Breast Cancer

1. Introduction

Breast cancer is the second most commonly diagnosed malignancy in the world, following lung cancer¹. Every year, nearly two million women across the globe are diagnosed with breast cancer. It is also the leading cause of cancer mortality in women in the world. Fortunately, with advances in screening and systemic therapies, breast cancer outcomes are improving^2-4.

2. Symptoms

With the increasing availability of screening, the majority of women with breast cancer present with an abnormal mammogram⁵. Symptoms of breast cancer include a palpable breast or axillary mass, skin changes, and/or nipple changes; however, 15% of palpable concerning breast masses are mammographically occult. Palpable axillary lymphadenopathy and skin dimpling and/or nipple changes are often signs of locally advanced disease. Inflammatory breast cancer in particular can present with erythema, skin thickening and edema, which represent characteristics of the classic peau d’orange appearance.

Symptoms of metastatic disease vary depending on the location of the metastases. The most common sites of breast cancer metastases are to the bone, liver, and lungs. Bone metastases may present as back or extremity pain. Liver metastases may present with bloating, abdominal pain, nausea, or jaundice. Lung metastases may present with shortness of breath or cough.

3. Screening

For women with an average breast cancer risk, screening is recommended beginning at age 40-50 years with mammography every one-two years, and continued through age 74 years^6,7. For women 75 years and older, screening is typically recommended to be continued only in those with a life expectancy of 10 years or greater.

Certain populations are considered to have a greater than average risk of breast cancer and should not ascribe to the same screening recommendations as those with average breast cancer risk. These include patients with a prior breast biopsy of a high-risk lesion, a personal history of chest radiation, a personal or family history of breast or ovarian cancer, and a known pathogenic mutation associated with a hereditary breast cancer syndrome (such as BRCA1, BRCA2, TP53). Initiation and timing of screening should be individually tailored for these patients.

4. Diagnosis

The classic mammographic presentation of breast cancer is as a soft tissue mass or density. Other mammographic findings which can be associated with malignancy include focal asymmetry, architectural distortions, and grouped microcalcifications. Microcalcifications represent calcium deposits within ducts due to increased cell proliferation and necrosis.

The first step following an abnormal screening mammogram or concerning clinical exam finding is to obtain a diagnostic mammogram and/or ultrasound. Compared to a screening mammogram, a diagnostic mammogram offers a magnified, targeted examination of the area of concern. Mammographic findings are categorized using the Breast Imaging-Reporting and Data System (BI-RADS) classification, which reflects the likelihood of the radiographic findings correlating with malignancy, as well as the recommended next step, whether it be continuing with routine screening, short interval imaging, or biopsy⁸.

An ultrasound can be performed at the same time to complement mammography. Sonographic features concerning for malignancy increase hypoechogenity, internal calcifications, posterior shadowing, height of lesion being greater than its width, and spiculated or indistinct margins^9,10.

A breast core biopsy is necessary to confirm a diagnosis of malignancy. For nonpalpable findings, this is performed under imaging guidance to ensure adequate sampling of the lesion of concern. For inflammatory breast cancer, a skin biopsy is performed and dermal lymphatic invasion is considered pathognomonic. At the same time, the presence of the clinical and histologic stigmata of inflammatory breast cancer (rapid onset of peau d’orange with or without breast skin erythema, breast swelling and presence of an underlying breast carcinoma) is sufficient for its diagnosis, and a negative skin biopsy does not rule it out. The treatment algorithm for inflammatory breast cancer requires “tri-modality” therapy: neoadjuvant chemotherapy followed by modified radical mastectomy without immediate reconstruction, followed by comprehensive chest wall and regional nodal radiation.

The most common invasive pathology is invasive ductal carcinoma. Invasive lobular carcinoma represents 10% of breast cancer diagnoses and mixed ductal/lobular occurs in 5% of breast cancers¹¹. Ductal carcinoma in-situ (DCIS) is a non-invasive lesion that also requires complete surgical excision. There are also atypical proliferative lesions that are not obligate breast cancer precursors but are associated with an increased likelihood of associated breast cancer are atypical ductal hyperplasia (ADH) and non-classical lobular carcinoma in-situ; these require additional surgical excisional biopsy to ensure adequate sampling of the area and to rule out and associated carcinoma. Core needle biopsy findings of atypical lobular hyperplasia (ALH), hyperplasia without atypia, papilloma without atypia and classical LCIS do not require surgical excision for BI-RADS <4 asymptomatic lesions felt to be concordant (i.e. when the biopsy pathology is in “agreement” with the appearance of the imaging abnormality)¹²; the management of flat epithelial atypia (FEA) under these circumstances remains to be determined as prospective data on it are forthcoming.

