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Diagnosis and surgical management of early stage breast cancer

Oncology
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Introduction (epidemiology, survival, benefits of breast screening)

Breast cancer has become the most commonly diagnosed cancer worldwide, surpassing lung cancer in 2021[1]. While breast cancer mortality has decreased in high-income countries, it continues to be elevated in low-middle and low-income countries[2].
Geographical differences in breast cancer mortality are influenced by several factors including delayed and/or constricted access to medical care, which can generate delays in diagnosis and treatment. Screening mammography aids in the early diagnosis of breast cancer and has been shown to decrease breast cancer mortality by 25-31% for women between 50-69 years old[3, 4].

Screening: Average risk and Increased risk

Breast cancer screening guidelines were developed to aid in the early detection of breast cancer and are based on a woman’s lifetime risk to develop breast cancer[5].
Women with an average lifetime risk of breast cancer should undergo a clinical breast exam by a medical provider every 1-3 years starting at age 25. At age 40-50 years, women should start screening mammography every 1-2 years and continue until age 74. From there, the decision to discontinue breast cancer screening should be individualized as screening for breast cancer in women with severe comorbidities and life expectancy less than 10 years may not be of benefit[6].
Women with an increased risk of breast cancer include those with a prior history of breast cancer, a breast biopsy showing lobular carcinoma in situ (LCIS), atypical ductal or atypical lobular hyperplasia (ADH and ALH)[7], a history of mantle irradiation between age 10 and 30, or a family history of breast or ovarian cancer and known genetic predisposition (eg BRCA1, BRCA2 mutations). Breast screening recommendations for women at increased risk should be tailored to the individual patient, but include clinical breast exam every 6 to 12 months associated with digital mammography and consideration for breast MRI[8].
Women with a genetic predisposition should also be counselled on risk-reducing bilateral mastectomy and bilateral salpingo-oophorectomy[9].

Presentation/Diagnostic work up (screening-detected vs symptomatic patients)

Early breast cancer is typically identified by abnormal screening mammography as most women will not present with clinical findings at the time of diagnosis[4]. However, concerning signs and symptoms of breast cancer include a palpable mass in the breast and/or axilla, skin thickening and/or redness, or nipple changes (retraction, ulceration or bloody discharge).
Patients should be evaluated with a thorough history including previous breast biopsies and/or surgeries, review of systems focused on common sites for distant metastatic disease (bone, lung, liver and brain) and oncologic family history.  Clinical examination should include evaluation of the bilateral breasts and draining nodal basins (axillary, supraclavicular, infraclavicular, and cervical) with the patient in both sitting and supine positions.
Diagnostic work up should include imaging with diagnostic mammography and breast ultrasound (US) for symptomatic patients. For asymptomatic patients undergoing annual screening mammogram, common radiologic findings of breast cancer include mass, architectural distortion and microalcifications. Once an abnormality is detected by screening mammogram, patients would then undergo diagnostic mammography and breast ultrasound (US)[10].
The need for further workup is determined based on the Breast Imaging-Reporting and Data System (BI-RADS) assessment (Table 1), which categorizes abnormalities found on imaging based upon their likelihood of cancer[11].
Table 1. BI-RADS* classification (from American College of Radiology (ACR).
ACR-BI-RADS®–5th Edition) [79]
CategoryRecommended ActionLikelihood of Cancer
0IncompleteNeed additional views/imaging to further evaluateN/A
1NegativeContinue routine annual screening0%
2BenignContinue routine annual screening0%
3Probably BenignShort interval follow-up (6 months)≤2%
4aSuspiciousTissue diagnosis>2-≤10%
4bSuspiciousTissue diagnosis>10-≤50%
4cSuspiciousTissue diagnosis>50-<95%
5Highly suggestive of malignancyTissue diagnosis>95% probability
6Known biopsy-proven malignancyAppropriate action should be taken100%
*Breast Imaging Reporting and Data System
For patients with BIRADS 4 or 5 lesions, current guidelines recommend percutaneous biopsy to establish a diagnosis. The preferred approach is a core needle biopsy under imaging guidance (US, mammogram or MRI), with the choice of imaging guidance dependent upon the modality on which the lesion is best visualized. Following completion of the biopsy, a radiopaque marker clip should be placed within the sampled area to mark the site of concern. Additionally, if a suspicious lymph node is identified during initial workup with ultrasonography, a core needle biopsy (CNB) or fine needle aspiration (FNA) under imaging guidance of the lymph node can provide additional information for staging and treatment purposes[12].
Microscopic evaluation and genetic profiling of the sampled tissue can differentiate between the various histologic types of breast cancer, including infiltrating ductal carcinoma, infiltrating lobular carcinoma and mixed ductal/lobular carcinoma, and provide additional information regarding hormone receptor status, human epidermal growth factor 2 (HER2), proliferation rate (Ki-67) and gene expression (Table 2) [13].
Table 2. The four subtypes of invasive breast cancer, based on the genomic signature.
SubtypesER*PR**HER2***Ki-67
Luminal A++/-–<14%
Luminal B (HER2-)++/-–≥14%
Luminal B (HER2+)++/-+Any
HER2 enriched––+Any
Basal-like–––Any
* Estrogen receptor
** Progesterone receptor
*** Human epidermal growth factor receptor 2

