Concordance between results of inexpensive statistical models and multigene signatures in patients with ER+/HER2- early breast cancer.

Multigene signatures (MGS) are used to guide adjuvant chemotherapy (aCT) decisions in patients diagnosed with estrogen receptor (ER)-positive HER2-negative early breast cancer. We used results from three MGS (Oncotype DX® (ODX), MammaPrint® (MP) or Prosigna®) and assessed the concordance between high or low risk of recurrence and the predicted risk of recurrence based on statistical models. In addition, we looked at the impact of MGS results on final aCT administration during the multidisciplinary meeting (MDM). We retrospectively included 129 patients with ER-positive HER2-negative early breast cancer for which MGS testing was performed after MDM at University Hospitals Leuven between May 2013 and April 2019 in case there was doubt about aCT recommendation. Tumor tissue was analyzed either by ODX (N = 44), MP (N = 28), or Prosigna® (N = 57). Eight statistical models were computed: Magee equations (ME), Memorial Sloan Kettering simplified risk score (MSK-SRS), Breast Cancer Recurrence Score Estimator (BCRSE), OncotypeDXCalculator (ODXC), new Adjuvant! Online (nAOL), Mymammaprint.com (MyMP), PREDICT, and SiNK. Concordance, negative percent agreement, and positive percent agreement were calculated. Of 129 cases, 53% were MGS low and 47% MGS high risk. Concordances of 100.0% were observed between risk results obtained by ODX and ME. For MP, BCRSE demonstrated the best concordance, and for Prosigna® the average of ME. Concordances of <50.0% were observed between risk results obtained by ODX and nAOL, ODX and MyMP, ODX and SiNK, MP and MSK-SRS, MP and nAOL, MP and MyMP, MP and SiNK, and Prosigna® and ODXC. Integration of MGS results during MDM resulted in change of aCT recommendation in 47% of patients and a 15% relative and 9% absolute reduction. In conclusion, statistical models, especially ME and BCRSE, can be useful in selecting ER-positive HER2-negative early breast cancer patients who may need MGS testing resulting in enhanced cost-effectiveness and reduced delay in therapeutic decision-making.

Decentralization of Next-Generation RNA Sequencing-Based MammaPrint® and BluePrint® Kit at University Hospitals Leuven and Curie Institute Paris.

A previously developed and centrally validated MammaPrint® (MP) and BluePrint® (BP) targeted RNA next-generation sequencing (NGS) kit was implemented and validated in two large academic European hospitals. Additionally, breast cancer molecular subtypes by MP and BP RNA sequencing were compared with immunohistochemistry (IHC). Patients with early breast cancer diagnosed at University Hospitals Leuven and Curie Institute Paris were prospectively included between September 2017 and January 2018. Formalin-fixed paraffin-embedded tissue sections were analyzed with MP and BP NGS technology at the beta sites and with both NGS and microarray technology at Agendia. Raw NGS data generated on Illumina MiSeq instruments at the beta sites were interpreted and compared with NGS and microarray data at Agendia. MP and BP NGS molecular subtypes were compared to surrogate IHC breast cancer subtypes. Equivalence of MP and BP indices was determined by Pearson's correlation coefficient. Acceptable limits were defined a priori, based on microarray data generated at Agendia between 2012 and 2016. The concordance, the Negative Percent Agreement and the Positive Percent Agreement were calculated based on the contingency tables and had to be equal to or higher than 90%. Out of 124 included samples, 48% were MP Low and 52% High Risk with microarray. Molecular subtypes were BP luminal, HER2 or basal in 82%, 8% and 10% respectively. Concordance between MP microarray at Agendia and MP NGS at the beta sites was 91.1%. Concordance of MP High and Low Risk classification between NGS at the beta sites and NGS at Agendia was 93.9%. Concordance of MP and BP molecular subtyping using NGS at the beta sites and microarray at Agendia was 89.5%. Concordance between MP and BP NGS subtyping, and IHC was 71.8% and 76.6%, for two IHC surrogate models. The MP/BP NGS kit was successfully validated in a decentralized setting.

Correction to: Unexpected Benefit from Alpelisib and Fulvestrant in a Woman with Highly Pre-treated ER-Positive, HER2-Negative PIK3CA Mutant Metastatic Breast Cancer.

Dr. Arteaga serves on an Advisory Board for Novartis and was a consultant for AstraZeneca from 2015 to 2016. All other authors declare that they have no competing interests.

Prognostic Value of the Progesterone Receptor by Subtype in Patients with Estrogen Receptor-Positive, HER-2 Negative Breast Cancer.

