Re-evaluation of HER2 status in 606 breast cancers—gene protein assay on tissue microarrays versus routine pathological assessment

Objective There is a decreased risk of breast cancer in systemic lupus erythematosus (SLE) versus the general population; little is known regarding the receptor status of breast cancers in SLE, or treatment. Methods Breast cancer cases occurring after SLE diagnosis were ascertained through linkage with tumor registries. We determined breast cancer positivity for estrogen receptors (ER), progesterone receptors (PR), and/or Human Epidermal Growth Factor Receptor 2 (HER2), as well as cancer treatment. Results We obtained information on ER, PR, and/or HER2 status for 63 SLE patients with breast cancer. Fifty-three had information on ER and/or PR status; 36 of these (69%) were ER positive. Thirty-six of the 63 had information on HER2 status; of these, 26 had complete information on all three receptors. Twenty-one of these 26 (81%) were HER2 negative; seven of 26(27%) were triple negative. All but one patient underwent surgery; 11.5% received both non-tamoxifen chemotherapy and radiotherapy, 16.4% radiotherapy without non-tamoxifen chemotherapy, and 14.7% received non-tamoxifen chemotherapy without radiotherapy. Conclusion ER positivity was similar to historical general population figures, with a trend toward a higher proportion of triple-negative breast cancers in SLE (possibly reflecting the relatively young age of our SLE patients).

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Active c-Src has prognostic and therapeutic value in ER-negative breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.10063 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 10063-10063

Author(s):

A. Arnaout ◽

L. Yang ◽

C. Holloway ◽

N. Steven ◽

P. Sun ◽

...

Keyword(s):

Breast Cancer ◽

Prognostic Significance ◽

Immunohistochemical Analysis ◽

Tissue Microarrays ◽

Distant Recurrence ◽

Breast Cancers ◽

Nonreceptor Tyrosine Kinase ◽

Human Breast Carcinomas ◽

Er Positive ◽

Er Status

10063 Background: Approximately 33% of newly diagnosed breast cancers lack ER and these tend to have a worse prognosis as compared to ER-positive breast cancers. Therapeutic options are limited as they are not responsive to antihormonal therapy and often develop resistance to chemotherapies. We have recently shown that activation of the nonreceptor tyrosine kinase protein c-Src leads to the accelerated ER degradation in ER-negative breast cancers. This study performs an immunohistochemical analysis of activated c-Src in a large cohort of primary human breast carcinomas to a) assess its prognostic significance and b) correlate its relationship to the ER status of breast cancers. Methods: A total of 916 patients with breast cancer diagnosed between 1987 and 1997 had clinicopathological data and paraffin-embedded tumor tissues for the study. Tissue microarrays were constructed. A four point scoring system based on immunostaining intensity was used to grade the levels of active phosphorylated c-Src. Grading was done by one pathologist. Statistical analysis was used to assess the prognostic significance of activated c-Src and its relationship to other prognostic variables. Results: Median follow-up was 7.31 years. Active c-Src grade was inversely correlated with ER status (p=0.004) and predicted for treatment with chemotherapy (p=0.002) and lack of treatment with Tamoxifen (p=0.007). Patients with greater levels of c-Src tended to be younger (p=0.004) and had higher Bloom Richardson scores for their tumors (p=0.004). Higher levels of c-Src also predicted for for shorter timing to distant recurrence (p=0.01) and shorter timing to death (p=0.04). There was a trend towards a shorter timing to regional recurrence with higher levels of c-Src but the relationship was not statistically significant (p=0.08). Conclusion: This study supports the hypothesis that the presence of active, phosphorylated c-Src contributes to the development of ER-negative status in breast cancers. The presence of c-Src also is associated with other poor prognostic factors and contributes to a worse prognostic outcome. This study suggests that c-Src inhibitors may be a novel therapeutic strategy for the treatment of ER-negative breast cancers. No significant financial relationships to disclose.

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Subgroup analysis of GEICAM 9906 trial comparing six cycles of FE90C (FEC) to four cycles of FE90C followed by 8 weekly paclitaxel administrations (FECP): Relevance of HER2 and hormonal status (HR)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.10598 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 10598-10598 ◽

Cited By ~ 4

Author(s):

Á. Rodríguez-Lescure ◽

M. Martín ◽

A. Ruiz ◽

E. Alba ◽

L. Calvo ◽

...

