ACHAIKI IATRIKI | 2022; 41(2): 79–85
Review
Ioannis Chaveles
Patras Centre for Breast Care, Patras, Greece
Received: 30 Jan 2022; Accepted: 21 Feb 2022
Corresponding author: Ioannis Chaveles MD, PhD, Oncoplastic Breast Surgeon, Patras Centre for Breast Care, Satovriandou 63-65, 26225, Patras, Greece, Tel.: +30 2610 279239, +30 6974 817140, E-mail: frontidamastou@gmail.com
Key words: Early-stage breast cancer, breast cancer surgery, breast cancer management, SLNB, oncoplastic surgery, neoadjuvant chemotherapy
Abstract
The management of breast cancer patients is multidisciplinary and requires the combined strengths of modern surgery, radiation therapy and oncological systemic treatments to yield the current excellent results. From initial diagnosis to long-term follow-up, new evidence continuously adds to our understanding regarding optimal treatment. As such, there is no “one size fits all” type of recommendation for the various types of breast cancer. In this review, the most recent guidelines are presented from the breast surgeon’s point of view and the most significant new data anticipated are mentioned. With the vast majority of women surviving breast cancer, communication with patients and taking into account their wishes regarding their treatment is of paramount importance in modern practice.
INTRODUCTION
Breast cancer is by far the most common form of cancer among women. However, despite its high incidence, implementation of rigorous screening programs, increased awareness and improved diagnosis and treatment have contributed to significant reduction in breast cancer (BC) mortality rates. Increased survivability indicates that extra care should be taken by clinicians to ensure BC survivors’ quality of life. Patients are more knowledgeable nowadays and clinician needs to be able to communicate facts and include them in the decision-making process.
Modern treatment is multidisciplinary and multimodal, including surgery, radiotherapy and systemic treatment. The goal is to determine the optimal combination of the aforementioned interventions which will offer oncological safety while de-escalating treatment and caring for patient preference at the same time.
Diagnostic work-up in early breast cancer patients
The surgeon plays a pivotal role in the initial diagnosis and work-up of BC patients. Alongside medical history, menopausal status, clinical examination of the breasts and axillae, the surgeon has to request radiological assessment of the primary tumor including mammography, ultrasound of the breast and lymph nodes, as well as magnetic resonance imaging (MRI) of the breast in selected cases. MRI indications include family history of BC or known genetic mutations, lobular BC, extremely dense breasts, large discrepancy between clinical examination and imaging, presence of implants, suspicion of multifocal or multicentral disease, occult primary tumor, need for neoadjuvant chemotherapy (NAC) [1,2]. Tissue samples for complete histological assessment need to be taken, in the form of core biopsies for the primary tumor and core biopsy or fine needle aspiration biopsy for any suspicious nodes. Assessment of metastatic disease with whole body computed tomography imaging, bone scintigram and blood tumor markers measurement is reserved for patients with suspicious symptoms, high disease burden and aggressive tumor biology on the biopsy. Genetic testing should be offered to high-risk patients such as those with a strong family history and BC diagnosis before the age of 50 [1].
Breast surgery in early-stage breast cancer
Breast conservation versus mastectomy
Both mastectomy and breast conserving surgery (BCS) combined with radiotherapy (RT) have been shown to be oncologically safe and bearing comparable results in multiple randomized clinical trials with a patient follow-up of up to 20 years. Local recurrence (LR) seems to vary predominantly according with tumor subtype and systemic therapy, rather than disease burden and type of surgery (BCS or mastectomy), thus, biologically aggressive cancers need not to be treated more aggressively from a surgical point of view [2]. The selection between BCS or mastectomy depends on tumor size compared to the size of the breast, anticipated aesthetic results, availability of oncoplastic techniques, patient’s candidacy for RT, and, ultimately, patient’s choice [1-4].
Oncoplastic breast conserving surgery
The blending of traditional breast oncologic surgery via wide local excision (WLE) and plastic surgery techniques, called oncoplastic BCS are increasingly being used by specially trained breast surgeons or teams of breast and plastic surgeons. These techniques have made possible BCS in the case of large tumors otherwise warranting mastectomy. Despite the additional disease burden in these patients, in a recent meta-analysis of all major relevant studies oncoplastic BCS has been proved safe in the setting of oncology when compared to both ‘traditional’ WLE and mastectomy [1,5].