BACKGROUND: In estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER-2) negative breast cancers, the progesterone receptor (PR) is an independent prognostic marker. Little is known about the prognostic value of PR by tumor grade. We assessed this in two independent datasets. PATIENTS AND METHODS: Women with primary operable, invasive ER+ HER-2 negative breast cancer diagnosed between 2000 and 2012, treated at University Hospitals Leuven, were included. We assessed the association of PR status and subtype (grade 1-2 vs. grade 3) with distant recurrence-free interval (DRFI) and breast cancer-specific survival. The interaction between PR status and subtype was investigated, and associations of PR status by subtype were calculated. The BIG 1-98 data set was used for validation. RESULTS: In total, 4,228 patients from Leuven and 5,419 from BIG 1-98 were analyzed. In the Leuven cohort, the adjusted hazard ratio (HR) of PR-positive versus PR-negative tumors for DRFI was 0.66 (95% confidence interval [CI], 0.50-0.89). For the interaction with subtype (p = .34), the HR of PR status was 0.79 (95% CI, 0.61-1.01) in luminal A-like and 0.59 (95% CI, 0.46-0.76) in luminal B-like tumors. In luminal A-like tumors, observed 5-year cumulative incidences of distant recurrence were 4.1% for PR-negative and 2.8% for PR-positive tumors, and in luminal B-like 18.7% and 9.2%, respectively. In the BIG 1-98 cohort, similar results were observed; for the interaction with subtype (p = .12), the adjusted HR of PR status for DRFI was 0.88 (95% CI, 0.57-1.35) in luminal A-like and 0.58 (95% CI, 0.43-0.77) in luminal B-like tumors. Observed 5-year cumulative incidences were similar. CONCLUSION: PR positivity may be more protective against metastatic relapse in luminal B-like versus luminal A-like breast cancer, but no strong conclusions can be made. In absolute risk, results suggest an absent PR is clinically more important in high compared with low proliferative ER+ HER-2 negative tumors. IMPLICATIONS FOR PRACTICE: An absent progesterone receptor (PR) predicts a worse outcome in women treated for an estrogen receptor-positive, human epidermal growth factor receptor 2 negative breast cancer. As low proliferative tumors lacking PR are now also classified high risk, the prognostic value of PR across risk groups was studied. Despite a negative test for interaction of the prognostic value of PR by tumor grade, the magnitude of an absent PR on breast cancer relapse is much larger in high than in low proliferative breast cancers.

Stromal characteristics are adequate prognosticators for recurrence risk in ductal carcinoma in situ of the breast.

BACKGROUND: Ductal carcinoma in situ (DCIS) of the breast constitutes a heterogeneous group of non-obligate precursors for invasive breast cancer. To date, adequate risk stratification is lacking, which is presumed to result in overtreatment. We previously identified myxoid stromal architecture as a potential prognosticator for loco-regional recurrence. In the present study, we investigated the prognostic potential of stromal characteristics. METHODS: Hematoxylin and eosin stained slides from 211 DCIS patients were reviewed. The following histological features were dichotomously assessed: nuclear grade, DCIS architecture, presence of necrosis, intraductal calcifications, stromal inflammation and myxoid stromal architecture. Loco-regional recurrences constituted the primary endpoint. RESULTS: Cox regression analysis showed that high nuclear grade, myxoid stromal architecture and moderate to extensive stromal inflammation were significantly associated with decreased recurrence-free survival, independent of radiotherapy. Based on these features, a combined risk score (CRS) was calculated, ranging from zero to three. A high CRS of three was associated with significantly shorter recurrence-free survival. Nineteen patients had a CRS of three, of which three relapsed (15.7%), whereas only one out of 113 patients with a CRS of zero relapsed (0.9%). CONCLUSIONS: We were able to validate our previously reported findings regarding the prognostic potential of myxoid periductal stroma in an independent DCIS patient cohort. A CRS based on nuclear grade, myxoid stromal architecture and stromal inflammation might facilitate discrimination of low risk from high risk patients. Consequently, the CRS may tailor adjuvant therapy. Future research should investigate whether radiotherapy can be safely omitted in patients with a low CRS.

Unexpected Benefit from Alpelisib and Fulvestrant in a Woman with Highly Pre-treated ER-Positive, HER2-Negative PIK3CA Mutant Metastatic Breast Cancer.

We present the case of a postmenopausal patient with a secondary metastatic ER-positive, HER2-negative breast cancer who was successfully treated with fulvestrant and alpelisib following six lines of therapy. The tumour showed two uncommon PIK3CA mutations, and with the combination of alpelisib and fulvestrant the patient went from ECOG grade 3, before the start of this therapy, to ECOG grade 1 during treatment until progressive disease after 6 months. This unexpected benefit emphasizes the importance of performing a Next Generation Sequencing (NGS)-based assay to screen for several cancer genes in the metastatic setting, even after more than four lines of therapy and a high ECOG grade. Moreover, the use of alpelisib may be beneficial for uncommon PIK3CA mutations.