Keyword(s):

Subgroup Analysis ◽

Disease Free Survival ◽

Tissue Microarrays ◽

Her2 Status ◽

Her2 Positive ◽

Kaplan Meier ◽

Maximum Benefit ◽

Embedded Blocks ◽

Secondary Objective ◽

Better Than

10598 Background: GEICAM 9906 interim analysis showed FECP improved disease-free survival (DFS) compared to FEC (SABCS 2005, abstract #39). As a secondary objective, predictive markers were centrally determined and DFS of subgroups analyzed. A prior report from CALGB 9344 trial suggested that patients (pt) with HER2+ tumors get the maximum benefit with adjuvant P (ASCO 2006, abstract #510). We aimed to confirm this finding in our dataset. Methods: 1248 node + pt received 6 q3wk cycles (cy) of FEC (600/90/600 mg/m2) or 4 cy of same FEC followed by 8 wk cy of P (100 mg/m2). Tumor paraffin-embedded blocks were prospectively collected from 889 pt (71%) for Tissue Microarrays. Statistical analysis used Kaplan-Meier estimates for DFS by treatment group at a median follow-up (FU) of 65 months (m). HER2 status was evaluated by FISH. HR status was determined by IHC, following Allred criteria. Results: At a median of 65 m FU, DFS for FECP remains better than FEC (79% vs. 72%; p=0.0042; HR= 0.71). HER2: DFS for HER2+ and HER2- pt were 66% vs. 78% (p=0.0008; HR= 0.60). HER2+ subgroup (n=177): DFS with FECP and FEC were 63% vs. 70% [p=0.5187, HR=1.18 (0.71–1.98)]. HER2- subgroup (n=712): FECP was significantly better than FEC [82% vs. 74%, p=0.0075; HR=0.65 (0.48–0.89)]. HR: DFS for HR+ and HR- pt were 80% vs. 68% (p<0.0001; HR= 0.52). HR+ subgroup (n=561): DFS with FECP and FEC were 82% vs. 79%, [p=0.2162; HR=0.79 (0.54–1.15)]. HR- subgroup (n=311): DFS was 72% vs. 65% [p=0.1633, HR=0.76 (0.51–1.12)]. DFS data in the four HER2/HR subgroups is summarized in the table . Conclusions: FECP is superior to FEC mostly in HER2-HR- (triple negative) tumors. Our subgroup analysis does not support the superiority of the paclitaxel-containing arm (FECP) in pt with HER2 positive tumors. [Table: see text] [Table: see text]

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Correlation of quantitative total HER2 expression and HER2 homodimers with histopathologic characteristics of breast cancers in the FinHer study

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.11061 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 11061-11061

Author(s):

W. Huang ◽

J. Weidler ◽

Y. Lie ◽

J. Whitcomb ◽

M. Leinonen ◽

...

Keyword(s):

Lymph Node ◽

Lymph Node Metastasis ◽

Tumor Size ◽

Dynamic Range ◽

Tumor Grade ◽

Her2 Status ◽

Breast Cancers ◽

Her2 Expression ◽

Node Metastasis ◽

Formalin Fixed Paraffin Embedded

11061 Background: We recently reported that the HERmark assay (Monogram Biosciences) accurately measures continua of total HER2 expression (H2T) and HER2 homodimers (H2D) over a wide (∼3 logs) dynamic range, and that a higher concordance was observed between H2T and HER2 status with more stringent central tests as compared with IHC tests performed locally (Joensuu et al, 2008 SABCS,abstract 2071). H2D/H2T ratio was reported as a marker of activated HER2 and a prognosticator of disease progression in HER2+ patients not treated with trastuzumab in the adjuvant setting (Bates et al, 2008 SABCS,abstract 1074). In this follow-up analysis, H2T, H2D, and H2D/H2T ratio were correlated with histopathologic characteristics of breast cancers in the FinHer study. Methods: The HERmark assay was used to measure H2T and H2D in 899 formalin-fixed, paraffin-embedded FinHer specimens. The results were correlated with histopathologic characteristics of breast cancers in the FinHer study (Joensuu et al, N Engl J Med2006;354), including estrogen receptor/progesterone receptor (ER/PR), tumor grade, tumor size, lymph node metastasis, and stage. Results: Higher H2T and H2D levels correlated with ER/PR negativity and high tumor grade (P<0.0001). 42% (102/244) of ER- and 37% (137/374) of PR- cases were HERmark Positive; while 17% (110/655) of ER+ and 14% (75/524) of PR+ cases were HERmark Positive. 10% (13/136) of grade 1, 18% (65/353) of grade 2, and 35% (131/375) of grade 3 tumors were HERmark Positive. No significant association was found between H2T or H2D and tumor size, lymph node metastasis or stage. ER/PR negative and poorly differentiated cancers had higher H2D/H2T ratios (P=0.013), and H2D/H2T ratios >0.6 were associated with smaller primary tumor diameters at the time of cancer detection (P=0.009). Conclusions: The quantitative H2T measurement confirms the known correlations between HER2 expression and histopathologic characteristics of breast cancer. The novel H2D measurement and H2D/H2T ratio may provide further insights into HER2 activation and better diagnostic tests for targeted HER2 therapy. [Table: see text]

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Use of mutational profiling of metastatic ER+/HER2- breast cancers and the coexistence of KRAS, MET, BRAF, and FGFR3 with PIK3CA mutations.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.11003 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 11003-11003

Author(s):

Debora Fumagalli ◽

Roberto Salgado ◽

Carmen Criscitiello ◽

Lina Pugliano ◽

Ioanna Laios ◽

...

