Patients with early breast cancer undergoing primary tumor removal (plus adjuvant chemotherapy for N+ cases) display a recurrence dynamics including an early major peak at the 2nd year after surgery, a smaller late peak near the 6th year and then a tapered plateau-like tail extending at least up to 15 years (14
). This event dynamics has been extensively validated in 12 independent databases and also is identifiable in at least 8 other studies (23
). The peak timing proved to be stable for all analyzed subsets (grouped by tumor size, nodal status, oestrogen receptor content, and menopausal status) of patients undergoing both radical and conservative surgery (14
), and for all sites of metastasis (26
). Such stability allows us to avoid detailed scrutiny of some characteristics (e.g., age, tumor size, whether they had adjuvant therapy, etc.) of analyzed patients who, moreover, had comparable treatments (surgery followed by similar adjuvant chemotherapy for N+ tumor and no further treatment for N- tumor). This recurrence dynamics may be suitably explained by a new paradigm of metastasis development based on the concepts of tumor homeostasis, tumor dormancy and surgery related enhancement of metastasis growth (14
). The model () assumes both cellular and micrometastatic tumor dormancy, with ordered transitions between these two quiescent states and subsequent development of overt metastasis and, in addition, a transient phase of acceleration of metastatic growth following surgical excision of the primary tumor (14
Figure 6 Outline of the metastatic process according to the proposed model. Tumor cells leave the primary tumor as single cells and seed the distant tissue, where they may lodge for some time in a quiescent state or go on proliferating. In the latter occurrence, (more ...)
In this study, the bimodal hazard rate pattern for DM after IBTR, which emerges when times are realigned as if IBTR was a newly diagnosed breast cancer (), suggests that the disease course following IBTR may be similar to the course subsequent to the first surgical manoeuvre. We attribute this noteworthy similarity to the IBTR surgical removal that, like primary tumor removal, impinges on the tumor-host equilibrium. We propose, therefore, that the surgery effect on tumor growth, well recognized in animals and human (27
) and which reasonably explains several clinical events after primary treatment (14
), is also operating during the treatment of IBTR.
Let us assume that IBTR removal originates an accelerating effect upon dormant micrometastases. After primary surgery, the tumor cell burden prone to wake up is time dependent, due to the orderly transitions between cellular and micrometastatic dormant states (14
) (). There is a progressive shift towards the avascular micrometastatic dormant phase that will cease following the emergence of an angiogenic phenotype (14
). The IBTR surgical removal is a new perturbing factor of this on-going process, initiating a sudden growing phase for tumor foci most of which, otherwise, would have reached the clinical level according to their own dynamics. The recruited subclinical metastases, therefore, will emerge earlier as overt metastases. This phenomenon should be mostly relevant during early follow-up after initial surgery (the metastasis development phase underlying the first dominant risk peak), thus explaining the exceedingly high early risk for DM after IBTR in comparison with the corresponding risk for N+ patients after primary tumor removal (). This explanation is also well supported by the reduction of the peak when patients with increasing time to IBTR are considered (). Moreover, the assumption provides a biological reason for the often reported cut-off value of 2-3 years separating IBTR patients with worse prognosis from patients with better outcome (2
The recurrence risk estimates suggest that patients with time to IBTR in excess of 2.5 years are similar to N+ patients (). This result is confirmed by the mortality dynamics where an early mortality risk excess for patients with IBTR in comparison with N+ patients disappears when only patients for whom IBTR occurred at more than 2.5 years of follow-up are considered (). It should be noted, however, that the risks of recurrence and mortality for N+ patients and IBTR patients are estimated at different times, as the time origin is at primary surgery for the former group and at IBTR surgical removal for the latter group. The recurrence and mortality risk levels associated to IBTR emerge when the corresponding risks for N+ patients may have reached low levels, because of the elapsed time from the initial surgery. Therefore, the clinical prognosis of a patient with IBTR at more than 2.5 years of follow-up may rank considerably poorer than that of an N+ patient with similar recurrence-free follow-up.
Since early reports, it was speculated that an IBTR following BCT may represent either a true recurrence of the original tumor, or, otherwise, a new primary tumor (8
). A variety of empiric criteria were proposed to distinguish between the two possibilities, yet without reaching a commonly accepted standard. In our analysis, we did not distinguish between the two events and our conclusions leave out of consideration such a distinction, the validity of which needs further investigations. With this caveat, our analysis supports the concept that when an IBTR is diagnosed and resected, the patient discloses a previously unrecognized high risk of recurrence and a favorable occasion for systemic treatment as well. Therefore, we advocate investigations on the value of an adjuvant therapy following IBTR removal, such as the international multicentre trial by the International Breast Cancer Study Group and the National Surgical Adjuvant Breast and Bowel Project that has been recently initiated to address this issue.
In summary, we propose that the surgical treatment due to IBTR diagnosis induces a change in the previous DM dynamics with a sudden acceleration of metastasis development. The resulting disease course will consequently be related to both the underlying time-dependent subclinical metastatic status and the growth enhancing effect of the IBTR treatment. The finding of an overlarge early recurrence risk of IBTR patients in comparison with N+ patients, while patients with time to IBTR exceeding 2.5 years behave as N+ patients supports this notion. In addition, these findings strengthen the Fisherian concept (7
) that patients with IBTR have an intrinsic high risk of DM that was undetectable by the usual prognostic factors at the initial treatment and that is revealed by the IBTR that emerges, for them, in advance of the competing DM event. Had the patient not displayed IBTR, the DM would have occurred in the majority of such patients, according to the bimodal dynamics driven by the initial treatment. Moreover, it is possible that although the majority of IBTR patients would have developed a DM in any case, in a few other patients, IBTR surgical removal may induce a growing phase of tumor foci that would have otherwise remained dormant for a long time. We suggest that these are the patients that produce the modest late mortality increase observed in the meta-analysis (6
). In the choice of the surgical approach for patients with IBTR, the need of further surgery for a second IBTR following BCT for the first one should be taken into account.
The clinical course of patients experiencing IBTR may be reasonably explained by assuming jointly both the B. Fisher’s paradigm (13
) and the concepts underlying the metastasis development model proposed by us (14
), without the need of other explanations (12