Differences in metastatic patterns in relation to time between primary surgery and first relapse from breast cancer suggest synchronized growth of dormant micrometastases

A significant variation in the metastatic pattern among breast cancer patients exists. Clinical observations suggest that these differences are related to time to recurrence (TTR), thus suggesting a common systemic growth signal at the time of surgery. Our goal was to identify a marker for synchronized growth of micrometastases. To quantify the metastatic pattern at first relapse, 180 patients with metastatic breast cancer were studied. Standard deviation (SD) of lesions size and lesion number was calculated and served as a marker for variation. Patients with low SD (multiple/similar sized lesions) were assumed to have synchronized growth, whereas patients with high SD were assumed to have unsynchronized growth. Patients were grouped according to TTR; early ( 3 years- after surgery). In patients not receiving systemic adjuvant treatment, median SD was significantly lower in the early group (2.5 mm) compared with 6.4 mm in the late group (p = 0.005). In node negative patients, median SD was significantly lower in the early group (3.0 mm) when compared with the late group (5.7 mm, p = 0.02). An additional drop in SD was observed immediately after end of adjuvant endocrine therapy. Our results identify SD as a marker of synchronized metastatic growth in breast cancer. A metastatic phenotype characterized by multiple similar sized metastases, suggesting synchronized onset of growth of micrometastases was predominantly found in patients recurring early after surgery and was counteracted by adjuvant treatment. Systemic growth signals caused by surgery might be antagonized during the time window following surgery

Abstract 1088: Differences in metastatic patterns in relation to time between primary surgery and first relapse from breast cancer suggest synchronized growth of dormant micrometastases

Abstract Purpose Compared with most other cancer types, breast cancer has a long natural history. In cases with delayed relapse, the unlinearity of disease progression indicates the presence of periods of tumor dormancy. Clinical and experimental studies indicate that growth might be induced by a physiological event like tissue injury following surgery. In this study we aimed to quantify size and number of metastatic lesions in relation to time between primary surgery and first relapse. Our goal was to find clinical support for the presence of a systemic synchronizing growth signal. Patients and methods All patients (n=209) recorded with metastatic breast cancer at our department during 2004-9 were identified. 180 cases with measurable metastases according to RECIST 1.1 and no metastases at the time of primary surgery (&amp;lt; 2 months), were evaluable. Number of metastatic lesions as well as size of each lesion was recorded at the time of first recurrence. Standard Deviation (SD) of the lesions sizes in each patient was calculated and served as a marker for variability in the metastatic pattern. Patients with a high SD were assumed to have unsynchronized (individual) growth of lesions, whereas patients with low SD were regarded to have synchronized growth. Results Median number of metastatic lesions at first recurrence was 7 (1- &amp;gt;10). Cases with only 1 metastasis (n=38) were excluded from the analyses on SD. Median SD was 5.4 (0.0 - 58). Low SD was significantly associated with low histological grade in primary tumors (Pearson Chi Square p= 0.002), absence of liver metastases (p= 0.001) and presence of lung metastases (p= 0.02). No significant association was found between SD and ER status, Her2 status, nodal status or stage. There was also no significant association between nodal status and time to recurrence (TTR). Patients were grouped according to TTR into two groups; early (&amp;lt; 3years-) or late (&amp;gt; 3 years- after primary diagnosis). In the subgroup of patients that were lymph node negative at primary diagnosis (N0), the median SD was significantly lower in the early group (3.0) when compared with the late group (5.7)(Mann-Whitney U test p= 0.02). This effect was not present in the lymph node positive (N1) patients. Conclusions Our data indicate the presence of a metastatic phenotype characterized by multiple, similar sized metastases. The results support synchronized growth of dormant micrometastases in some cases of breast cancer. The fact that this effect was only present in lymph node negative patients, suggests that micrometastatic tumor dormancy is especially important in this group, with otherwise favorable prognosis. Systemic effects of growth factors released during wound healing following surgery might induce a switch from the dormant state into simultaneous growth of occult micrometastases. Further studies to explore these mechanisms are ongoing. Citation Format: Hanna Dillekås, Monica Transeth, Martin Pilskog, Jörg Assmus, Oddbjorn Straume. Differences in metastatic patterns in relation to time between primary surgery and first relapse from breast cancer suggest synchronized growth of dormant micrometastases. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1088. doi:10.1158/1538-7445.AM2014-1088</jats:p