SEOM clinical guidelines in early-stage breast cancer 2015

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 31.4 % [1].

Breast cancer is a heterogeneous disease with multiple intrinsic tumor subtypes [2]. Up to one in three patients will develop metastases during the disease depending on lymph node involvement and breast cancer subtype, despite remarkable progress in early diagnosis and treatment [3]. A better understanding of prognostic and predictive factors is allowing to individualize the treatment of early-stage breast cancer patients. The aim of these guidelines is to summarize current evidence and to give evidence-based recommendations for clinical practice.

These SEOM Guidelines have been developed with the consensus of ten breast cancer 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).

The following tests allow for a correct diagnostic and prognostic approach to all patients in whom the presence of a breast tumor is suspected.

Breast-conserving surgery based on lumpectomy is equivalent to mastectomy and must be considered as first option in most cases of stages I–II [Level of evidence, Grade of recommendation A] [7, 8]. Lumpectomy is not indicated in case of diffuse disease in the breast, and in cases with positive margins when re-excision shows residual disease or it can not be performed with adequate cosmetic results.

Additionally, other relative contraindications for lumpectomy are previous radiation therapy in the breast, active connective diseases with skin involvement, or tumors with diameter greater than five cm when neoadjuvant treatment is not indicated or has been not effective. Radiation therapy during pregnancy is contraindicated, so mastectomy must be considered if locoregional treatment must be completed before childbirth.

When mastectomy is performed, contralateral mastectomy as a prophylactic procedure is not indicated in most of the patients. Younger women, in which BRCA mutations are more common, can benefit most from this strategy. However, decision of contralateral mastectomy must be considered only after an adequate process of counseling and discussion of risk–benefit [9].

Sentinel lymph node (SLN) mapping is recommended for assessment of the involvement of axillary lymph nodes and should be performed in patients with clinically negative axillary nodes (Level of Evidence I, Grade of recommendation A). In patients with clinically positive axillary nodes, pathologic confirmation must be done by fine needle aspiration (FNA) or core biopsy to confirm pathologic involvement.

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 postoperative treatment is provided [I, A] [10].

Regarding SLN biopsy in patients receiving treatment with neoadjuvant (primary systemic) therapy, ALND is recommended for cases with pathologically confirmed axillary lymph node involvement by FNA or core biopsy before neoadjuvant treatment. In patients with clinically positive axillary nodes before neoadjuvant and negative SLN biopsy after chemotherapy, the rate of false negative is higher than 10 % and ALND is recommended as standard procedure. However, some studies indicated that for these patients, when at least three sentinel nodes are identified and all of them are negative, ALND can be avoided (Level of evidence II, Grade of recommendation B). For cases with clinically negative axillary nodes, SLN biopsy can be performed before or after neoadjuvant treatment [11].

Systemic adjuvant treatment is commonly used in early breast cancer with the intention to reduce the rate of locoregional or systemic relapses a death derived from the disease. Unfortunately, treatment decisions are based on statistical models in which patients have indirect estimations of the risk of relapse and death, and therefore of the potential benefits of implementing adjuvant strategies.

Multigenic tests provide information beyond standard clinical and pathologic prognostic factors that can help in making treatment decisions in ER-positive breast cancer. All of these tests have been validated for prognosis in year 1–5, but there are some differences, especially beyond 5 years and regarding predicting usefulness of chemotherapy. We reviewed validation studies of the most commonly used tests in our country with level of evidence according to Simon et al. [12].

Oncotype DX. It has been validated for predicting risk of distance recurrence to 10 years in breast cancer patients treated with hormone therapy. Oncotype has also proved predictive value of the benefit of chemotherapy in two randomized studies (NSABP B-20 and SWOG) [13‐15]. In the German prospective study Plan B, high-risk patients according to classical clinicopathological factors, in case of positive ER, and 0–3 nodes and RS of 11 or less, were treated with hormone therapy alone; results recently presented showed a 3 years event-free survival of 98.3 %, in spite of features of high risk by the traditional parameters [16]. In a recently report, based on studies NSABP B-28 and B-14, RS was associated with 5–15 years distant relapse risk in 86 % of patients, who had expression of RE greater than 0.9 [17]. Recently, a prospectively conducted study concluded that ER+, HER2- N0 patients with tumors that had a favorable gene expression profile had very low rates of recurrence at 5 years with endocrine therapy alone [18]. Level of evidence: IA for the prediction of adjuvant chemotherapy benefit in low risk group patients. IB for the prediction of the risk of distant recurrence at 10 years and benefit of adjuvant chemotherapy in the other ER-positive, HER2-negative groups.

PAM50 ROR. The PAM50 gene signature classify a tumor as one of four intrinsic subtypes (Luminal A, Luminal B, HER2-enriched, and Basal-like), which have been shown to be prognostic in both untreated and tamoxifen-treated patient populations. PAM50 estimates patient’s probability of disease recurrence by weighting the molecular subtype correlations, a subset of proliferation genes, and pathologic tumor size [19, 20]. PAM50 ROR score has clearly demonstrated its prognostic value beyond 5 years and added significant prognostic information beyond the Oncotype RS in ER-positive, postmenopausal patients treated with endocrine therapy alone (from the ATAC trial) [21]. It has demonstrated additional prognostic value in node-positive patients for the risk of late recurrence on patients from the ABCSG-8 trial [22, 23]. In a recent report, ROR obtained from core needle biopsy predicted response to neoadjuvant chemotherapy in hormone-sensitive HER2-negative patients [24]. Level of evidence: IB for the prediction of the risk of recurrence 10 years away.

Mammaprint: this signature was validated in 295 patients with pT1 or pT2 tumors with pN0 or pN+, with a median follow-up of 7.8 years, showing a prognostic value. This prognostic value has been validated in other studies, including patients with up to 4–9 positive lymph nodes [25, 26]. Level of evidence: IB for prognostic value.

EndoPredict. EPclin (EndoPredict combined with nodal status and tumor size) was validated in two randomized phase III trials, showing prognostic value, for year 1-5 and beyond [27, 28]. Level of evidence: IB for prognostic value.

For patients with ER+/HER2- tumors, multigenic tests appear to identify a group of very good prognosis patients for whom, the benefits of chemotherapy are so small that they do not outweigh the risks. The assays reviewed have their own individual advantages. Oncotype, Mammaprint, PAM-50 ROR score, and EndoPredict are useful in predicting relapse risk for year 1–5. Beyond 5 years Oncotype, EndoPredict has showed prognostic value. But PAM-50 ROR showed the strongest prognostic value beyond 5 years. Oncotype showed the strongest predictive value of the benefit of chemotherapy [29].

Adjuvant radiotherapy (RT) should be performed in the case of:

Radiotherapy treatment is generally well tolerated, with minimal toxicity in the medium and long term, with planning and management methods of treatment introduced in recent years. In the indications shown, radiation therapy has proved effective and very relevant in decreasing the risk of local recurrence and improving breast cancer mortality. Despite these recommendations, it is important to note that in elderly patients with stage I, specific studies have not shown improved survival and should therefore be assessed individually [I, A] [57]. Furthermore, some low-risk patients treated with conservative surgery could be spared whole breast RT and receive only partial breast radiation or intraoperative treatment, although less evidence exists to support this approach