Treatment decision in early stage ER+ HER2− breast cancer without the 70-gene signature test: a retrospective analysis

Aim MINDACT concluded that all breast cancer patients with a high clinical risk using a modified version of Adjuvant! Online need the 70-gene signature test (MammaPrint) to avoid adjuvant chemotherapy (aCT). As such aCT can safely be avoided in 71.5% (1093/1529) women with a high clinical risk grade 1-2 lesion. The aim of this study was to investigate distant recurrence free interval (DRFI) by use of aCT based on demographic and clinicopathological criteria only. Methods In this retrospective study we evaluated patients that were diagnosed in the Multidisciplinary Breast Center in the University Hospitals Leuven between 2000 and 2012. We assessed DRFI by use of aCT in our series of 942 consecutive grade 1-2 lesions with a high clinical risk (<71 years, grade 1, pN0, tumor size 3.1-5cm; <71 years, grade 1, pN1, tumor size 2.1-5cm; <71 years, grade 2, pN0, tumor size 2.1-5cm; <71 years, grade 2, pN1, any tumor size) as in MINDACT. Patients were estrogen receptor (ER) positive, human epidermal growth factor receptor2 (HER2) negative and received adjuvant endocrine therapy. Results In our center, aCT was used based on demographic and clinicopathological criteria only and 550 (58%) of high clinical risk patients did not receive aCT. The median follow-up was 8.2 years. The overall 5-year cumulative DRFI was 2.4% (95% CI, 1.5-3.2); this was 1.7% (95% CI, 0.9-3.1) in those who did not receive and 3.2% (95% CI, 1.8-5.4) amongst those who did receive aCT. Table 1 describes the patients who did not receive and who did receive aCT. Conclusion Omission of aCT based on clinicopathological results, in ‘MINDACT clinical high risk’, ER positive, grade 1-2 tumors, resulted in a low 5-year cumulative DRFI (1.7%). Clinicopathological factors may contribute to the most cost-effective use of gene expression profiles.status: publishe

Unexpected Benefit from Alpelisib and Fulvestrant in a Woman with Highly Pre-treated ER-Positive, HER2-Negative PIK3CA Mutant Metastatic Breast Cancer (vol 38, pg 1071, 2018)

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.status: publishe

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.status: publishe

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.status: publishe

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

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.status: publishe