Staging

Following percutaneous biopsy, a pathological diagnosis should be made according to the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system. The recently published 8th edition system includes anatomical and prognostic information related to tumor biology[14].
While a detailed description of the TNM staging system is outside the scope of this chapter, it is important to understand the basics.
Stage 0 corresponds to ductal carcinoma in situ, which indicates proliferation of malignant cells within the mammary ductal system with no evidence of invasion into surrounding tissue.
Stage I cancers are confined to the breast only, while stage II cancers can be either confined to the breast or have spread to the lymph nodes.
Stage III cancers are considered locally advanced cancer with larger tumors and/or more extensive nodal involvement and Stage IV cancers include those which have metastasized to distant organs.
As mentioned, the 8th edition of the AJCC staging system includes prognostic staging as well. This incorporates tumor grade, hormone receptor status and multipanel genetic results into the patient’s staging designation and provides more accurate individualized prognostic information[15].

Surgical management

The treatment of early-stage breast cancer requires a multidisciplinary approach and consideration of multiple factors including tumor size and location, number of lesions, lymph node involvement, tumor markers, age and comorbidities. By definition, early-stage breast cancer patients have smaller tumors with limited to no nodal disease; however, treatment often consists of a combination of multiple modalities.
Neoadjuvant systemic therapy (NAST) should be discussed for patients with triple-negative and HER2 positive tumors greater than 2cm, large tumor size relative to breast size in a patient desiring breast conserving surgery (BCS), and/or in those with axillary nodal involvement[16]. However, for most patients with early-stage breast cancer, treatment entails upfront surgical intervention followed by adjuvant systemic and/or radiation therapy.
Breast conservation therapy
Breast conservation therapy (BCT) utilizes BCS to remove a patient’s tumor, while preserving their remaining breast tissue, and adjuvant radiation therapy (RT), the latter administered to try to eradicate any residual microscopic disease[17].
Several randomized trials and recent observational studies have demonstrated equivalent, if not improved, overall survival between BCT and mastectomy for patients with early-stage breast cancer[18-20].  While BCT is an excellent option for many patients with early-stage breast cancer, it may be contraindicated in the following situations:
  • Multicentric disease
  • Inability to achieve acceptable cosmetic outcome
  • Extensive indeterminate breast imaging abnormalities not amenable to conclusive percutaneous biopsy and/or not deemed appropriate for safe imaging follow-up
  • Prior radiation to chest wall and/or breast or other contraindications to RT (such history of systemic lupus erythematosus and scleroderma)
  • Inability to achieve negative margins after multiple resections
  • Inflammatory breast cancer
  • Large tumor size relative to breast (relative contraindication)
BCT can be safely performed on palpable and nonpalpable breast lesions, but for nonpalpable lesions, intraoperative guidance is required to localize the lesion and to help achieve negative margins while sparing as much normal tissue as possible. There are several techniques used for intraoperative localization including ultrasound, wire-guided localization and wireless seed localization.
Traditional wire localization relies on image-guided placement of a wire into the breast lesion and is most often performed by a radiologist in the radiology suite on the same day as surgery. While this remains the oldest and most widely used technique for localization, disadvantages of this method include wire displacement or migration prior to surgical resection. Wireless seed localization has emerged as a new preoperative localization technique and requires image-guided placement of a probe-identifiable seed into the breast lesion and can be easily performed prior to the day of surgery[21-24].
While there are several different wireless seed products in use, the technique is the same regardless of product used. A wireless seed is placed within or near the lesion and then the seed and lesion are surgically excised under the guidance of an intraoperative handheld seed-specific probe (Figure 1). This technique is a safe and feasible option for localization.
Figure 1. Left lumpectomy specimen radiograph. Red arrow: seed localization (Savi Scout®). Green Circle: radiopaque biopsy clip
Regardless of the intraoperative localization technique used, the tumor bed should be marked with surgical clips prior to conclusion of the case to facilitate accurate radiation planning by the radiation oncology team. Postoperative radiation is an essential component of BCT. The NSABP B-06 randomized trial evaluated whether BCS with or without radiation therapy was as effective as total mastectomy for the treatment of invasive breast cancer[18, 25].
