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Randomized Controlled Trial
. 2020 Jan;179(1):197-206.
doi: 10.1007/s10549-019-05446-y. Epub 2019 Sep 21.

Research-based PAM50 signature and long-term breast cancer survival

Minya Pu  1 , Karen Messer  2 , Sherri R Davies  3 , Tammi L Vickery  4 , Emily Pittman  1 , Barbara A Parker  5 , Matthew J Ellis  6 , Shirley W Flatt  1 , Catherine R Marinac  7   8 , Sandahl H Nelson  9 , Elaine R Mardis  10 , John P Pierce  2 , Loki Natarajan  11
Affiliations
Randomized Controlled Trial

Research-based PAM50 signature and long-term breast cancer survival

Minya Pu et al. Breast Cancer Res Treat. 2020 Jan.

Abstract

Purpose: Multi-gene signatures provide biological insight and risk stratification in breast cancer. Intrinsic molecular subtypes defined by mRNA expression of 50 genes (PAM50) are prognostic in hormone-receptor positive postmenopausal breast cancer. Yet, for 25-40% in the PAM50 intermediate risk group, long-term risk remains uncertain. Our study aimed to (i) test the long-term prognostic value of the PAM50 signature in pre- and post-menopausal breast cancer; (ii) investigate if the PAM50 model could be improved by addition of other mRNAs implicated in oncogenesis.

Methods: We used archived FFPE samples from 1723 breast cancer survivors; high quality reads were obtained on 1253 samples. Transcript expression was quantified using a custom codeset with probes for > 100 targets. Cox models assessed gene signatures for breast cancer relapse and survival.

Results: Over 15 + years of follow-up, PAM50 subtypes were (P < 0.01) associated with breast cancer outcomes after accounting for tumor stage, grade and age at diagnosis. Results did not differ by menopausal status at diagnosis. Women with Luminal B (versus Luminal A) subtype had a > 60% higher hazard. Addition of a 13-gene hypoxia signature improved prognostication with > 40% higher hazard in the highest vs lowest hypoxia tertiles.

Conclusions: PAM50 intrinsic subtypes were independently prognostic for long-term breast cancer survival, irrespective of menopausal status. Addition of hypoxia signatures improved risk prediction. If replicated, incorporating the 13-gene hypoxia signature into the existing PAM50 risk assessment tool, may refine risk stratification and further clarify treatment for breast cancer.

Keywords: Breast cancer; Gene signatures; Hypoxia; Long-term survival; PAM50 subtypes; Prognostic modeling.

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Conflict of interest statement

SD has stock or other ownership in NanoString Techologies. BAP has a consulting or advisory Role with Bioalta; Research Funding from Genetech, Glaxo Smith Kline, and Novartis; and Patents, Royalties, Other Intellectual Property with Salk Institute Licensed Technology. MJE has a leadership role, Employment of Immediate Family Member, and stock or other ownership, consulting or advisory role, and Honoraria with Bioclassifier, Prosigna, and NanoString Technologies. ERM has a leadership role and stock with Qiagen N.V., and a consulting or advisory role with Regeneron. The remaining authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
a Kaplan–Meier curve of PAM50 subtype and Disease-free survival (left, P < 0.001) and Breast cancer survival (right P < 0.001). b Kaplan–Meier curve of ROR-PT category and Breast cancer survival by nodal status (left node-negative P = 0.007; right node-positive P = 0.003). P-value based on likelihood ratio test comparing null (unadjusted) to PAM50 model
See this image and copyright information in PMC

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