Personalizing the Treatment of Women With Early Breast Cancer

Highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013

A. Goldhirsch; E. P. Winer; A. S. Coates; R. D. Gelber; M. Piccart-Gebhart; B. Thürlimann; H.-J. Senn; Panel members

Disclosures

Ann Oncol. 2013;24(9):2206-2223. 

In This Article

Panel Deliberations

The Panel reviewed a series of questions developed by iterative consultation over the months preceding the conference. Voting on most questions was in the format yes, no or abstain, where abstaining was recommended if the Panel member felt a conflict of interest in the question, that there was insufficient evidence to support an opinion either way or that he or she lacked the relevant expertise. Detailed voting records for each of the questions put to the Panel are provided in the supplementary Appendix S1,availableat Annals of Oncology online.

Surgery of the Primary

The Panel found very few absolute contraindications to breast-conserving therapy. Margins involved with invasive carcinoma or DCIS after repeated resection were one such absolute contraindication. The minimal acceptable surgical margin was felt to be 'no ink on invasive tumour' (i.e. margins free of tumour) by nearly three quarters of the Panellists and most of the others would accept a minimum clearance of 1 mm. The Panel was almost unanimous that breast-conserving surgery should not be carried out unless postoperative radiation (if indicated, as described below in the radiation therapy section) could be delivered.

A majority of the Panel considered that relative but not absolute contraindications to breast-conserving therapy included very young age (<35 years); extensive or diffuse microcalcifications where the presence of malignancy cannot be reliably excluded without complete excision; multicentric disease; tumour location near the nipple and mutations of the BRCA1 or BRCA2 genes. Substantial minority support added multifocal disease, extensive vascular invasion and an extensive intraductal component to this list of relative contraindications. Positive family history and unfavourable biology based on genomic profiling were not considered to be contraindications to breast-conserving therapy.

Nipple-sparing surgery was considered acceptable, provided the margin close to the nipple was not involved. The vast majority of Panel members thought magnetic resonance imaging should not be routinely used in the assessment of newly diagnosed breast cancer.

Surgery of the Axilla

The Panel believed that axillary dissection could be safely omitted in patients with one or two positive sentinel nodes following breast-conserving surgery when whole breast radiation therapy is planned. The Panel was nearly equally divided whether this recommendation also applied to mastectomy followed by radiotherapy, but was almost unanimous in the need for axillary dissection if no radiotherapy was planned.

The Panel also considered that axillary dissection was required with three or more involved sentinel nodes or if nodes were clinically involved before surgery and confirmed by biopsy.

Radiation Therapy

The Panel strongly agreed that 'short course' radiotherapy, such as 40 Gy in 15 or 42.5 Gy in 16 fractions, could be offered as a standard for at least some patients, with a slim majority thinking that this would be suitable for almost all patients. The Panel agreed that short course radiotherapy was an option whether or not a boost to the tumour bed was planned. A large majority of Panel members thought that there were definable groups of patients not requiring radiotherapy following breast-conserving surgery, and that these might include the elderly and those with substantial comorbidity. The Panel could not reach a majority view regarding the current acceptability of the various techniques for partial breast radiation as definitive treatment.

Post-mastectomy radiotherapy was considered indicated by almost all Panel members for patients with four or more positive nodes, while the majority would not advise post-mastectomy irradiation for those with one to three positive nodes, except in the presence of adverse tumour pathology. The Panel was content to omit post-mastectomy radiotherapy with pathologic uninvolved nodes even when fewer than eight nodes had been examined and if the tumour was ≤5 cm. Two-thirds felt that radiation therapy should be given after mastectomy if positive sentinel nodes were not followed by axillary dissection.

Other indications recommended by the Panel for post-mastectomy radiotherapy included positive deep margins and, for two-thirds of the Panel, tumours greater than 5 cm regardless of the nodal status. However, the Panel strongly rejected needing radiotherapy solely based on Grade 3, lymphovascular invasion, HER2-positive status or triple-negative disease.

Areas to be irradiated following mastectomy and axillary dissection should not be influenced by any neoadjuvant systemic therapy or by the intrinsic subtype of the tumour. There was no clear agreement about the necessity to include the supraclavicular fossa, though trials have routinely included this area. Most Panel members would not include the internal mammary nodes and a strong majority felt that the axilla should not be radiated after dissection.