Resection margins
In the excision of invasive disease, the “no-tumor on ink” guideline is universally accepted, regardless of patient characteristics, tumor histology or surgical technique employed [1,3,6]. For ductal carcinoma in situ (DCIS) a minimum clear margin of 2 mm is required, with wider margins not reducing the risk of LR [1,6,7]. When striving to achieve negative margins at the initial operation and reduce the reoperation rate for re-excisions, oncoplastic BCS has proven valuable, allowing for larger tissue resection volumes without compromising the cosmetic outcomes [1,6].
Mastectomy with or without reconstruction
For patients having to undergo mastectomy, the operation of choice is no longer straightforward, as nowadays there is a wide range of reconstructive techniques available. Beyond simple mastectomy, skin and/or nipple areola complex sparing mastectomy is employed, in the immediate or delayed setting, as well as autologous or not techniques, all with comparable oncologic safety and a significant advantage for quality of life [2,6]. The choice among the above operations is made after careful consideration of patient’s expectations, her general health and potential comorbidities, tumor location, availability of genetic screening, pursuit of risk reducing surgery and overall cost of the procedure(-s). More specifically, nipple sparing operations require tumor to nipple distance of at least 1cm, detailed review of the imaging for retroareolar intraductal calcifications and intraoperative frozen section pathology of retroareolar biopsy to ensure major duct integrity [2,6].
Contralateral Prophylactic Mastectomy
It has been shown that women with unilateral sporadic BC do not gain significant oncological benefit when undergoing contralateral prophylactic mastectomy (CPM), apart from a marked decrease in the incidence of future contralateral BC (96%). However, the absolute benefit remains very low, given that for every 1000 women treated with CPM, only 2-3 CBCs will be avoided. Among women without a family history or genetic predisposition, factors that favor CPM are young age, white race, higher education and economic status/private security. What fuels the rise in CPM is the more widespread availability of skin/nipple-sparing mastectomy (SNSM) with immediate reconstruction. Indeed, women having bilateral simultaneous SNSMs will end up with increased symmetry and breast satisfaction. However, there is a cost in the form of a 2.7-fold increase in major surgical complications following CPM. These could lead to delays in the onset of adjuvant chemotherapy, which is of great importance especially for high-risk patients. The increased financial burden associated with CPM and its potential complications is of note and should be taken into account. Surgeons need to be prepared for a comprehensive and unbiased conversation with patients interested in CPM [8].
Postmastectomy radiotherapy
Postmastectomy radiotherapy (PMRT) for early-stage breast cancer is a quite controversial issue, as LR rates have decreased due to more comprehensive modern systemic treatment. The decision to proceed with PMRT should be multidisciplinary, taking into account various factors determining the risk of recurrence (age, life expectancy and disease burden in both the breast and the axilla [2,9]. PMRT is especially critical as it poses a very significant threat to implant-based reconstruction (IBR), especially immediate IBR. The radiation of the reconstructed breast causes increased infection rates, implant loss and severe capsular contracture leading to reconstructive failure. Even when trying to address this problem with two-stage reconstruction with expander, reconstructive failure remains higher [6,10].
Axillary surgery in early-stage breast cancer
Sentinel lymph node biopsy
Axillary surgery for breast cancer plays a dual role, both therapeutic, as well as staging and prognostic. Initially axillary lymph node dissection (ALND) regardless of disease burden has been the norm. However, ALND comes with significant morbidity, such as arm lymphedema, sensory nerve damage and paresthesia, restriction of arm mobility and weakness, seroma formation and, rarely, chyle leak [6,11]. With an increasing understanding of tumor biology and the availability of constantly improving adjuvant treatments, it became clear that de-escalation was needed for patients without obvious lymph node involvement. Hence, in the 1990s multiple randomized clinical trials compared ALND to sentinel lymph node biopsy (SLNB)-only for node negative patients. SLNB has been the standard of care ever since its validation [1,3,6,11,12].
