Extent of Primary Breast Cancer Surgery: Standards and Individualized Concepts

Abstract

Surgery is still a main therapeutic option in breast cancer treatment. Nowadays, methods of resection and reconstruction vary according to different tumors and patients. This review presents and discusses standards of care and arising questions on how radical primary breast cancer surgery should be according to different clinical situations. In most early breast cancer patients, breast conservation is the method of choice. The discussion on resection margins is still controversial as different studies show conflicting results. Modified radical mastectomy is the standard in locally advanced breast cancer patients, although there are different promising approaches to spare skin or even the nipple-areola complex. A sentinel node biopsy is the standard of care in clinically node-negative invasive breast cancer patients, whereas the significance of axillary lymphonodectomy seems to be questioned through a number of different findings. Although there are interesting findings to modify surgical approaches in very young or elderly breast cancer patients, it will always be an individualized approach if we do not adhere to current guidelines. Up to date, there are no special surgical procedures in BRCA mutation carriers or patients of high-risk families.

Introduction

Breast cancer surgery is still a main therapeutic option in breast cancer treatment. Meanwhile, methods of resection and reconstruction vary according to different tumors and patients. The goals of breast cancer surgery in combination with all other treatment efforts remain the same: amelioration of (disease-free) survival and quality of life. In line with efforts to individualize systemic treatment, one even might discuss individual surgical approaches in specific situations. Do we need to perform or especially recommend to the patient the same surgical procedures regardless of age, medical history, family history, or tumor biology? Surgeons and patients might be interested in individualized surgical concepts.

This review will present and discuss standards of care and arising questions on how radical primary breast cancer surgery should be according to different clinical/patient situations.

Review of the Literature and Discussion

Early Breast Cancer

During the last century, breast cancer surgery has become less radical, starting with radical mastectomy [1] through modified radical mastectomy (MRM) to breast-conserving surgery (BCS) [2]. BCS with subsequent radiotherapy has proven to be equivalent to MRM alone with respect to survival [3, 4]. Since then, we may therefore conclude that BCS is the standard of care for patients with early breast cancer – in cases where it is technically feasible.

The aim of tumor-free resection margins (R0) has to be achieved [5, 6] because margin status is an important risk factor for local recurrence [7, 8, 9, 10]. The optimal margin width is unclear up to now [7, 11, 12]. With respect to local recurrences, margins > 1 mm seem not necessarily to be more secure than margins of 1 mm in invasive tumors [13, 14, 15, 16]. Even clear margins do not guarantee complete excision, because positive reexcisions are even found in 21% of cases with initially negative margins [17]. In invasive cancers with extensive intraductal component (EIC), there are also studies proposing a safety distance of ≥ 5 mm [18]. On the other hand, we may adapt these aims according to topographic circumstances; e.g., when performing segmental resection up to the pectoralis fascia, margins may be less in direction to the pectoralis fascia and in relation to neighboring skin [19]. With respect to resection margins in ductal carcinoma in situ (DCIS) only cases, there is a consensus that 2 mm should be achieved [19, 20] if a radiation therapy will be applied. A recent meta-analysis even favors more radical resection margins [21] on the basis of less long-term local recurrences, even in cases with radiation therapy. In summary, the current guidelines propose a margin width of 1 mm in invasive cancers (regardless of an accompanying in situ component) and 2 mm in DCIS only cancers [22].

Locally Advanced Breast Cancer

In locally advanced breast cancer – meaning large tumors (absolute and relative to breast size), tumors infiltrating the pectoralis muscle or even the thoracic wall (intercostal muscles), and skin involvement – one may consider more radical approaches. Standard of care is the MRM [23, 24]. There are no randomized controlled trials comparing MRM with skin-sparing or even nipple-sparing approaches. Nevertheless, these techniques may be applied in selected situations and will probably not impair the oncological security [25]. It is difficult to properly define these selected situations because different studies reported on different surgical techniques (‘subcutaneous’ mastectomy with more subcutaneous tissue left behind the skin, skin-sparing or even nipple-sparing with or without intraoperative radiation, etc.). A rational approach might be to at least adhere to minimal resection margins as stated above (1 mm invasive, 2 mm DCIS).

Primary systemic treatment should be considered in locally advanced breast cancer. Even in these situations, complete tumor resection (i.e. tumor-free resection margins) is necessary. In the majority of cases, mastectomy is needed. For appropriately selected patients whose tumors show adequate downstaging after primary chemotherapy, breast preservation appears to be feasible and oncologically secure [26, 27, 28, 29, 30].

There is little information on inflammatory breast cancer (IBC) alone. It is defined as clinical signs of affected skin of > 1/3 of the breast involved (previous definition > 2/3 of the breast) [31]. Most retrospective analyses focus on T4 carcinomas without separating T4d cancers. IBC might be a distinct biological entity. Prospective randomized trials for the diagnosis and treatment of patients suffering from IBC are still missing.

