U Narbe, P -O Bendahl, M Fernö, C Ingvar, L Dihge, L Rydén
Invasive lobular breast cancer is the second most common histological subtype and constitutes around 10-15% of all breast cancer. It is recognized by a peculiar diffuse growth pattern and disseminated spread of cancer cells contributing to diagnostic delay and difficulties in detecting the primary tumors by mammography and nodal metastasis by axillary ultrasound. Consequently, although invasive lobular breast cancer mainly displays a favorable luminal A molecular subtype, it is often diagnosed at a higher stage than invasive cancer of no special type. Despite these characteristics, histopathological subtype is not accounted for in Clinical Guidelines, in contrast to the molecular subtypes. In the BJS publication “The St. Gallen 2019 Guidelines understage the Axilla in Lobular Breast Cancer: a Population-Based Study” by Ulrik Narbe and co-authors, we have elaborated on the consequences for patients with invasive lobular cancers if completion axillary clearance would be omitted in patients with 1-2 nodal metastases.
For the breast surgeon, lobular cancer poses a challenge to surgery of the breast and to the axilla. Large tumor size and diffuse infiltrating margins are associated with an increased risk of positive margins after breast conserving surgery and in breast centers where MRI is available, complementary imaging is recommended ahead of primary surgery. Still a larger proportion of patients (66%) with lobular cancer undergo a mastectomy compared to other histological subtypes (43%) according to our registry study, supporting previous publications. So the dogma of de-escalating breast surgery from mastectomy to partial mastectomy in lobular cancer is challenging, keeping in mind that positive resection margins is a mandatory quality criteria in most centers pushing the choice of initial surgery towards upfront mastectomy.
Axillary surgery is moving towards de-escalation of surgical interventions for patients with 1-2 sentinel node metastases after the results of the Z0011 trial have been implemented worldwide and clearly supports that omission of completion axillary dissection is non-inferior provided the inclusion criteria for the trial is fulfilled. The Z0011 criteria for omission of completion axillary dissection is restricted to patients undergoing breast-conserving surgery, and is thus not applicable for lobular cancers operated by mastectomy. The St. Gallen 2019 guidelines extended the indication for abstaining completion axillary dissection to all patients of any tumor size irrespective of type of breast surgery. In addition, the guidelines recommended that the decision on adjuvant chemotherapy for luminal A-like tumors should include nodal staging and patients with 4 or more nodal metastasis (nodal stage II) were recommended adjuvant chemotherapy. For these patients there is hitherto no data on the role of genomic tests for risk stratification until the results of OPTIMA trial are presented. In this paper, we present data from the National Swedish Quality Registry with prospectively collected data retrieved from the period when a completion axillary clearance for patients with sentinel node metastases was recommended. We found a strong association between invasive lobular breast cancer and nodal stage II disease independent of other determinants such as tumour size.
Moreover, we validated the predominance of luminal A-like subtype in lobular cancer and among those the risk of nodal stage II disease was higher than for the corresponding group of invasive cancers of no specific type (19% compared with 3%). Importantly, patients with lobular cancer retained a predominance (60%) for luminal A-like subtype in the nodal stage II subgroup. In contrast, patients with nodal stage II disease and non-lobular cancers had a lower fraction of luminal A-like tumors (23%) compared with patients with a lower nodal status implicating that for most patients with nodal stage II and non-lobular cancers, the molecular subtype would guide adjuvant treatment decisions rather than nodal stage.
The biological mechanism behind the prevalence of a higher nodal burden in lobular cancer is today speculative. Hormone responsive tumors (ER positive) of all histological subtypes are characterized by a slightly increased risk of nodal metastasis, probably linked to a lower immunologic reaction in the primary tumor facilitating lymphatic spread. Moreover, the cornerstone of lobular cancers – loss of E-cadherin – facilitates detachment of cancer cells which might be of importance for metastatic spread. In the present study, we clearly present data on the independent association of lobular cancer with nodal spread underscoring that this association is not solely explained by a hormone responsive phenotype or a larger tumor size.
This study highlights that lobular cancer is associated with a higher nodal burden than non-lobular cancer and omission of completion axillary clearance in sentinel node positive patients could thus understage the axilla. The consequence of this is that some 19% of all patients with invasive lobular cancer and luminal A-like subtype would be dismissed from recommendation of adjuvant chemotherapy. Today, the updated St. Gallen 2021 guidelines states that completion axillary clearance is recommended for patients where staging is necessary for adjuvant treatment recommendations and would largely correspond to lobular cancers with a luminal A-like molecular subtype. The challenge of de-escalating axillary surgery in lobular cancer is thus unresolved.
The consequence of understaging of the axilla in lobular cancer in terms of clinical outcome is, however, unclear while the responsiveness of chemotherapy in lobular cancer is considered poorer than the corresponding effect in non-lobular cancer. Despite the findings from neoadjuvant trials, lobular cancer is included in general recommendations on adjuvant chemo-endocrine therapy due to the lack of data specific for lobular cancer. The ongoing randomized trial SENOMAC holds some promise to shed light on the outcome for lobular cancers in the experimental arm in which adjuvant recommendations are not based on complete axillary staging. A strong recommendation for the future is to always include data on histological subtype in clinical trials to be able to stratify the cohort in future analysis. The small but aggressive molecular subtypes, triple-negative and HER2-positive, represent subgroups as small as the lobular histological subtype and today clin.trials.gov is overloaded by adjuvant and neoadjuvant treatment protocols specific for these molecular subtypes. So isn´t it time to reconsider protocols on invasive lobular breast cancer with luminal A-like subtypes? The phenotype indicates cancers at low-risk of distant spread which is balanced by a higher stage at diagnosis associated with a substantial risk of recurrence and death after long-term follow-up. The role of neoadjuvant endocrine therapy in this subgroup is far from settled and might open up for de-escalating surgery of the breast and axilla and shed light on the fascinating biology of lobular breast cancer.