Pathology

The Panel recognized substantial progress in the pathological characterization of tumour subtypes. There was little change in the classification of HER2-positive or triple-negative disease. The majority of the Panel accepted that a useful surrogate definition of Luminal A-like as distinct from Luminal B-like disease could be made using a combination of ER, PgR and Ki-67, without requiring molecular diagnostics. Ki-67 has been used for more than two decades as a prognostic marker in early breast cancer.[110–118] The Panel did not accept that distinction between Luminal A-like and Luminal B-like tumours could be made with ER and PgR alone, and a clear majority voted that grade 3 could not be used as a substitute for high Ki-67 for this purpose. The Panel noted that standardized cut-offs for Ki-67 have not been established and laboratory specific values should be used, but the majority of the Panel voted that a threshold of ≥20% was clearly indicative of 'high' Ki-67 status. A minority questioned the role of Ki-67 in breast cancer treatment decisions. The Panel stressed the need for standardization, and that laboratories should participate in quality assurance programmes.

The Panel was strongly of the opinion that intrinsic subtypes, including those defined by the clinico-pathological surrogates, should influence whether or not chemotherapy was used, but not the choice of the cytotoxic regimen. After clinico-pathological assessment, a slim majority of the Panel was in favour of requesting a multi-gene assay in node-negative, ER-positive and HER2-negative cases. The Panel considered that only the 21-gene RS was predictive of chemotherapy responsiveness, though a substantial minority would also endorse PAM50 or the 70-gene signature for this purpose. This led to a recommendation that selection of patients who might forego chemotherapy could be based on the 21-gene RS, but the Panel did not offer majority endorsement for PAM50, the 70-gene signature or EPClin as yet established for this purpose.

For patients with ER-positive, HER2-negative disease, the use of molecular diagnostics was felt to be unnecessary in low-risk patients such as those with a tumour size of ≤1 cm in the setting of negative lymph nodes, since chemotherapy would be unlikely to be given anyway. Similarly, patients with a higher risk such as those with a tumour size >5 cm, inflammatory breast cancer, those with four or more involved nodes, or a very low ER positivity (e.g. 5%) might not benefit from molecular diagnostics because chemotherapy would be likely to be offered in any case. Patients in whom chemotherapy was thought to be of uncertain indication and who might, therefore, benefit from molecular diagnostics were felt to include selected patients with node-negative disease, those with one to three positive nodes, and patients aged <35.

In the determination of HER2 status for treatment purposes, the Panel did not believe that polysomy of chromosome 17, or heterogeneity of expression of HER2 need to be considered.

Adjuvant Endocrine Therapy in Premenopausal Women

The large majority of the Panel said that tamoxifen alone was the default adjuvant endocrine therapy for premenopausal patients. In light of recent trial evidence, it was felt that at least some patients should have a treatment duration of 10 years, although this may not be needed by all patients. Most Panellists thought ovarian suppression need not be added to tamoxifen, but Panellists were evenly divided for patients <40 years of age. Most of the Panel regarded both ovarian suppression alone without tamoxifen and its combination with aromatase inhibitors as inappropriate unless tamoxifen was contraindicated.

Adjuvant Endocrine Therapy in Postmenopausal Women

The Panel strongly believed that some postmenopausal women could be treated with tamoxifen alone. If an aromatase inhibitor were included in the regimen, Panellists were equally divided whether treatment should start with the aromatase inhibitor, although this strategy was strongly preferred for patients at high risk. Most Panellists believed that initial aromatase inhibitor therapy could be replaced by tamoxifen after 2 years, if there were a reason to do so. Extension of aromatase inhibitor therapy beyond the first five years for patients with node-positive, but not node-negative disease was strongly supported, for patients whose initial treatment was tamoxifen or whose initial therapy was <5 years of an aromatase inhibitor. The Panel was equally divided concerning an extended duration of aromatase inhibitor therapy beyond 5 years of treatment with these agents. Extended adjuvant endocrine therapy using tamoxifen is a consideration after a 5-year course of an aromatase inhibitor, though this approach has not been directly studied.

Adjuvant Cytotoxic Chemotherapy

The Panel was clearly of the opinion that factors arguing for the inclusion of chemotherapy were histological grade 3 tumours, high Ki-67, low hormone receptor status, HER2 positivity or triple-negative status, high 21-gene RS, high-risk 70-gene signature and the involvement of more than three lymph nodes. Most felt that nodal positivity per se was not an indication for chemotherapy but very few would forego chemotherapy for patients with four or more positive nodes. Lymphovascular invasion was not recognized as an indication, while the Panel was equally divided whether young age (<35 years) was an indication.