Management of Axillary Lymph Nodes

One aspect of the surgical approach in patients with invasive breast cancer is determination of the histological lymph node status (pN). Nowadays, this is mainly reached by removing the sentinel node(s) [32, 33, 34]. In invasive breast cancer, sentinel lymph node biopsy (SNB) is the standard of care in patients without clinical or imaging signs of nodal involvement [35, 36]. SNB is equal to dissection of the whole axilla concerning all oncological outcome measures (beginning with local control to overall survival (OS)), but morbidity is reduced significantly by performance of SNB [34, 37, 38, 39, 40, 41, 42]. Contraindications are clinical suspicion of advanced lymph node involvement and positive lymph nodes, as well as after neoadjuvant chemotherapy, particularly if lymph nodes are suspicious before chemotherapy [32, 33]. In case of neoadjuvant chemotherapy, the results of the SENTINA trial will perhaps change the clinical practice [43]. SNB can also be performed to reliably predict the nodal status in multicentric carcinomas, shown by functional studies of the patterns of lymph drainage and initial clinical data; however, empirical evidence is limited [44, 45, 46, 47].

In cases of 1 or 2 metastases in sentinel lymph nodes, it is unclear if these patients will benefit from performing a secondary axillary lymphonodectomy – provided that BCS was performed, no suspicious lymph nodes were found pre- and intraoperatively and that tangential whole breast irradiation will be applied [48]. In the referred ACOSOG Z0011 trial, no subgroup was found to benefit from a secondary lymphonodectomy; however, one has to take into account the short follow-up period and the small patient groups.

In patients with clinical nodal involvement, surgical removal of axillary lymph nodes is still indicated because the amount of positive nodes might be relevant for systemic and radiation therapy decisions. There might also be minimally better local control of complete axillary dissection compared with radiation alone. In some special cases, only radiotherapy may be performed, e.g., if there is no information needed for the decision on systemic therapy or if the patient is very old [49, 50, 51]. In patients with tumors with microinvasion or very old patients, one may consider giving up all axillary intervention [49, 52, 53]. In case of distant metastasis, axillary staging is not reasonable.

An axillary dissection in DCIS patients should not be applied; even an SNB should only be performed in mastectomy procedures or tumor resection near the axilla. In these cases, a secondary sentinel node biopsy is not technically feasible [36, 54]. In cases in which tumor invasion is assumed, an SNB may be performed [55, 56] to avoid a secondary surgical procedure.

Breast Cancer in Young Patients

Young age (mostly defined as age at first diagnosis ≤ 35 years) seems to be an independent risk factor for local recurrence and even OS [8, 10, 16, 57, 58, 59], even if the latter (effect of age on breast cancer survival) is still a matter of controversy. When adjusting for all prognostic variables, age was not significantly related to mortality from breast cancer with a hazard ratio (HR) of 0.8 (95% confidence interval (CI): 0.3–2.0) for very young and 1.1 (95% CI: 0.8–1.4) for young patients compared to older women [60]. Nevertheless large-scale genomic analyses propose that breast cancer in young women might be a unique biologic entity driven by unifying oncogenic signaling pathways and characterized by less hormone sensitivity and higher HER2 expression [61]. Young breast cancer patients are more likely to experience ipsilateral breast tumor recurrence (IBTR) after BCS. This difference is seen mainly among women with HER2 subtype. Based on these findings, more aggressive efforts to achieve local and systemic control might be considered for young women with HER2-subtype breast cancer [62].

Breast Cancer in Elderly Patients

In aging societies, breast cancer in older patients is an important topic. Recently, the International Society of Geriatric Oncology (SIOG) and the European Society of Breast Cancer Specialists (EUSOMA) updated their recommendations on screening, primary endocrine therapy, surgery, radiotherapy, neoadjuvant and adjuvant systemic therapy, and metastatic breast cancer in elderly patients [63]. In different studies, age has been described as an independent risk factor for non-receipt of effective cancer therapies, even when comorbidity and risk of recurrence are taken into account. After adjustment for comorbidity score, race, marital status, educational status, clinical stage, and tumor characteristics, increasing patient age was independently associated with decreased guideline concordance for definitive surgery, adjuvant chemotherapy, and adjuvant hormonal therapy [64]. The findings of the NORA (National Oncological Research observatory on Adjuvant therapy in breast cancer) study that indicate that age is significantly related to later diagnosis and different, less efficient patterns of treatment may help to change attitudes that currently exclude a significant proportion of breast cancer patients from secondary prevention policies, more active treatment strategies, and clinical research trials based on age [65].

