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SEOM clinical guidelines in early stage breast cancer (2018)

Breast cancer is the most common cancer in women in our country and it is usually diagnosed in the early and potentially curable stages. Nevertheless, around 20–30% of patients will relapse despite appropriate locoregional and systemic therapies. A better knowledge of this disease is improving our ability to select the most appropriate therapy for each patient with a recent diagnosis of an early stage breast cancer, minimizing unnecessary toxicities and improving long-term efficacy.


Introduction
Breast cancer is a major public health problem due to its high incidence, prevalence, and mortality. It is by far the most common cancer among women in Spain (2012), accounting for 29% of all new cases of cancer in females. Moreover, it is the first cause of cancer-related mortality in the female population, accounting for 15.5% of female cancer deaths, and the 5-year prevalence is 40.8% [1].
Breast cancer is a heterogeneous disease with multiple intrinsic tumor subtypes [2]. Up to one in three patients will develop metastases depending on lymph node involvement and breast cancer subtype, despite remarkable progress in early diagnosis and treatment. A better understanding of prognostic and predictive factors is allowing individualization of treatment for early stage breast cancer patients. The aim of these guidelines is to summarize current evidence and to give evidence-based recommendations for clinical practice [3].

Methodology
These SEOM Guidelines have been developed with the consensus of ten breast cancer medical oncologists from the cooperative groups GEICAM (Spanish Breast Cancer Research Group) and SOLTI (Spanish Collaborative Group for the Study, Treatment and Other Experimental Strategies in Solid Tumors). To assign a level of evidence and a grade of recommendation to the different statements of this treatment guideline, it was decided to use the Infectious Diseases Society of America-US Public Health Service Grading System for Ranking Recommendations in Clinical Guidelines to determine the quality of evidence and strength of recommendation in each of the consensus recommendations (Table 1). A full list of recommendations is provided in Table 2.

Diagnosis and initial workup
The following tests allow a correct diagnosis and prognosis approach to all patients in whom the presence of a breast tumor is suspected.
-Bilateral mammography and ultrasound of the breast and regional lymph nodes [I, A] [4]. Several new techniques such as 3D mammography or 3D ultrasound can increase diagnostic accuracy but are not routinely implemented. -Core needle biopsy (preferably by ultrasound or stereotactic guidance). The study has to include the evaluation of the estrogen and progesterone receptor and HER2 gene expression [I, A]. Given the high inter-observer variability in the Ki-67 determination, it is important to be careful when using Ki67 to inform the decision-making process [5]. Fine needle aspiration or core biopsy of suspicious lymph nodes is recommended [II, A]. -MRI: is the most sensitive method for breast cancer staging but additional findings must be confirmed histologically due to the high false-positivity rate. Its use is not mandatory [I, B] and should be considered in cases of positive axillary nodes and occult primary breast cancer,  Nodal (supra-and infra-clavicular) irradiation is recommended in patients with one to three involved nodes after breastconserving surgery I, B In cN0 patients with pT1-2 tumors and positive SLNB, axillary irradiation may be used as an alternative to ALND I, B Chest wall and regional node (supraclavicular and internal mammary) irradiation should be administered in patients with four or more involved nodes, T4 or T3N+ tumors after mastectomy Chest wall irradiation is recommended in patients with close or positive margins after mastectomy II, A Post-mastectomy irradiation should be considered in patients with T1-2 tumors and one to three involved nodes, or in patients with T3N0 tumors, after individually balancing risk factors for recurrence and patient preferences I, B Adjuvant radiotherapy is recommended after NAC in patients with stage III and T3N0 disease, regardless of response to NAC, and in patients with node-positive disease after NACT   When disease is detected in stage III or when signs or symptoms or laboratory values suggest suspected metastasis, a more extensive study with thoracic CT, abdominal CT and bone scan [III, B] should be performed. PET/CT is also recommended for initial staging in locally advanced BC (LABC) [II, A] [8].
Evaluation of cardiac function is imperative when using anthracyclines or trastuzumab [I, A] [9].