Initial data and subsequent reporting at 20 year follow-up demonstrated that lumpectomy plus breast radiation therapy, as compared to lumpectomy alone, significantly decreased the incidence of recurrence in the ipsilateral breast (14% vs 39%, p <0.001), but importantly, there was no significant difference in overall survival among women who underwent mastectomy and those who underwent lumpectomy with or without postoperative radiation. Several additional studies have confirmed the equivalency of BCT and mastectomy from an overall survival perspective with more recent studies questioning a possible survival advantage of BCT over mastectomy in early-stage breast cancer[26-31].
Mastectomy
A mastectomy should be considered for patients who are not BCT candidates (as listed above) and for those who desire a mastectomy over BCT. The term mastectomy encompasses three different surgical techniques; nipple-sparing, skin-sparing and simple/total[32].
In all 3 types of a mastectomy, complete removal of breast tissue and the underlying fascia of the pectoralis major muscle is performed. A nipple-sparing mastectomy (NSM) and skin-sparing mastectomy (SSM) both preserve the breast skin envelope, but unlike a SSM, a NSM also preserves the nipple areolar complex (NAC). NSM is a desirable option for select patients and has been shown to be safe from an oncologic perspective (Figure 2)[33].
While a consensus on inclusion criteria for NSM has yet to be established, most institutions select for patients with a tumor distance to NAC >2cm, BMI <35 and lack of grade 3 ptosis of the NAC.  For those patients who decide to proceed with a simple or total mastectomy, a larger portion of the overlying skin is removed, resulting in a flat incision along the chest wall[34].
Post mastectomy radiation therapy (PMRT) is used to treat patients with breast cancer and increased risk for locoregional recurrence after mastectomy. It is recommended in patients with tumor invading skin and/or chest wall (pT4), 4 or more involved axillary lymph nodes (pN2), and primary tumors greater than 5 cm (pT3). Additionally, it should be considered in select patients with limited nodal disease (pT1) and/or high-risk features, such as lymphovascular  invasion (LVI), high grade histology, high genomic score and ER-negative tumors[35-38].
However, there is significant variability amongst practices in the recommendations of PRMT in this patient population. The SUPREMO trial is currently evaluating the impact of PMRT on locoregional recurrence, survival and morbidity in patients with limited or no nodal disease to better determine which subgroups would benefit from PMRT[39].
Margin Evaluation
Regardless of surgical technique, the current accepted margin width is no ink on tumor for invasive cancer and 2 mm for ductal carcinoma in situ (DCIS)[40, 41].  Ensuring negative margins at the time of initial operation is a major goal of a breast surgeon as a positive margin often warrants additional surgery with potential for increased morbidity, increased healthcare costs, patient anxiety and/or a less desirable cosmetic outcome[42, 43].
To determine the final margin status of an operation, a time-consuming and labor-intensive microscopic pathologic evaluation of the specimen must be performed, often requiring at least 7-10 days to complete. As such, many institutions have implemented intraoperative protocols to rapidly and accurately evaluate surgical margin status to help guide further excisions during the initial operation[44].
Techniques for intraoperative evaluation include gross specimen evaluation, imaging and/or intraoperative pathologic evaluation[45, 46]. However, while intraoperative pathologic evaluation results in extremely low positive margin rates, this technique is not widely available at most institutions[47].
To help reduce positive margin rates without the use of intraoperative pathologic evaluation, several studies have evaluated the role of cavity shave margins on re-excision rates. A recent multicenter randomized controlled trial sought to determine the effect of utilizing cavity shave margins (CSM) on margin status and re-excision rates after BCT[48].
This trial demonstrated a significantly reduced positive margin rate following systematic cavity shave margins compared to no cavity shave margins (9.7% vs. 36%) and a reduced rate of re-excision or mastectomy for margin clearance (8.7% vs. 23.5%).
Reconstruction
A discussion of breast reconstructive options should be included in the multidisciplinary approach to breast cancer treatment, particularly in women requiring mastectomy. Reconstructive options include local tissue rearrangement, oncoplastic reduction, implant-based reconstruction and autologous tissue-based reconstruction[49].
Patients undergoing BCT who are at risk of a cosmetic defect following tumor removal often benefit from either local tissue rearrangement or oncoplastic reduction[50]. Both techniques use the patient’s remaining breast tissue to fill or close the defect to provide an improved cosmetic outcome.