Information regarding treatment effectiveness in this age group and tools that allow physicians and patients to estimate the benefits versus the risks of therapies, taking into account age and comorbidity burden, are critically needed [66]. Treatments need to be adapted to the patient's health status, but should also offer the best chance of cure [67].

Nonetheless, some data suggest adapted approaches in elderly breast cancer patients:

Some years ago a Cochrane review on the topic ‘surgery and endocrine therapy in older women’ was published. The published literature comparing surgery, with or without adjuvant endocrine therapy, with endocrine therapy alone in older women with operable breast cancer was systematically reviewed. When surgery alone was compared to endocrine therapy alone, there was no significant difference in OS (HR 0.98, 95% CI 0.74–1.30, p = 0.9), but a significant difference was found in progression-free survival (PFS) (HR 0.55, 95% CI 0.39–0.77, p = 0.0006). When surgery with adjuvant endocrine therapy was compared to endocrine therapy alone, there was no significant difference in OS (HR 0.86, 95% CI 0.73–1.00, p = 0.06), but a significant difference was found in PFS (HR 0.65, 95% CI 0.53–0.81, p = 0.0001) for surgery plus endocrine therapy versus primary endocrine. Primary endocrine therapy with tamoxifen has been associated with inferior local disease control but non-inferior survival to surgery for breast cancer in older women [68].

With respect to older patients, the current data increasingly suggest that operation of the axilla could be avoided in cases of small tumors and a clinically negative axilla [69]. Martelli et al. [69] presented the update of a study including 671 patients ≥ 70 years (172 with axillary dissection and 499 patients without an operation of the axilla) at a median follow-up time interval of 15 years. There was no significant difference in mortality within this group in the case of pT1 cN0 disease (10.7% vs. 10.7%, p = 0.836). Another study concluded that avoiding axillary clearance for women ≥ 60 years who have clinically node-negative disease and receive tamoxifen for endocrine-responsive disease yields similar efficacy, with better early quality of life [53].

Breast Cancer in BRCA Mutation Carriers or Family History of Breast Cancers

In about 5–10% of breast cancer patients, we assume a genetic disposition; woman with germ-line mutations in BRCA1 or BRCA2 have a lifetime risk of 50–80% of developing breast cancer, a 30–40% risk of cancer in the contralateral breast after breast cancer, and a 10–40% risk of developing ovarian carcinoma [70, 71, 72, 73, 74]. Up to date, there is no special therapeutical recommendation for these cases of obvious family history; therapy therefore follows guidelines for sporadic breast cancer. Nevertheless, prophylactic mastectomy of the second breast can be considered to reduce the risk of second contralateral carcinoma, but there seems to be no benefit with respect to improved OS [74, 75, 76].

Also bilateral oophorectomy can be performed to reduce the risk of a second carcinoma of ovaries and breast, but there is also no evidence for advantage in terms of survival [72]. On the other hand, there is some evidence in women with stage I or II carcinoma of the breast that a survival advantage might be possible through the reduced incidence of ovarian carcinoma after bilateral oophorectomy [77].

Incidence of metachronic ipsilateral breast cancer recurrence does not seem to be higher, so breast-conserving therapy is an adequate procedure if the woman does not want mastectomy [73]. Some studies have shown a lowered incidence and mortality of BRCA-associated cancers if prophylactic bilateral mastectomy was done [75, 76], but probably without effects on OS [78].

‘Targeted’ Breast Cancer Surgery

As already implied above, there are some ideas to further individualize breast cancer surgery according to patient- and tumor-related factors. Unfortunately, there is still a gap between explorative, hypothesis-generating studies and confirmative trials to justify or falsify these approaches. Well-designed and conducted surgical trials are necessary.

Conclusions

Breast cancer surgery is still a main therapeutic option in breast cancer treatment. Meanwhile, methods of resection and reconstruction vary according to different tumors and patients.

In most early breast cancer patients, breast conservation is the method of choice. The discussion on resection margins is still controversial and the results of many studies show conflicting results. MRM is the standard in locally advanced breast cancer patients, although there are different promising approaches to spare skin or even the areola, or even the whole nipple-areola complex. A sentinel node biopsy is the standard of care in clinically node-negative invasive breast cancer patients, whereas the significance of axillary lymphonodectomy seems to be questioned through a number of different findings. Although there are interesting findings to modify surgical approaches in very young or elderly breast cancer patients, it will always be an individualized approach if we do not adhere to current guidelines. Up to date, there are no special surgical procedures in BRCA mutation carriers or patients of high-risk families because the performed surgeries (mastectomy instead of breast conservation, contralateral prophylactic mastectomy, and bilateral salpingoovarectomy) improve local control but probably not OS.

Disclosure Statement

The authors declare no conflict of interest.