Principles of surgery
Breast-conserving surgery is equivalent to mastectomy and must be considered as first option in most cases of stages I-II (I, A) [10]. No ink on invasive tumor or DCIS is considered an adequate margin after breast-conserving surgery [I, A] [11]. Mastectomy is still indicated in the following situations: tumor multicentricity, inability to achieve negative surgical margins after multiple resections, small breast size according to tumor volume, prior radiation therapy in the breast, or other contraindications for radiotherapy.
When mastectomy is performed, contralateral mastectomy as a prophylactic procedure is not indicated in most of the patients [12]. However, for carriers of BRCA1/2 mutations, the contralateral mastectomy should be offered through an appropriate risk-benefit assessment and counseling process [I, A] [13].
Sentinel lymph node biopsy (SLNB) is recommended for assessment of the involvement of axillary lymph nodes and should be performed in patients with clinically negative axillary nodes [I, A]. In patients with clinically positive axillary nodes, pathologic confirmation must be done by ultrasonography-guided fine needle aspiration (FNA) or core biopsy. Axillary lymph node dissection (ALND) is indicated in patients with positive SLN biopsy or confirmed preoperative pathologic axillary lymph node involvement. However, in patients with stage I-II disease and less than three positive axillary nodes after SLN biopsy and lumpectomy (and adjuvant radiotherapy indicated), ALND can be avoided without significant negative impact in DFS and OS when an adequate systemic postoperative treatment is provided [I, A] [14]. SLNB may be offered in patients with operable breast cancer before or after neoadjuvant chemotherapy (NACT). In patients with cN0 axilla, additional axillary treatment is not necessary if SLNB is negative after NACT [I, A] [15]. In patients with cN+ axilla who achieved ycN0 status after NACT, the ALND is recommended as standard procedure due to the high false-negative rate of the SLNB [I, A] [16]. In selected cN+ cases, in which positive axillary node has been marked prior to NACT, the identification and recovery of > 2 SLNs (including the marked node) with a doublecontrast technique (Tc99 and methylene blue) may avoid ALND [II, C]. Despite these recommendations, benefit of RT for stage I elderly patients has not been proved and should, therefore, be assessed individually [I, A] [24]. Some low-risk patients treated with conservative surgery could be spared whole breast RT and receive partial breast radiation or intraoperative treatment, although less evidence exists to support this approach [25].

Principles of adjuvant systemic therapy
Breast cancer (BC) is a heterogeneous disease, with different subtypes having a distinct biological, molecular, and clinical outcome. Systemic adjuvant treatment is commonly used in early breast cancer with the intention to reduce the rate of locoregional or systemic relapses and death derived from the disease. Treatment decisions are based on clinical (age, comorbidities) and pathologic factors (tumor size, nodal status, grade, hormone receptor (HR) status and HER2 status). Multigenic tests provide information beyond standard clinical and pathologic prognostic factors that can help in making treatment decisions.

Oncotype DX
The test was initially validated as a prognostic biomarker in tumor samples from several prospective clinical trials (e.g., NSABP-B14 and TransATAC) [30][31][32][33][34][35]. A score cutpoint of less than 18 identified low-risk patients at 10 years that could be spared multi-agent chemotherapy, specially in node-negative disease. Less clear was the need of adjuvant chemotherapy in patients with a score of 18 to 31. TAI-LORx prospective trial in HR+/HER2−/node-negative disease reported that in the intermediate risk group, defined as 11-25, no benefit of adding chemotherapy to endocrine therapy was observed in the overall population at 9 years, although some benefit of chemotherapy was found in women ≤ 50 years of age [29]. An important point is that the vast majority of patients (74%) recruited in TAILORx were clinically low risk (i.e., 63% had tumor sizes 1-2 cm). Indeed, no clear differences in survival outcomes were observed between the intermediate groups (with or without chemotherapy) compared to the low-risk group (i.e., < 11). The RxPONDER prospective clinical trial in 1-3 positive nodes and RS < 25 will shed more light regarding the ability of OncotypeDX RS to predict chemotherapy benefit. Level of evidence: IA for the prediction of adjuvant chemotherapy benefit in patients with clinically low-risk disease and a recurrence score 11-25; IA for the prediction of the risk of distant recurrence at 9 years if treated with adjuvant endocrine therapy-only.