The Panel was of the strong opinion that patients with Luminal A-like disease were 'less responsive to chemotherapy', but this treatment could be added to endocrine therapy based on the large tumour volume, assessment of risk or patient preference. The Panel did not select a specific chemotherapy regimen for these patients and expressed the view that any of the standard regimens, including the first- and second-generation regimens (CMF, AC, TC), could be considered.

For patients with Luminal B (HER2-negative) disease, the majority of the Panel considered chemotherapy to be indicated. Chemotherapy regimens for Luminal B (HER2-negative) disease should generally contain anthracyclines and (by a slim majority) taxanes. Half the Panel agreed that such chemotherapy should be delivered for at least six cycles, but the Panel did not endorse the exclusive use of a dose dense regimen.

For patients with HER2-positive disease, the Panel strongly believed, while there was no specifically preferred regimen, chemotherapy should include a taxane and, for most Panel members, also an anthracycline.

For patients with 'basal-like' (triple-negative ductal) disease, the Panel strongly endorsed both anthracyclines and taxanes, and did not believe that platinum, or regimens emphasizing alkylating agents were specifically required. There was no clear consensus on the role of dose dense regimens, though a substantial minority expressed support for such treatment.

General considerations influencing the choice of chemotherapy regimen were thought to include a desire to preserve fertility, the avoidance of alopecia and the presence of co-morbidities, but not intrinsic subtype or the presence of BRCA1 or BRCA2 mutation. Older chronological age should not necessarily influence the choice of regimen,[119] but assessment of co-morbidities and general health was considered, especially important in older patients.

Anti-HER2 Therapies

For patients whose tumours show amplification or overexpression of HER2, the Panel considered that trastuzumab therapy was indicated for patients with tumours >5 mm, while some Panellists would treat patients with such tumours of any size. Most felt that trastuzumab should be given concurrently with a taxane, but not with an anthracycline. The Panel was prepared to endorse trastuzumab (with endocrine therapy, if indicated) without chemotherapy only if chemotherapy were contraindicated. The Panel was unanimous that the duration of trastuzumab should be 1 year.

Neoadjuvant Cytotoxic Chemotherapy

The Panel was split about whether neoadjuvant chemotherapy had benefits beyond local downstaging. The Panel did not support additional postoperative adjuvant chemotherapy following a full course of neoadjuvant chemotherapy, whether or not pCR were achieved. Most believe when neoadjuvant therapy is given outside of a clinical trial, the full course of chemotherapy should be completed before surgery. In the unusual situation in which a surgery is carried out after less than a full course of neoadjuvant chemotherapy most Panel members would complete the course postoperatively.

Neoadjuvant Anti-HER2 Therapy

For patients with HER2-positive disease, the Panel was strongly of the opinion that neoadjuvant treatment should include anti-HER2 drugs, and the majority recommended the use of chemotherapy plus trastuzumab alone (without additional anti-HER agents).

Neoadjuvant Endocrine Therapy

The Panel strongly endorsed endocrine therapy alone as neoadjuvant treatment for postmenopausal patients with strongly positive hormone receptors and low proliferating disease, and most thought that such treatment should be continued until maximal response.

Bisphosphonates

The Panel considered several situations in which bisphosphonates might be used with the aim of improving disease-free survival, but did not endorse such treatment for this purpose in any group, though a substantial minority felt that premenopausal patients receiving an LHRH agonist plus tamoxifen or clearly postmenopausal patients might derive benefit from such treatment. Denosumab was not endorsed for adjuvant use.

Follow-up

The majority of the Panel believed that regular follow-up after the completion of immediate treatment (excluding long-term endocrine therapy) was appropriate, but that this could be supervised by a nurse specialist, rather than a surgeon or oncologist. The majority of the Panel also believed that follow-up should be done in person and not by telephone.

Summary of Treatment Recommendations

The conference endorsed recent trial evidence supporting less extensive local therapies. It refined and re-iterated the value of clinico-pathological surrogate definitions resembling intrinsic subtypes to guide selection of systemic adjuvant therapies. The Panel recognized the superior accuracy and reproducibility of multi-gene molecular assays, but recognized that these assays are not available in all parts of the world. The Panel also noted the variability in the current levels of evidence to support the use of the individual multi-gene assays. Ongoing trials will prospectively define the value of chemotherapy in addition to endocrine therapy in patients with luminal disease in the node-negative (TAILORx, MINDACT) and node-positive (MINDACT, RxPONDER) cohorts. It is therefore to be hoped that a future St Gallen Consensus conference will be able to provide more robustly supported recommendations for treatment of such patients.

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