Breast cancers are also tested for their receptor status for estrogen, progesterone, and HER2neu which are used to guide treatment decisions. Breast cancers can be further classified by their molecular phenotypes which has been shown to be a better marker of the tumor biology, behavior, and prognosis^13,14. This can be performed by genomic analysis or by using the receptor status and the tumor grade as a surrogate¹⁵.

Magnetic resonance imaging (MRI) can also be used as an adjunct to mammography and ultrasound and has been shown to be more accurate than either mammography or ultrasound in determining the radiographic extent of disease. MRI features of malignancy include increased heterogeneous enhancement, irregular or spiculated margins, enhancing internal septa, and non-mass enhancement¹⁶. However, because of its highly sensitive nature, MRI may also identify additional imaging lesions that may require further evaluation and/or biopsy and these may lead to patient anxiety and have been associated with increased rates of mastectomy^17,18.

5. Staging

Breast cancer is staged using the American Joint Committee on Cancer (AJCC) staging system¹⁹. This recently updated staging system incorporates both the anatomic tumor, node, metastasis (TNM) stage as well as the receptor status to produce a clinical prognostic stage. The primary tumor clinical stage (T) is determined by clinical exam and/or imaging. The clinical nodal status (N) is determined by physical exam and/or imaging. The metastasis status (M) is only evaluated with additional imaging in patients with locally advanced (T3 or greater, N2 or N3) disease; staging for metastatic disease is not routinely performed nor recommended for patients presenting with early stage breast cancer. Based on preoperative clinical exam and/imaging, patients are assigned a cTNM stage; their prognostic stage can also be calculated incorporating the hormone receptor status which can be obtained from their core biopsy. Postoperatively, patients are assigned a pathologic (p)TNM stage based on their final surgical pathology.

6. Treatment

The mainstays for the surgical treatment of breast cancer are breast conserving therapy (BCT) or mastectomy. BCT includes both lumpectomy with negative margins and radiation. For non-palpable lesions, localization is performed preoperatively with a radioactive seed or wire, to guide the surgeon to the lesion of concern. A lumpectomy must completely excise all evidence of disease with clear margins. For invasive cancer, negative margin is defined as “no tumor on ink”²⁰. For DCIS, negative margin is defined as greater than 2 mm²¹. Whole breast radiation is administered following lumpectomy as part of BCT. Mastectomy involves removal of all the breast tissue and pectoralis major fascia. The Milan trial, NSABP B-06, and EORTC 10801 were the pioneering trials that demonstrated BCT and mastectomy to be equivalent in terms of the long-term overall survival outcomes^22-24. The rates of local recurrence are slightly lower after mastectomy compared to BCT but this difference is not statistically significant. Contraindications to BCT include inflammatory breast cancer, multicentric disease (disease in more than one quadrant of the breast), anticipated poor cosmetic outcome, prior whole breast or chest radiation, systemic lupus erythematosus and scleroderma. Relative contraindications to BCT include skin involvement, or presence of a genetic mutation known to be associated with high lifetime risk of breast cancer.

Axillary staging is also performed at the time of the breast surgery. In patients with clinically node-negative disease, a sentinel lymph node biopsy (SLNB) is performed to sample representative axillary lymph nodes. Either a blue dye (isosulfan blue or methylene blue) and/or radio-labeled colloid tracer is injected at the time of surgery and is used to identify the first draining lymph nodes of the breast, termed the sentinel lymph node(s) (SLN). For patients undergoing BCT, traditionally, a positive SLN was followed by axillary lymph node dissection (ALND). Currently, it is accepted practice for women with early stage (cT1-2N0 at diagnosis), undergoing BCT with one or two positive SLNs to no longer require a completion ALND. This is based on from the ACOSOG Z0011 trial, which enrolled 891 women, and demonstrated that women with one or two SLN who did not undergo ALND had no differences in survival or axillary recurrence outcomes compared with those who underwent additional ALND^25-27. At a median follow-up of 9.3 years, the 10-year overall survival was 86.3% in the SLNB only group and 83.6% in the completion ALND group²⁶. There was also no difference in the cumulative incidence of axillary recurrences at 10 years between the two groups (SLNB only 1.5% vs. completion ALND was 0.5%, p=0.36). Patients with three or more positive SLNs should undergo completion ALND.