Prosigna
This assay classifies a tumor to one of the 4 intrinsic subtypes (Luminal A, Luminal B, HER2-enriched and basal-like) and provides a prognostic 10-year Risk of distant Recurrence (ROR) score [36], which integrates genomic data together with tumor size and nodal status (to determine the risk cutoffs). ROR has now been validated retrospectively in nodenegative and node-positive disease in tumor samples from several large adjuvant studies (i.e., TransATAC, ABCSG-08 and Danish cohort) [37][38][39][40][41]. In a recent head-to-head comparison with OncotypeDX RS and EndoPredict in 774 tumor samples from TransATAC, ROR provided a more accurate long-term prognostic information than OncotypeDX, similar to EndoPredict [41,42]. Prospective validation of the ability of Prosigna to predict adjuvant chemotherapy survival benefit is currently ongoing in large phase III trial in UK (i.e., the OPTIMA trial), in patients ≥ 40 years of age with HR+/HER2−, > 3 cm or node-positive tumors and an ROR below 60 (i.e., low/intermediate). A recent published trial showed the prognostic and predictive value of Prosigna in premenopausal high-risk breast cancer patients treated with cyclophosphamide-based adjuvant chemotherapy [43]. Level of evidence: IB for the prediction of the risk of distant recurrence at 10 years if treated with 5 years of adjuvant endocrine therapy-only; Level of evidence: IB for the prediction of late distant recurrence (years 5-10) if treated with 5 years of adjuvant endocrine therapy-only.

Mammaprint
The prognostic value of Mammaprint was first validated in 295 patients with pT1 or pT2 tumors with node-negative or node-positive disease [26,27]. Since then, other retrospective validations of its prognostic value have been reported. Recently, the primary results of the prospective prognostic validation of Mammaprint have been reported. The MIN-DACT trial was an international phase III trial designed to evaluate the 5-year distant relapse-free survival (DRFS) in 748 patients, largely HR+/HER2-negative, with a genomic low-risk score and a clinically high-risk score (defined by a modified version of AdjuvantOnline!) when treated without adjuvant chemotherapy. The study met its primary endpoint and this group of patients had a 5-year DRFS of 94.7% (92.5-96.2). However, longer follow-up is needed to determine if this group of patients continues to have an outstanding outcome after 5 years in order to spare them from adjuvant chemotherapy [44]. As a secondary underpowered analysis of the MINDACT trial, Mammaprint did not demonstrate the ability to predict chemotherapy survival benefit. Level of evidence: IA for the prediction of the risk of distant recurrence at 5 years if treated with adjuvant endocrine therapy-only.

EndoPredict
The prognostic value of EPclin has been validated retrospectively in tumors samples from 3 large phase III trials (ABCSG-6/ABCSG-8 [45] and TransATAC [46]), where patients did not receive any adjuvant chemotherapy. In addition, the assay has shown ability to predict late distant recurrence [46,47]. Level of evidence: IB for the prediction of the risk of distant recurrence at 10 years if treated with 5 years of adjuvant endocrine therapy-only. Level of evidence: IB for the prediction of late distant recurrence (years 5 to 10) if treated with 5 years of adjuvant endocrine therapy-only.