DCIS and SLNB
Currently, SLNB in patients with DCIS is not routinely performed in all patients. Women with DCIS undergoing mastectomy are offered SLNB because in case of upgrade to invasive disease the sentinel nodes will not be detectable following mastectomy. Other patients at high risk of pathological upgrade such as clinical presence of mass lesion or area of DCIS of >5cm, may be offered SLNB [11].
Omission of ALND in low axillary disease burden
In 2013, ALND was shown not to provide any advantage in patients with micrometastatic disease in the SLNB (one or more foci of <2mm), as there was no impact on survival [13-15].
The 2010s saw a further significant de-escalation of axillary surgery, in patients with limited macrometastatic disease. The 2011 American College of Surgeons Oncology Group (ACOSOG) Z0011 trial [16] and the 2014 European multicenter AMAROS trial [17] demonstrated that clinically node negative patients with limited positivity in the sentinel lymph nodes (1-2 positive SLNs) have similar axillary disease control whether being spared ALND or not. Radiotherapy and systemic treatment will still be applied appropriately. The ACOSOG Z0011 trial reports good outcome results even without radiotherapy to the axilla, consequently criteria have been proposed for the recommendation of radiotherapy: (1) tumor size ≥3 cm; (2) lymphovascular invasion at tumor pathology; (3) SLNs with extracapsular extension of the metastasis [11,18].
Breast surgery after neoadjuvant chemotherapy (NAC) in early-stage breast cancer
NAC has been the standard of care for locally advanced, inflammatory and metastatic breast cancers. It has been used to render inoperable tumors rejectable. More recently NAC has been used with the intent to downstage large tumors so that BCS becomes feasible [2,3]. However, nowadays NAC is being increasingly used in the setting of early-stage breast cancer, being suggested by the St. Gallen International Consensus Guidelines for the treatment of early breast cancer 2021 for stage II and III HER2-positive disease and triple negative breast cancers (TNBCs) [3]. Pathological complete response (pCR) is an excellent prognostic factor with a significant impact on overall survival (OS) and recurrence-free survival, especially in biologically more aggressive subtypes of BC.
Breast Conserving Surgery post-NAC
BCS post-NAC can be performed whether there is a radiological complete response (rCR) or residual disease, as long as it is technically possible. BCS in the setting of oncology is safe, with comparable LR rates disease free survival (DFS) and OS to patients treated with mastectomy [6,19].
Breast Imaging post-NAC
Breast MRI is required both before the onset of NAC, as well as upon completion preoperatively [2,6] and is the major determinant of rCR and the extent of excision during the operation [20].
Moreover, localization of the tumor bed is imperative for BCS post-NAC, usually by means of radiopaque clips inserted after diagnosis and subsequent wire localization before surgery [21].
Axillary surgery after NAC in early-stage breast cancer
The management of the axilla after NAC is an area of actively ongoing research. Some cases are uncontroversial: Patients with clinically positive axillary nodes post-NAC will undergo ALND. Also, patients downstaged to node-negative by the NAC are candidates for SLNB and in the case of significant positivity in the pathology, ALND is performed [2,3,6,11]. However, there was a concern that false negative rates (FNR) could be too high for post-NAC SLNB to offer a satisfactory result. This has been addressed in a few major studies: ACOSOG Z1071 (22), SENTINA (23) and SN FNAC [24] which highlight the importance of excision of at least 3 lymph nodes for the FNR to be kept below the acceptable 10% [2,3,6,11]. Another concern was whether the known positive node was actually sampled during the SLNB. This issue was addressed in the ACOSOG Z1071 [22,25] with the use of tailored axillary surgery (TAD). With this technique the proven positive node is marked and removed specifically, with a further reduction of FNR at 6.8%.
Controversy remains as to whether clinically negative patients with residual low burden disease in the SLNB can be spared ALND in favor of axillary radiotherapy, as per the Z0011 patients at upfront surgery. This is being addressed in the Alliance A011202 trial, expected to end in 2024.