The data are less robust for patients with clinically-node negative disease who undergo mastectomy and are found to have a positive SLN. For patients undergoing mastectomy with micrometastases in one or two SLNs, some management strategies have been extrapolated from the Internal Breast Cancer Study Group (IBCSG) 23-01 trial which randomized 934 patients with invasive cancers up to 3 cm and clinically negative nodes, found to have sentinel node micrometastases to either SLNB only or completion ALND²⁸. At a median follow-up of 9.7 years, there was no difference in 10-year disease free survival (no ALND 76.8% vs ALND 74.9%, p=0.24) or incidence of axillary recurrence (no ALND 2% vs ALND 0.4%)²⁹. However, it is important to note that only 9% of patients enrolled in the IBCSG 23-01 trial underwent mastectomy. Until more robust data is available, patients undergoing mastectomy with a positive SLN should still undergo additional axillary treatment. The AMAROS trial compared the use of axillary radiation (AxRT) to ALND for patients with cT1-2N0 breast cancer and one or two positive SLNs³⁰. At a median follow-up of 6.1 years, there was no significant difference in disease-free survival (AxRT 82.7% vs. ALND 86.9%), overall survival (92.5% vs. 93.3%), or axillary recurrence (1.2% vs. 0.4%).

For patients who undergo neoadjuvant systemic therapies, additional considerations need to be made both in the treatment of the breast as well as the axilla. Prior to the initiation of neoadjuvant therapy, clinically node negative patients should undergo an axillary ultrasound; if there are any abnormal appearing nodes, a biopsy should be performed as well as a clip placed to facilitate future identification of the node should the biopsy return to be positive for metastatic disease. Patients with clinically node positive disease should also undergo biopsy and clip placement of the most abnormal appearing node. If neoadjuvant systemic therapy is utilized to reduce the volume of disease in the breast in order to reduce the extent of surgery (i.e. to downstage a patient to become BCT-eligible), repeat imaging is often obtained at the completion of neoadjuvant therapy to evaluate response and BCT candidacy.

Patients who present with clinically node-negative disease are still candidates for SLNB at the time of their definitive breast surgery following neoadjuvant chemotherapy. Given the potential changes in breast lymphatic drainage following neoadjuvant therapy, providers are recommended to use both a blue dye and radio-labeled colloid tracer and to obtain at least three SLN to improve the accuracy of axillary staging in this population^31-33. Similarly, patients who present with clinically node-positive disease and become clinically node-negative following neoadjuvant therapy are also eligible for SLNB. Providers are also recommended to use dual tracer and to obtain at least three SLN, including the clipped biopsy-proven node³⁴. If any axillary disease is found at the time of surgery, or if the clipped node is not found at the time of surgery, completion ALND is recommended.

Adjuvant therapies following definitive breast surgery can be divided into locoregional and systemic therapies. Locoregional therapy is comprised of radiation, following lumpectomy or mastectomy. Patients who undergo lumpectomy should receive adjuvant whole-breast radiation (WBRT) as part of BCT³⁵. Regional nodal radiation to the infraclavicular, supraclavicular, and internal mammary nodes should also be administered for patients with four or more positive lymph nodes, T3 or T4 tumors, or T2 tumors with other high-risk features; there is also emerging data that regional radiation may also be helpful in reducing recurrence in patients with one to three positive lymph nodes^36,37. Older women aged ≥65 years of age with node-negative, early stage 1-II hormone-receptor positive tumors who receive adjuvant endocrine therapy can be considered for omission of radiation^38,39. Patients who undergo mastectomy and have four or more positive lymph nodes or certain poor prognostic features should also undergo radiation (post-mastectomy radiation PMRT)^40,41. Some patients with one to three positive lymph nodes may also benefit from PMRT and this should be considered on an individualized basis⁴².

Systemic therapy for breast cancer is primary comprised of endocrine therapy and chemotherapy. Patients with hormone receptor-positive breast cancer should receive endocrine therapy. Patients with early stage hormone receptor-positive breast cancer and high-risk features as well as patients with triple-negative breast cancer should be considered for chemotherapy. Patients with HER2-positive breast cancers should be treated with a combination of chemotherapy and HER2-targeted therapy.