Adjuvant endocrine therapy for early stage breast cancer
There is robust evidence that endocrine therapy (ET) improves survival of early stage luminal breast cancer (BC). Adjuvant ET should be offered to any of these patients regardless of age, menopausal status, chemotherapy exposure, expression level of ER or PgR (if any or both are positive defined as ER and/or PR > 1%), and/or Her2 status [I, A]. There are several ET options. The individual choice would be adjusted to menopause status, comorbidity, and the risk of recurrence.
Tamoxifen is the most established adjuvant ET for both premenopausal and postmenopausal women as it reduces the risk of recurrence by 40% in all subgroups [48]. Two large trials (ATLAS and aTTom trial) concluded a higher benefit of continuing Tamoxifen until 10 years, which is recommended for high-risk tumors (at the cost of greater toxicity) [I, B] [49,50].
Five years of tamoxifen remain the standard treatment for premenopausal women [I, A] [51], but other alternatives should be considered. Adjuvant exemestane plus ovarian function suppression as compared with tamoxifen plus ovarian function suppression or tamoxifen alone significantly reduced the likelihood of distant recurrence in highrisk adjuvant chemotherapy-treated premenopausal breast cancer patients [I, A]. After a median follow-up of 8 years, a survival improvement favoring ovarian suppression plus tamoxifen has been shown [52]. EBCTCG and SOFT trials also support adjuvant tamoxifen plus GnRH analogs as an alternative for high-risk patients not suitable to aromatase inhibitors [II, B] [53].
Several studies explored aromatase inhibitors (AIs) as an initial therapy [54][55][56], as sequential therapy following 2-3 years of tamoxifen [55][56][57][58][59] or as extended therapy [60,61] for postmenopausal patients. Different options can be recommended: an AI for 5 years [I, A], tamoxifen for 2 to 3 years followed by an AI to complete 5 years [I, A] or during 5 years [II, B], or tamoxifen for 4.5 to 6 years followed by 2.5 to 5 years of an AI [I, A]. The recently published IDEAL trial did not find differences between 2.5 or 5 years of an AI after 5 years of any ET [62]. The option of 10 years of tamoxifen could be considered in patients with contraindication to AIs or who remain premenopausal.
There is strong evidence to consider the use of bisphosphonates (zoledronic acid 4 mg intravenously every 6 months or clodronate 1.600 mg/d orally) but not an anti-RANK-ligand antibody as additional adjuvant therapy for postmenopausal patients with breast cancer who are candidates for adjuvant systemic therapy. [I, A] [63].

Adjuvant chemotherapy in hormone receptor-positive early BC
The use of chemotherapy as adjuvant treatment for ER+ Her2-negative disease is recommended for high-risk tumors defined by either clinical or genomic profiling characteristics [I, A], considering: T2 to T4 tumors and/or axillary N2-3 involvement; extensive LVI, high KI67, low ER expression, younger age or premenopausal status; and intermediate to high genomic score. Standard anthracycline and taxane regimens are recommended [90] [I, A].

Neoadjuvant chemotherapy for luminal breast cancer
Neoadjuvant CT is indicated in LABC [I, A] to reduce the extent of surgery, to treat micrometastases promptly and to monitor the response.
All treatments recommended in the adjuvant setting may also be used in the preoperative setting. If chemotherapy is used, it should be delivered before surgery, without breaks, with the aim to increase the rate of breast-conserving surgery (pCR are infrequent in this setting). A sequential regimen of anthracyclines and taxanes is associated with increased probability of pCR and must be recommended [II, B] [64,65]. In selected cases of postmenopausal patients with ER+/Her2− disease, neoadjuvant endocrine therapy (NET) during at least 16 weeks is a good option. The available data directly comparing neoadjuvant endocrine therapy (NET) with neoadjuvant chemotherapy are very limited. Some phase II trials and one meta-analysis showed similar response rates, but a significantly lower toxicity with NET [66]. AIs are better to tamoxifen as NET [I, A] [67]. The efficacy evaluation of NET has been performed according to surrogate parameters such as the decrease of the Ki67 levels or the preoperative endocrine prognostic index (PEPI) score [68]. Neoadjuvant ET in premenopausal patients is debatable; an AI with ovarian suppression or tamoxifen could be considered in selected cases in which chemotherapy is not an option [II, D].
In the neoadjuvant setting, chemotherapy is an accepted treatment for tumors with node metastases and for tumors greater than 2 cm who are candidates to mastectomy. We use clinical and pathologic parameters (HR status, grade, Ki-67) to select patients for neoadjuvant chemotherapy (NCT), though there is no agreement about the cutoff point of Ki-67 and about the accuracy of this marker to predict chemotherapy response. Different genetic signatures have been evaluated in core needle biopsy before neoadjuvant therapy, as good predictors of response to neoadjuvant therapy, especially PAM50 ROR score [69], although this approach is currently considered experimental.

