity, it is considered a pregnancy associated breast cancer (PAB). Many pregnancy-associated cancers are diagnosed at late stage, often in the locally advanced setting. There is an increasing literature on the treatment of pregnancy-associated breast cancers and the treatment for women who do not want termination of the pregnancy but who require treatment while still pregnant. Care should be coordinated with the obstetrician and the oncologist with plans often to deliver the baby a few weeks early, when it can safely be done.

Radiation for both diagnosis and therapy is usually avoided if possible. Surgery is often done for local control. Although chemotherapy has been given during all pregnancy trimesters, most oncologists try to avoid chemotherapy in the first trimester if possible; it can be given in the second and third trimester.

Doxorubicin and cyclophosphamide have been used most frequently and therefore are most often recommended. There is some increasing literature on the taxanes and on trastuzumab. Bisphosphanates should be avoided as should antimetabolites such as methotrexate. Radiation, completion of surgery, and/or chemotherapy may be given after delivery.

Fertility issues in early breast cancer

For many young women, a diagnosis of breast cancer can be devastating in terms of disrupting reproductive plans. Preserving fertility may be of great importance to the woman, despite the obvious priority of treating the cancer. Increasingly, these aspects of survivorship are considered and weighed with the risk of the cancer itself.

Many chemotherapeutic agents cause disruption of menses which is partially idiosyncratic but also linked to age, which drugs are administered and duration of treatment. The incidence of amenorrhea rises steeply with increasing age and is also more frequent with alkylating agents compared to other classes. Although amenorrhea is common during or right after chemotherapy, many women eventually resume menses often a few years after treatment completion, especially women who are younger than age 35 years during treatment. Importantly, absence of menses does not necessarily imply a lack of fertility; conversely their presence does not guarantee it.

Studies have been done with the use of LHRH agonists prior to chemotherapy and have suggested preservation of fertility. A recent study in estrogen-negative patients showed a benefit and no risk to their outcome. There is less data in estrogen receptor-positive patients. These trials have been small. Fertility experts should be consulted prior to the initiation of systemic therapy as there are many new methods for storage of embryos and eggs that can be considered. These may result in delays in the initiation of systemic therapy. Although short delays may be reasonable, longer delays may be detrimental to the outcome.

Stimulation techniques may be safe but there is no data to prove this and all patients should be carefully counseled on these issues. The decisions may be based partially on the risk of relapse for the patient as delays and future pregnancies may impact less on a low risk-patient compared to one with a higher risk.

There is no data to suggest that a pregnancy after a diagnosis of breast cancer is harmful but, again, there are no randomized studies. Generally it is recommended that women wait at least two years after treatment completion. However, this may not be practical for older pre-menopausal women on 5 years of hormone therapy. Women on chemotherapy, anti-HER2 agents, hormone therapy or radiation should not get pregnant. It is recommended that women wait at least 6 months after discontinuing tamoxifen prior to attempting a pregnancy.

Recommended birth control methods are intrauterine devices (IUD), barrier methods or surgical intervention with vasectomy or tubal ligation.

Follow-up surveillance and therapy/management of recurrences.

Increased emphasis on survivorship has improved the follow-up recommendations for breast cancer patients and highlighted the need for more holistic approaches, many of which may be administered more effectively by family physicians and nurse practitioners than by oncologists. The follow-up recommendations should concentrate on the following:

Diagnosis of local recurrence – recommendations include annual mammography. The role of MRI needs to be individualized as it may be recommended for those persons with BRCA mutations, dense breasts, prior exposure the chest wall radiation or young age but may not be necessary for older women in whom mammography is adequate. Clinical examinations are recommended at least every 6 months for the first five years and annually after that. Local recurrences are often curable and therefore of most importance to diagnose early.
Diagnosis of distant recurrence which is usually based on symptoms. There is no evidence at this time for any routine radiologic or laboratory testing for diagnosing distant recurrences in asymptomatic women. However any symptoms should be investigated promptly.
Lifestyle issues including maintaining a normal BMI through a balanced diet and regular exercise. Bone health is also important and maintained with weight bearing exercise, calcium and vitamin D supplements and pharmaceutical interventions if appropriate. Moderate to minimum alcohol intake may be important for both bone health and to decrease breast cancer recurrence.
Managing the toxicity of treatments. This may include the side effects from endocrine therapy, post-radiation and surgical issues of arm health, chest wall discomfort, and post chemotherapy toxicities of fatigue, arthritic complaints, neurotoxicity, chemo (brain), and menopausal symptoms.
Sexuality and hormonal issues which may be significant and often require counseling, reassurance, local lubricants and in some situations, hormonal therapy.
Psychological health and support for post diagnosis issues for the patient and her family.

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