7. Surveillance

Following breast cancer treatment, current guidelines recommend that patients should be seen for clinical follow-up every three to six months for the first three years, then every six to twelve months for the next two years, then annually. During these clinical follow-ups, patients should undergo a thorough examination of the affected and contralateral breasts, chest wall, axilla, and supraclavicular regions. Patients should undergo surveillance mammograms annually for both the affected breast (if breast conservation was performed) as well as the contralateral breast. Patients who underwent mastectomy (with or without reconstruction) do not need additional surveillance imaging of that side, and should be followed with clinical examination only.

8. Controversies

Much debate remains around the management of patients who present with clinically node-positive disease who become clinically node-negative following neoadjuvant therapy. While many agree that these patients can undergo safe and effective axillary staging with SLNB following neoadjuvant therapy, the subsequent axillary management strategy following SLNB remains an area of active investigation. For patients whose disease is downstaged to a clinically node-negative axilla and yet having persistent pathologic disease on SLNB, this is currently being addressed in the Alliance 011202 trial which enrolls such patients and randomizes them to either completion ALND with regional nodal radiation or axillary and regional nodal radiation⁴³. Patients in the ALND arm receive regional nodal radiation delivered to the breast/chest wall, the undissected level III of the axilla, the supraclavicular and internal mammary nodes. Patients in the radiation only arm receive radiation delivered to the breast/chest wall, all three levels of the axilla, and the supraclavicular and internal mammary nodes. The primary outcome of this trial is the interval of recurrence free survival from invasive breast cancer. Secondary outcomes include the incidence of invasive locoregional recurrence, the residual disease burden, overall survival, occurrence of lymphedema, and the adequacy of radiation fields. 

Patients whose disease is downstaged to a clinically node-negative axilla and also have a negative SLNB are currently being studied within the context of another randomized trial, the NSABP B-51/RTOG 1304 (NRG 9353)⁴⁴. In this trial, patients are randomized to either regional nodal radiation or no regional nodal radiation. All patients receive additional breast radiation if they had undergone BCS as their primary breast operation. Patients in the regional nodal radiation arm also received chest wall radiation if they had a mastectomy as their primary operation; patients in the no regional nodal radiation arm did not receive chest wall radiation following mastectomy. The primary outcome of this trial is the interval of recurrence free survival from invasive breast cancer. Secondary outcomes include overall survival, locoregional recurrence-free survival, distant recurrence-free survival, occurrence of a second primary cancer, and cosmesis and quality of life.

9. Summary and recommendations

• Breast cancer is the leading cause of cancer-related mortality worldwide.
• For women with average breast cancer risk, breast cancer screening with mammography should begin at age 50. Early screening should be considered on an individual basis based on any additional personal or family risk factors.
• Patients with a concerning breast clinical or imaging finding should undergo diagnostic mammogram and/or ultrasound, as well as a core biopsy to confirm the diagnosis and obtain hormone and HER2 receptor marker status.
• Breast cancer is staged using a TNM classification system; in addition, hormone receptor status can be incorporated to determine the clinical prognostic stage. Routine imaging for metastatic disease is not indicated for patients with early stage breast cancer.
• The mainstays for the surgical treatment of early stage breast cancer are BCT (lumpectomy with radiation) or mastectomy. These are equivalent in their long-term survival outcomes.
• Patients with non-metastatic inflammatory breast cancer require “tri-modality” therapy: neoadjuvant chemotherapy followed by modified radical mastectomy without immediate reconstruction, followed by comprehensive chest wall and regional nodal radiotherapy
• SLNB is performed at the time of the primary breast surgery for axillary staging. Patients with early stage, hormone-receptor positive breast cancer, who undergo BCT and are found to have 2 or fewer positive SLN do not need to undergo further axillary surgery; patients with three or more positive SLN should undergo completion ALND. Patients who undergo mastectomy and are found to have one or two positive SLN should still receive additional axillary therapy; these patients can be considered for axillary radiation as an alternative to completion ALND.
• Patients who undergo lumpectomy should also receive WBRT. Patients who undergo mastectomy and are found to have four or more positive lymph nodes or additional poor prognostic features should be treated with PMRT.
• Endocrine therapy is recommended for hormone-receptor positive patients. Patients with triple negative breast cancer should receive chemotherapy. Patients with HER2-positive tumors should receive both chemotherapy and HER2-targeted therapy.