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. 2020 Oct 1;3(10):e2018790.
doi: 10.1001/jamanetworkopen.2020.18790.

Regional Lymph Node Involvement Among Patients With De Novo Metastatic Breast Cancer

Almir Bitencourt  1   2 , Carolina Rossi Saccarelli  1   3 , Elizabeth A Morris  1 , Jessica Flynn  4 , Zhigang Zhang  4 , Atif Khan  5 , Erin Gillespie  5 , Oren Cahlon  5 , Boris Mueller  5 , John J Cuaron  5 , Beryl McCormick  5 , Simon N Powell  5 , George Plitas  6 , Pedram Razavi  7 , Katja Pinker  1 , Christopher C Riedl  1 , Elizabeth J Sutton  1 , Lior Z Braunstein  5
Affiliations

Regional Lymph Node Involvement Among Patients With De Novo Metastatic Breast Cancer

Almir Bitencourt et al. JAMA Netw Open. .

Abstract

Importance: Regional nodal irradiation (RNI) for node-positive breast cancer reduces distant metastases and improves survival, albeit with limited reduction in regional nodal recurrences. The mechanism by which RNI robustly reduces distant metastases while modestly influencing nodal recurrences (ie, the presumed target of RNI) remains unclear.

Objective: To determine whether some distant metastases putatively arise from occult regional nodal disease and whether regional recurrences otherwise remain largely undetected until an advanced cancer presentation.

Design, setting, and participants: This cohort study examined patients presenting with de novo stage IV breast cancer to the Memorial Sloan Kettering Cancer Center in New York, New York, from 2006 to 2018. Medical records were reviewed to ascertain clinicopathological parameters, including estrogen receptor status and survival. Pretreatment positron emission tomography-computed tomography (PET-CT) imaging was reviewed to ascertain the extent of regional nodal involvement at metastatic diagnosis using standard nodal assessment criteria. A subset underwent regional lymph node biopsy for diagnostic confirmation and served to validate the radiographic nodal assessment. Data analysis was performed from October 2019 to February 2020.

Exposures: Untreated metastatic breast cancer.

Main outcome and measures: The primary outcome was the likelihood of regional nodal involvement at the time of metastatic breast cancer presentation and was determined by reviewing pretreatment PET-CT imaging and lymph node biopsy findings.

Results: Among 597 women (median [interquartile range] age, 53 [44-65] years) with untreated metastatic breast cancer, 512 (85.8%) exhibited regional lymph node involvement by PET-CT or nodal biopsy, 509 (85%) had involvement of axillary level I, 328 (55%) had involvement in axillary level II, 136 (23%) had involvement in axillary level III, 101 (17%) had involvement in the supraclavicular fossa, and 96 (16%) had involvement in the internal mammary chain. Lymph node involvement was more prevalent among estrogen receptor-negative tumors (92.4%) than estrogen receptor-positive tumors (83.6%). Nodal involvement at the time of metastatic diagnosis was not associated with overall survival.

Conclusions and relevance: These findings suggest that a majority of patients with de novo metastatic breast cancer harbor regional lymph node disease at presentation, consistent with the hypothesis that regional involvement may precede metastatic dissemination. This is in alignment with the findings of landmark trials suggesting that RNI reduces distant recurrences. It is possible that this distant effect of RNI may act via eradication of occult regional disease prior to systemic seeding. The challenges inherent in detecting isolated nodal disease (which is typically asymptomatic) may account for the more modest observed benefit of RNI on regional recurrences. Alternative explanations of nodal involvement that arises concurrently or after metastatic dissemination remain possible, but do not otherwise explain the association of RNI with distant recurrence.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Morris reported receiving a grant from GRAIL Inc for research not related to the present study. Dr Plitas reported receiving consulting fees from Tizona Therapeutics, Merck, and Takeda outside the submitted work. Dr Razavi reported receiving grants from GRAIL Inc and Novartis outside the submitted work, and personal fees from Novartis, AstraZeneca, and Foundation Medicine. Dr Pinker reported receiving the following grants for research not related to the present study: H2020–Research and Innovation Framework Programme PHC-11-2015 (grant 667211-2), H2020-FETOPEN-2018-2019-2020-01 (grant 828978), Jubiläumsfonds of the Austrian National Bank (grant 18207), and The Vienna Science and Technology Fund (grant LS19-046). Dr Sutton reported receiving grants from Memorial Sloan Kettering Cancer Center during the conduct of the study. Dr Braunstein reported receiving financial support from the Lois Green Fund. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patients With De Novo Metastatic Breast Cancer Who Were Exlcuded From the Study
PET-CT indicates positron emission tomography–computed tomography.
Figure 2.
Figure 2.. Types of Nodal Involvement for Patients With De Novo Metastatic Breast Cancer
A, For patients with involvement of any nodal basin, various combinations of axilla, internal mammary, and supraclavicular involvement are shown. B, For patients with axillary involvement, various combinations of level I, level II, and level III involvement are shown.
Figure 3.
Figure 3.. Kaplan-Meier Estimates of Survival for Patients With De Novo Metastatic Breast Cancer by Nodal Involvement
See this image and copyright information in PMC

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