Patients desiring reconstruction after mastectomy should be considered for autologous tissue-based and implant-based techniques. Autologous tissue-based reconstruction relies on an understanding of musculocutaneous units and cutaneous vascular territories and has several advantages over implant-based reconstruction including volume restoration, absence of a foreign body, long-lasting results and a more natural feel[51].
Reconstructive options include a pedicled latissimus dorsi muscle flap, abdomen-based flaps or gluteal and thigh-based flaps. While autologous tissue-based reconstruction is an excellent option for most patients, it is important to note that these operations are technically demanding, often requiring the use of microsurgical techniques, and can add significant operative time.  Implant-based reconstruction is a shorter and less invasive option for patients, but has several disadvantages including higher surgical site infection rate, unnatural texture, implant rupture and capsular contracture. Despite this, there has been a growth in the number of implant-based reconstructions performed in the United States[52].
This is thought to be related to greater long-term data on safety, greater variety in size and shape of silicone implants, improved adjunctive procedures for fine-tuning the final cosmetic outcome, decreased operative hours, and faster post-operative recovery compared to autologous reconstruction.  
The discussion of autologous vs. implant-based reconstruction should involve the surgical oncologist, plastic surgeon, radiation oncologist and patient, as the possibility of PMRT will influence the patient’s reconstructive options. Autologous reconstruction can tolerate PMRT well; however, implant-based reconstruction may result in unfavorable cosmetic outcomes[53].
As such, for patients desiring implant-based reconstruction and requiring PMRT, placement of a temporary tissue expander is recommended followed by delayed implant replacement once PMRT is complete (Figure 2).  
Figure 2. Postoperative day 7: left nipple sparing mastectomy with placement of tissue expander
Figure 3. Left total mastectomy (no reconstruction)
Axillary management
The management of the axilla has evolved significantly over the last several decades, particularly in patients with early-stage breast cancer. Axillary lymph node dissection (ALND) was the historical gold standard of axillary staging in breast cancer; however, because it is associated with significant morbidity including lymphedema, seroma, shoulder dysfunction and paraesthesia, the need for an equally effective but less morbid means of staging the axilla emerged[54].
Following the publication of a landmark paper in 1994 demonstrating the reliability and feasibility of sentinel lymph node biopsy (SLNB) in breast cancer patients, there has been a trend to de-escalate axillary surgery in breast cancer treatment[55].
A SLNB involves the injection of radiocolloid tracer (Figure 4) and/or blue dye (isosulfan blue or methylene blue) into the breast at the time of surgery to identify the first draining lymph nodes of the breast, called sentinel lymph nodes (SLNs), which are excised and sent for pathologic evaluation (Figure 5).
Figure 4. Lymphoscintigraphy after injection of Tc99 showing drainage to an axillary lymph node.
Figure 5. Sentinel lymph node marked with lymphazurin blue
The use of SLNB has been evaluated in multiple randomized controlled trials, demonstrating low false-negative rates and acceptably low axillary recurrence rates for patients with clinically node-negative disease and/or limited axillary disease. For patients with pathologically negative SLNs, multiple trials have confirmed the noninferiority of SLNB only compared to SLNB + ALND[56-61].
Once the safety and efficacy of SLNB was proven for patients with pathologically negative SLNs, several trials began to assess the therapeutic efficacy of SLNB alone vs. SLNB + ALND in patients with limited SLN involvement.
The randomized controlled trial ACOSOG-Z0011 evaluated patients with clinical T1-T2 cN0 disease and 1-2 positive SLNs and reported non-inferior rates of overall survival (OS), disease-free survival (DFS) and locoregional recurrence-free survival when ALND was avoided in patients undergoing BCT[62].
Similarly, the IBCSG 23-01 trial demonstrated no benefit of further axillary treatment for patients with a SLN with invasive cancers up to 3 cm and SLN micrometastases (0.2-2mm) and there have been several studies demonstrating no benefit of ALND for patients with only isolated tumor cells (ITCs, < or = 0.2mm) in the SLNs[63-66].
More recently, the AMAROS trial compared axillary RT and ALND for clinically node-negative, SLN positive patients with T1-T2 breast cancer and demonstrated comparable axillary control and less morbidity with axillary RT over ALND[67].
