Carmen Criscitiello: “ Breast conservation following neoadjuvant therapy for breast cancer in the modern era: Are we losing the opportunity”.

My comments:
Carmen Criscitiello is the medical oncologist of the faculty of our interactive course. We invited her after reading this article published on EJSO in 2016. It is very unusual for medical oncologists being involved in surgical discussions but the case of pre-surgical medical treatment (Primary Systemic Treatment, PST) is certainly the most appropriate one.

Carmen highlights the current paradox of PST that, despite higher rates of pathological complete response in trials with modern drugs, seems not able to increase the breast conservation rates when compared to historical studies with modest response (for example NSABP-B18). What are the reasons for such disappointing results? Why only 67% of patients deemed eligible for breast conservation in the CALGB 40601 trial attempted breast preservation that was successful in a further reduced number of cases? Why low breast conserving rates are reported by Criscitiello herself in a sub analysis of the Neo-ALTTO trial (around 40% ) and by Mehra Golsham in the CALGB 40603 trial (47%)?
As a surgical oncologist I may offer several explanations. The first could be the precise moment in history in which each trial started its recruitment. The NSABP-B18 was opened in 1995, at that time, in the US, breast reconstruction with implants was not well developed, breast conserving surgery was invariably considered the best option for every surgical patient and the mastectomy rates were declining (see fig.1). Therefore, the low response to treatment, leaving the original cancer palpable, together with poor diagnostic tools may have prompted surgeons to remove a “lump” considering a partial response still a response. The level of expectation on cosmetic results after breast conserving surgery was very low and saving a certain amount of breast tissue and the nipple areola complex was considered a good outcome by definition. Noteworthy, genetic testing was far from standard practice as well as the association between gene mutations and specific subtypes now considered a key point in the decision process for bilateral prophylactic mastectomies.
The mastectomy rates declined globally until the first decade of year 2000, during which some of the largest international databases observed a generalized increase that was more evident in the US. This was probably the effect of the improvement in breast reconstruction with modern implants; the widespread access to gene testing and the use of MRI. The increase in the mastectomy rates was more evident in the US and overlapped with the opening of the modern trials referred by Criscitiello. In this view it is not surprising that a European trial like the GepaR-Sixto is the only modern trial reported in this editorial showing very high breast conservation rates (approximately 75%).
So my conclusion is that the lack of surgical impact of the higher pathological complete response warranted by modern drugs is due to a context that was unfavorable to breast conserving surgery especially in the US. It may be difficult to explain in other ways why some patients who were declared eligible for breast conservation after PST still required a mastectomy (like in the CALG-B 40601).
How can we investigate the reasons for this phenomenon? As an oncoplastic surgeon I made some considerations.
First of all trials on pre-operative systemic treatments are poorly focused on surgical outcomes. Breast conservation or mastectomy rates per se cannot be considered representative of good results. It is really a matter of denominators, trials should not account for the breast conservation rate as an endpoint of PST, indeed they should account the number of women actually preserving the breast among those who were wishing breast preservation that was not possible just because of a poor tumor to breast ratio at the onset (Uni-focal-no widespread DCIS and sensitive to PST). In this respect also patients with gene mutations and subsequent decisions for prophylactic procedures should not be included in this ratio. Clearly, crude rates cannot express surgical results that need to be assessed with proper outcome measurements that are now validated and easily available.
Secondly and according to this, we need more sophisticated tools to assess patients preferences on treatments. Adequate pre-operative consultations should enable the patient to decide for a mastectomy for well-established reasons (i.e. avoid radiotherapy, fear of recurrence, no interest in keeping the breast, etc). On the other side surgeons should be compelled to demonstrate that breast preservation has more benefits than harms, and that the claimed higher rate of local recurrences, proven also by the recent metanalysis from the EBCTCG, is not going to affect survival.
The third aspect, and the very big missing one in this discussion, is oncoplastic surgery. The generalized lack of evidence has ruled out oncoplastic surgery from experimental research. Nowadays we could hypothesize that bilateral therapeutic mammoplasties may lead to wider excisions and possibly prevent mastectomies when multiple foci are evident on pre-operative diagnostic assessment. No experimental data are available on this aspect so far, possibly the MIAMI (Multiple Ipsilateral breast conserving surgery versus mastectomy) trial will provide us reliable suggestions in the setting of primary surgical treatment. We hope that its results, if favorable, could promote a trial with similar design in the setting of PST.
Finally, if we really want to let primary systemic treatment become the very first tool in the hands of surgeons, we need to understand better patients motivation and desires, test integrated treatments in randomized trials and evaluate surgical outcomes in a standard and validated way.

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