Systemic treatment for early stage her2-positive breast cancer
Adjuvant treatment for HER2-positive disease [70][71][72][73][74][75][76][77] The addition of trastuzumab to chemotherapy has dramatically improved prognosis for early stage HER2-positive breast cancer patients. The benefits of trastuzumab are independent of age, tumor size, nodal and HR status. Adjuvant trastuzumab is recommended in node-positive and node-negative tumors with a tumor size > 1 cm [I, A]. No level I evidence exists regarding the use of trastuzumab in node-negative and tumors ≤ 1 cm, although it might be considered in most patients with tumor size 0.5-1.0 cm [II, B]. While trastuzumab added sequentially after chemotherapy has demonstrated activity, results from the NCCTG N9831 study and a meta-analysis suggest better outcomes when trastuzumab is given concurrently with taxane-based treatment. Thus, AC or EC for 4 cycles followed by 3 months of paclitaxel (P) or docetaxel (D or T) both in combination with trastuzumab (AC/EC → P/D + H) or docetaxel, carboplatin and trastuzumab (TCH) are preferred regimens [I, A]. It is important to consider cardiac risk factors when determining the appropriate chemotherapy backbone to administer with trastuzumab. In small, node-negative tumors (stage-I), although not all patients require adjuvant trastuzumabbased chemotherapy (particularly those with pT1aN0), a less intense chemotherapy regimen such as single-agent paclitaxel and trastuzumab for 12 weeks followed by singleagent trastuzumab to complete one year provides excellent outcomes [II, B]. To date, 12-month duration of trastuzumab remains the standard of care in most situations [I, A]. However, in patients with cardiac toxicity or at very high risk of cardiac toxicity, a shorter course (i.e., 6 months duration) can be considered. Trastuzumab may also be safely combined with either radiotherapy or endocrine therapy.
While there have been many efforts to improve outcomes even further, the addition of novel anti-HER2 therapies to trastuzumab, such as pertuzumab or neratinib, has led to significant, but modest improvements in DFS, and no impact on OS has yet been reported. Balancing risks and 1 3 benefits is critical when evaluating adjuvant dual blockade with pertuzumab plus trastuzumab or extended HER2 inhibition with neratinib following 1-year of trastuzumab. Up to 18 cycles of adjuvant pertuzumab in combination with trastuzumab-based chemotherapy showed a 19% relative reduction in invasive disease-free survival (iDFS) at 3 years in the large phase III APHINITY trial. When stratification factors were evaluated, patients with highrisk features such as node positive or HR negative derived a significant iDFS, whereas patients with node negative or HR+ disease did not. Although longer follow-up is needed, EMA states that the available data do not allow concluding for a positive benefit-risk ratio in the overall population. However, EMA considers that benefit is clearly shown in the high-risk population (HR-negative or node-positive) [I, B] for a total duration of 18 cycles of dual blockade, regardless if it was initiated in the adjuvant or the neoadjuvant setting.
The addition of 1 year of adjuvant neratinib improved iDFS in patients with HER2-positive early breast cancer after 1 year of trastuzumab, as demonstrated in the phase III EXTENET trial. However, the benefit was higher in patients with HR-positive and node-positive disease, at the expense of increased diarrhea [I, B]. Recently, neratinib has been approved by EMA, which restricted its use to HR+ disease. However, there are no data on the added benefit of neratinib in patients who also received pertuzumab.

Neoadjuvant treatment for HER2-positive disease [78-81]
In the neoadjuvant setting, trastuzumab in combination with chemotherapy (taxane and anthracycline based) has been the standard treatment for HER2-positive tumors with nodal involvement or tumor size > 2 cm. Two phase II trials evaluated the addition of pertuzumab to trastuzumab-based chemotherapy, demonstrating higher rates of pCR. These data, along with its efficacy in terms of OS in the metastatic setting, led to the accelerated approval of this combination in the neoadjuvant scenario. Dual blockade with trastuzumab and pertuzumab and chemotherapy (anthracycline plus taxane based, or anthracycline-free regimens) should be considered for the treatment of HER2-positive breast cancer patients who meet criteria for neoadjuvant treatment (i.e., > 2 cm tumor size or node positive). According to EMA and FDA, treatment with dual HER2 blockade can be continued after surgery for up to 18 cycles [I, B]. At this point, the type of pathological response at surgery should not guide the duration of trastuzumab or pertuzumab since there are no data supporting one strategy or another. Finally, the addition of lapatinib to trastuzumab and chemotherapy has not consistently improved pCR rates and long-term outcome. To date, this combination cannot be recommended for the treatment of patients with early stage HER2-positive breast cancer [I,E].