Together, these trials emphasize the safety and efficacy of SLNB for axillary staging in early stage, clinically node-negative breast cancer as well as the safe omission of further axillary surgery for patients with no or limited disease in the axilla[68]. For early stage breast cancer patients with clinically node-positive disease undergoing upfront surgery, clinically node-positive disease after neoadjuvant systemic therapy, >2+ SLNs for BCT patients, or >3+ SLNs for mastectomy patients, ALND is recommended[68].
Additionally, the omission of axillary staging in early-stage breast cancer should be considered for patients in whom nodal information would not change adjuvant treatment recommendations, such as in patients with serious comorbidities, and patients ≥ 70 years old with cT1-T2N0 hormone receptor positive breast cancer[69-71].
For patients undergoing treatment with neoadjuvant systemic therapy, clinical nodal staging with ultrasound is recommended prior to treatment initiation. If abnormal appearing lymph nodes are identified, the index lymph node should be biopsied and clipped, in case it is positive for metastatic disease. The clipped biopsy-proven positive lymph node can be later identified at the time of surgery and evaluated for treatment response.
In patients with clinically node-negative disease treated with neoadjuvant systemic therapy, SLNB is recommended for surgical staging of the axilla. In those with clinically positive nodes at diagnosis, with low nodal disease burden (≤ 3 abnormal axillary lymph nodes), limited axillary surgery can be performed with SLNB plus targeted excision of clipped axillary lymph node (Figure 6) as long as there is no residual disease in the SLNs and the clipped node[72].
Figure 6. Intraoperative radiograph of clipped axillary lymph node. Red arrow highlights seed localization (Savi Scout®). Yellow circle: Tumark® U-shaped clip
ALND is recommended for patients who remain clinically node positive after completion of neoadjuvant systemic therapy or if the clipped axillary lymph node cannot be identified and excised. It is important to emphasize that the use of dual tracer with blue dye and radiocolloid tracer is recommended in order to improve accuracy of the procedure with removal of at least 3 SLNs[73].
Management of breast cancer in the elderly
In an effort to avoid unnecessary medical tests, treatments and procedures for breast cancer patients over the age of 70, the Choosing Wisely Organization proposed two recommendations for medical providers to consider when evaluating and treating these patients.
  1. The first recommendation sought to limit unnecessary imaging by recommending the omission of screening mammography in patients with a life expectancy of less than 10 years.
  2. The second recommendation was to consider the omission of SLNB for women over 70 with clinically node-negative hormone receptor positive breast cancer. This recommendation was based on the results of the CALGB-9343 trial which included early stage hormone receptor-positive breast cancer patients >70 years old[71].
Within this study population, 62% of patients did not undergo axillary staging yet survival was unaffected and only 3% developed axillary recurrence. This trial also demonstrated no difference in distant metastases or overall survival in patients who received RT plus tamoxifen or tamoxifen alone after BCS, leading to the American College of Surgeons (ACS) recommendation to omit RT for older women undergoing BCS with clinical stage I (T1N0M0) hormone receptor-positive breast cancer[74].
Primary endocrine therapy can be considered for elderly patients with early-stage, hormone receptor-positive disease and a short life expectancy. When primary endocrine therapy involves aromatase inhibitors, the median time to progression is approximately 5 years and therefore the benefit of primary endocrine therapy, compared to upfront surgery, is most pronounced if a patient’s life expectancy is less than 5 years[75-77].
Management of breast cancer in pregnancy
Pregnancy-associated breast cancer (PABC) is defined as breast cancer occurring during pregnancy or within 1 year postpartum. Surgery, including radioisotope-based sentinel lymph node biopsies, can be performed throughout pregnancy and chemotherapy can be administered following the first trimester, but radiation therapy, blue dye, hormonal therapy and anti-Her2 therapy must be avoided while the patient is still pregnant.
Because radiation therapy must be avoided during pregnancy, the preferred surgical treatment during the first and second trimester is a mastectomy, but BCS can be considered during the third trimester if the patient is able to undergo XRT soon after delivery. The multidisciplinary management of PABC should include the breast oncology team as well as obstetrics and perinatal medicine specialists[78].

Summary

The management of early-stage breast cancer is an evolving field. Ongoing trials will continue to direct and personalize the multidisciplinary management of these patients in an effort to maximize oncologic outcomes and minimize morbidity.

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