Special considerations
BC management in the young patient
Young women under the age of 40 constitute a special subset of patients due to the following reasons: Formal breast cancer screening will not have started at this age; thus, they will usually present with palpable disease, i.e., higher stage of disease than the screen-detected older counterparts. In addition, it is more likely that women in this age group will suffer from more aggressive BC subtypes, such as TNBC, higher grade or HER2+ disease. As such, even young women at high risk for BC who are indeed under surveillance, will routinely present with interval cancers [26].
Genetic predisposition is another major issue within this age group, regardless of the presence of positive family history. It is believed that every BC patient under the age of 45 years should undergo genetic testing for BRCA1, BRCA2, PALB2, ATM, p53 and CHEK 2 genes. Ideally the testing needs to be completed prior to the surgical treatment, as the results may influence the surgical plan by dictating the need for a risk reducing operation [26]. BC patients under 40 years of age have been shown to have increased local recurrence rates, however this does not impact overall survival. As a consequence, in the absence of genetic predisposition, breast surgery principles in young women are identical to their older counterparts [26].
Of note is the assessment of the patients’ wishes for a future pregnancy, as fertility preservation may be required. This may be in the form of gonadotropin-releasing hormone agonist administration for ovarian protection during pregnancy or may include embryo and/or oocyte preservation [2].
Breast cancer during pregnancy
One of the most challenging forms of BC is BC during pregnancy. Its current incidence is one case every 1000 pregnancies; however, this is expected to rise due to the social trend of increasing age at first pregnancy. In terms of BC biology, TNBC and HER2+ types seem to be dominant and a higher presence of tumor-infiltrating lymphocytes (TILs) is noted. The worse prognosis associated with BC in pregnancy can be attributed to late/delayed diagnosis, inability of optimal staging and the possibility of suboptimal treatment if an expert multidisciplinary team is not involved. Surgical treatment is considered safe to be applied for the whole duration of the pregnancy. The limiting factor for operation choice is the absolute contraindication of radiotherapy during pregnancy, the delay of which will lead to increased rates of LR after breast conserving surgery. As a consequence, there is a bias towards performing a mastectomy, especially if the operation takes place at the initial stages of the pregnancy. In this case, performing immediate reconstruction with a tissue expander is not contraindicated. Axillary surgery in pregnant women is a point of controversy. ALND is routinely performed, however recent studies have shown that SLNB can be offered utilizing Technetium-99m by the one-day protocol only. In these cases, the identification rate is high and is not accompanied by increased axillary LR rates [27].
Neo-adjuvant Endocrine Treatment (NET)
A less common modality for neo-adjuvant treatment is endocrine treatment alone. It is used as a tool to preoperatively downstage ER+/HER2- disease with treatment duration of 4-6 months, as well as to maintain oncologic safety when surgery needs to be delayed (e.g., COVID-19-induced delays). A recent meta-analysis of available data shows that when paired with OncotypeDX© Recurrence Score (RS) assessment on the diagnostic core tissue biopsy samples, NET can yield satisfactory results. Patients with low (<18) or intermediate (18-30) RS were found to be four times more likely to respond than high risk patients and this cohort of patients will simultaneously be spared overtreatment in the form of NAC. Nonetheless, it should be noted that pCR is rarely achieved in the settings of NET (2.8%) [28].
Multifocal or multicentric breast cancer
Multifocal or multicentric (MF/MC) presents a surgical challenge and the implementation of BCT remains a point of controversy, especially in the case of MC disease. Further complicating treatment decisions, rarely, MF/MC presents with heterogeneous histology for different foci. The main concern is local recurrence (LR) after BCT. A recent meta-analysis showed that while LR after breast conserving surgery (BCS) for MF/MC BCs is higher than LR after BCS for unifocal BCs, interestingly there is no significant difference when comparing LR for MF/MC BCs treated with BCS versus mastectomy [29]. Consequently, the use of BCS for MF/MC disease has to be considered an equally efficacious alternative approach, as far as a pleasing cosmetic outcome can be achieved given disease size, patient characteristics and surgeon’s oncoplastic expertise [30].