Adjuvant treatment for triple-negative disease
Triple-negative breast cancer (TNBC) is a heterogeneous disease comprising approximately 15% of all breast cancers. With the exception of medullary, adenoid cystic, and apocrine carcinomas that have a better outcome, TNBCs have generally an aggressive behavior.
Conventional chemotherapy remains the mainstay of adjuvant systemic treatment for most patients with early TNBC. Adjuvant chemotherapy should include an anthracycline and a taxane [I, B], although the regimen docetaxelcyclophosphamide might be considered in patients with a high risk for cardiac toxicity. Nevertheless, women with T1a/bN0 tumors have an excellent prognosis without chemotherapy [82]. No adjuvant chemotherapy is recommended in tumors equal or less than 0.5 cm (pT1a), and for 0.6-1 cm tumors, it has to be discussed and balanced [III, B]. No robust, prospective randomised data exist on the use of platinum compounds in the adjuvant setting, either in unselected triple-negative tumors or BRCA 1/2 mutation carriers.

Neoadjuvant treatment for triple-negative disease
Neoadjuvant therapy in TNBC leads to pCR rates of 30-40%, which has been associated with an excellent prognosis [65]. It is recommended that a sequential regimen of anthracyclines and taxanes is used for the vast majority of patients [I, B]. An improved pCR was observed with Nabpaclitaxel compared to solvent-based weekly paclitaxel (43 vs 34%) in a head to head phase III neoadjuvant trial. This effect was seen in all subgroups, especially in TNBC patients [83].
Platinum-based neoadjuvant chemotherapy significantly increased pCR from 37.0% to 52.1% (OR 1.96, 95% CI 1.46-2.62, P < 0.001), with significant higher risk of grade 3 and 4 hematological AEs [I, A]. In the 96 BRCA-mutated patients included in two randomized controlled trials, the addition of carboplatin was not associated with significantly increased pCR rate [84]. The effect of those compounds on long-term outcomes is unknown [I, B].
Addition of 6-8 cycles of adjuvant capecitabine therapy among patients who had residual invasive disease on pathological testing after anthracycline and taxane-based neoadjuvant chemotherapy was safe and effective in prolonging DFS and OS in the randomized phase III CREATE-X trial [85]. Based on those results and a meta-analysis [86], adjuvant 1 3 capecitabine can be considered in high-risk TNBC patients with residual invasive disease at surgery following standard neoadjuvant chemotherapy [I, B] This treatment, though, must be balanced against potential toxicities.
Recommendation: sequential regimens of anthracyclines followed by taxanes are the standard treatment. Platinumbased neoadjuvant chemotherapy may be considered an option in TNBC patients [I, A].

Follow-up
Follow-up after surgery and adjuvant treatment of breast cancer patients is widely reported in guidelines worldwide. Surveillance for breast cancer recurrence, screening for second primary cancers, assessment and management of physical and psychosocial long-term and late effects of breast cancer and its treatment, and health promotion are encouragingly recommended [I, A] [87]. Healthy lifestyles, such as physical exercise and avoidance of obesity, are recommended to prevent tumor recurrence [II, A] [88].
Despite the fact that no randomized data exist to support any particular follow-up sequence or protocol, balancing patient needs and follow-up costs, we recommend regular visits every 3-6 months in the first 2 years, every 6 months from years 3-5 and annually thereafter [III, A]. Every visit should include a thorough history, eliciting of symptoms and a physical examination. Annual ipsilateral (after BCT) and/ or a contralateral mammography with ultrasound is recommended [II, A]. An MRI of the breast may be indicated for young patients, especially in cases of dense breast tissue and genetic or familial predispositions [89].