Abstract
Breast cancer (BC) adjuvant therapy after mastectomy in the setting of 1–3 positive lymph nodes has been controversial. This retrospective Translational Breast Cancer Research Consortium study evaluated molecular aberrations in primary cancers associated with locoregional recurrence (LRR) or distant metastasis (DM) compared to non-recurrent controls. We identified 115 HER2 negative, therapy naïve, T 1–3 and N 0-1 BC patients treated with mastectomy but no post-mastectomy radiotherapy. This included 32 LRR, 34 DM, and 49 controls. RNAseq was performed on primary tumors in 110 patients; with no difference in RNA profiles between patients with LRR, DM, or controls. DNA analysis on 57 primary tumors (17 LRR, 15 DM, and 25 controls) identified significantly more NF1 mutations and mitogen-activated protein kinase (MAPK) pathway gene mutations in patients with LRR (24%, 47%) and DM (27%, 40%) compared to controls (0%, 0%; p < 0.0001 and p = 0.0070, respectively). Three patients had matched primary vs. LRR samples, one patient had a gain of a NF1 mutation in the LRR. There was no significant difference between the groups for PTEN loss or cleaved caspase 3 expression. The mean percentage Ki 67 labeling index was higher in patients with LRR (29.2%) and DM (26%) vs. controls (14%, p = 0.0045). In summary, mutations in the MAPK pathway, specifically NF1, were associated with both LRR and DM, suggesting that alterations in MAPK signaling are associated with a more aggressive tumor phenotype. Validation of these associations in tissues from randomized trials may support targeted therapy to reduce breast cancer recurrence.
Highlights
Breast cancer represents a heterogeneous disease process with markedly different treatment outcomes despite similar clinical staging.[1,2,3] Even with the most aggressive and modern therapy, as much as 15% of patients develop local-regional recurrences (LRR) which in turn increase the risk of distant disease and death.[4,5,6] The population who remains at increased risk of a LRR may benefit from either more intensive therapy, such as an increased radiation boost dose, addition of a radiation sensitizer, an increase in the volume irradiated, such as the addition of a supraclavicular field, or additional targeted systemic therapy.An area of specific controversy is the management of postmastectomy patients with 1–3 positive nodes
A total of 193 FFPE samples were received from 10 Translational Breast Cancer Research Consortium (TBCRC) institutions
Often one of the samples of each case-control pair submitted had inadequate cellularity, the demographic and clinicopathological characteristics were similar among the evaluable patients with LRR, distant metastasis (DM), and control patients (Table 1)
Summary
An area of specific controversy is the management of postmastectomy patients with 1–3 positive nodes. The relative risk of LRR in this setting has been controversial and the benefit of radiation is felt to be minimal in many of these patients. Radiation therapy is increasingly offered to post-mastectomy patients with 1–3 positive nodes, with potential radiation-related morbidity.[7] In spite of the greatly variable practice in this area, a randomized trial testing the efficacy of post-mastectomy radiation failed to adequately accrue. The use of radiation in this setting has important implications for surgical planning (e.g. utilization of immediate breast reconstruction) and is a significant economic burden on the health care system.
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