Inflammatory breast cancer
Inflammatory breast cancer (IBC) is a distinct subtype of BC characterized by rapid progression and early occurrence of distant disease. Notoriously difficult to treat in the past, 5-year overall survival rates still remain less than 71%, with triple negative variants being as low as 44%. The diagnosis of IBC will be based upon core biopsy tissue samples from the main tumor (when present) or skin punch biopsy samples showing dermal lymphatic invasion. Surgeons need to be aware that 25% of punch biopsies will miss the dermal cancer and only show lymphedema. This leaves the rapidity of symptoms onset (<6 months) as the main diagnostic criterion. Use of MRI and PET/CT are optimal for local and systemic staging. The mainstay of IBC treatment is the tri-modality approach: Preoperative systemic treatment, surgery and post-operative radiotherapy. During systemic treatment clinicians need to re-examine the patient for the detection of disease progression despite treatment. Surgery for IBC usually comes in the form of mastectomy including previously involved skin and ALND of levels 1 and 2. If primary closure cannot be achieved due to the extent of skin excision, a latissimus dorsi or abdominal flap has to be considered. Breast conserving surgery and skin sparing reconstruction techniques are contraindicated. As systemic treatment evolves and cPR rates increase, less aggressive surgical approaches will have to be considered, tailored to individual patients’ needs [1,31].
Occult breast cancer
This rare occurrence of BC (<0.5% of all BCs) presents with axillary lymph node disease without an apparent primary tumor at the breast. A breast MRI needs to be performed, in search of the breast primary site, as well as a PET-CT for the exclusion of any other primary site. Surgical treatment usually comprises mastectomy and ALND, however axillary radiotherapy after SLNB with low disease burden is still a valid option and whole breast radiotherapy is a valid alternative to mastectomy. Systemic treatment is administered accordingly [1].
Surgery for locally recurrent breast cancer
Local recurrence (LR) on the chest wall after mastectomy can be excised if focal and not extending beyond the pectoralis muscles. Depending on the extent of skin involvement, local flaps may be required for skin closure. When multifocal or infiltrating the ribcage, systemic treatment and radiotherapy may be a better solution. LR after BCS is usually treated with completion mastectomy, since radiotherapy to the breast cannot be repeated when initially performed. However, small recurrent tumors <2 cm with a long time to relapse from initial surgery (>48 months) have been treated with redo BCS successfully. Lastly, redo BCS should not be considered in high-risk patients such as carriers of genetic mutations. LR in the axilla after SLNB warrants ALND of levels 1 and 2. LR after ALND is treated with axillary exploration for removal of the disease [32].
Male breast cancer
Approximately only 1% of breast cancers occur in men, so, unsurprisingly, research is focused on female BC. Men are often diagnosed at a later stage, with almost half presenting with locally advanced or distant disease. From the point of view of surgery, it is very common for male patients to undergo mastectomy (due to nipple or skin involvement) and SLNB (or ALND when obvious disease is present in the axilla). BCS is seldom used and, in these cases, it usually applies to T1 disease. Surgery is followed by radiotherapy to the chest wall and axilla as appropriate. Most BCs in men express ER, PR and AR receptors, so endocrine treatment is used. Tamoxifen is the treatment of choice, as aromatase inhibitors can cause an unwanted increase in androgens, but significant side effects impacting quality of life, such as hot flushes and lowered sex drive, lead to a quarter (25%) of patients discontinuing their treatment [33].
CONCLUSIONS
We live in the era of de-escalation and personalization of breast cancer treatment. Significant advances are in the works. TAD is being assessed as a completely personalized and least invasive means of axillary surgery [34]. Elimination of surgery after pCR is a sensible goal, however much remains to be addressed regarding adequacy of tissue sampling, minimizing FNRs and optimal patient follow-up [35]. From the point of view of breast surgery, oncoplastic techniques are essential, as are reconstruction techniques that are continuously requested by women today [36]. These requirements highlight the need for highly specialized and qualified breast surgeons alongside all other members of the multidisciplinary team, always cognizant of the latest advances in this everchanging field.
Conflict of interest disclosure
None to declare.
Declaration of funding sources
None to declare.
Author contributions
Ioannis Chaveles is the sole author of this work.
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