Keyword(s):

Hormonal Treatment ◽

Primary Diagnosis ◽

Outcome Data ◽

Her2 Status ◽

Breast Cancers ◽

Genetic Changes ◽

Pik3ca Mutations ◽

Paired Samples ◽

Adjuvant Hormonal Treatment ◽

High Concordance

11003 Background: ER+/HER2- breast cancers (BCs) constitute the most frequent BC subtype. Their response to endocrine therapy and degree of estrogen dependence are heterogeneous. There is little data available about the genetic changes associated with disease progression in this subtype. This information could facilitate drug development. Methods: A series of 132 ER+/HER2- BC patients diagnosed between 1982 and 2008, with known local-regional (n=10) or distant (n=98) relapse or both (n=24), and available FFPE blocks from their primary (P; n=132) and paired relapse (R; n=49) were identified at a single institution. ER and HER2 status were centrally confirmed. 120 mutations from 11 actionable genes and PTEN protein expression were determined using Fluidigm-based real-time PCR and IHC, respectively. Results: At primary diagnosis, median age was 57 years (27-90); median tumor size 2.5 cm (0.5-11); 75% had positive nodes, 26.5% were pre-menopausal; 80% received adjuvant hormonal treatment. Mutation frequency in P and R samples is presented in the Table. PIK3CA mutations were identified in 44% (58/132) P samples. HRAS, AKT1 and PIK3CA mutations were mutually exclusive. 62.5% (5/8) of KRAS-mutated, 75% (6/8) of MET-mutated, 100% (2/2) of BRAF-mutated and 33.3% (1/3) of FGFR3-mutated P had coexistent PIK3CA mutations. For the 49 evaluated pairs, high concordance for the mutations status was found between P and R. Conclusions: KRAS, BRAF, MET and FGFR3 mutations, found at relatively high frequency in this population of relapsed ER+/HER2- BCs, could represent clinically relevant targets and contribute to mechanisms of recurrence, particularly in PIK3CA-mutated BCs. Mutation profiling of additional paired samples is ongoing and clinical outcome data will be presented. [Table: see text]

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Hormone receptor-dependent regulation of ABAT and beta-alanine metabolism in breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.11112 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 11112-11112 ◽

Cited By ~ 1

Author(s):

Jan Budczies ◽

Scarlet F. Brockmoeller ◽

Berit Mueller ◽

Manfred Dietel ◽

Oliver Fiehn ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Grade ◽

Staining Intensity ◽

Tumor Stage ◽

Her2 Status ◽

Rna Expression ◽

Breast Cancers ◽

Strong Negative Correlation ◽

Data Set ◽

Beta Alanine

11112 Background: Recently, we identified beta-alanine as biomarker for breast cancer using GC-MS based metabolomics. Beta-alanine is increased in breast cancer compared to normal tissues and in the more aggressive ER- subtype compared to ER+ breast cancer. Beta-alanine is a substrate of 4-aminobutyrate aminotransferase (ABAT), can be catabolised to malonate semialdehyde and used for reduction of NAD and acetylation of coenzyme A. The aim of the current study is to analyze ABAT protein and RNA expression in a large cohort of breast cancers. Methods: The specificity of a polyclonal antibody against ABAT was validated using siRNA in MFC7 cells. A cohort of 164 paraffin-embedded breast cancer tissues from the METAcancer biobank was investgated by immunohistochemistry. Tumor cells were evaluated separately for staining intensity (low, moderate or high) and percentage of stained cells. A cohort of 156 METAcancer samples was investigated for gene expression using whole genome DASL. Results: ABAT protein intensity correlated strongly with estrogen receptor (ER) status (p < 0.001), but not with HER2 status. In particular, the ABAT protein was highly expressed in 41% of the ER+ tissues, but only in 2% of the ER- tissues. Further, ABAT intensity correlated strongly with tumor grade (p < 0.001). ABAT intensity did not correlate with tumor stage or nodal status. Explorative evaluation of ABAT protein in normal cells revealed weak expression in some of the ducts and negative expression in adipose cells. ABAT protein and RNA expression strongly correlated in the subcohort investigated by DASL. Analysis of a large external data set (publicly available at www.kmplot.com) showed that low ABAT expression is associated with an unfavorable prognosis of breast cancer. Both, ABAT protein and RNA expression, showed a strong negative correlation with beta-alanine abundance. Conclusions: We reported on changes in beta-alanine metabolism that occur between the molecular subtypes of breast cancer and normal breast tissue. High expression of ABAT in ER+ breast cancer is compatible with catabolic use of beta-alanine. Differently, beta-alanine might be preferable used anabolic in ER- breast cancer, possibly for the synthesis of carnosine.

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