Abstract P2-04-01: HER2 Status as Predictor of Mammographic Screening Detection: Comparison of Interval-and Screen-Detected Breast Cancers

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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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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Activation of P38MAP kinase in estrogen-positive invasive breast cancers: Relation with HER2 and downstream signaling phosphorylated proteins expression.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e11560 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e11560-e11560

Author(s):

Jean-Louis Merlin ◽

Alexandre Harle ◽

Maeva Lion ◽

Anne-Sophie Chrétien ◽

Carole Ramacci ◽

...

Keyword(s):

Estrogen Receptor ◽

Mitogen Activated Protein Kinase ◽

Her2 Status ◽

Signaling Proteins ◽

Breast Cancers ◽

Her2 Expression ◽

Downstream Signaling ◽

Phosphorylated Proteins ◽

Significant Difference ◽

Mitogen Activated Protein

e11560 Background: P38 kinases are members of the mitogen-activated protein kinase (MAPK) family. In breast cancers MAPK, as well as PI3 kinase-AKT pathway signaling proteins have major implication in molecular oncogenesis and are extensively investigated as putative targets for therapy. The present study reports the investigation of the expression of P38MAPK and its phosphorylated form (p-P38MAPK) in clinical specimens of invasive breast carcinomas in relation with estrogen receptor and HER2 expression, as well as MAPK and PI3K signaling phosphorylated proteins. Methods: The expression of P38MAPK and p-P38MAPK as well as p-AKT, p-GSK3β, p-S6 kinase, p-MEK1, p-ERK1/2 were semi-quantitatively assessed using multiplex bead immuno-assay. The analyses were performed retrospectively in frozen specimens from 46 invasive breast tumors classified according to estrogen receptor (ER) and HER2 status. Results: All specimens were taken at diagnosis and validated for tumor content >50%. Twenty-nine were ER+, 17 were HER2+, 10 were triple negative (TN) tumors. Analyses were performed in triplicate from total protein extracts and were achievable in all specimens. P38MAPK was found to be expressed in all tumor specimen and significantly (P=0.002) overexpressed in ER+ tumors. P38MAPK was lower in TN tumors than in all others. The median expression of phosphorylated-P38MAPK was also higher in ER+ than in ER- tumors and lower in TN tumors than in all others. HER2 status had no influence on P38MAPK and p-P38MAPK expression. No variation in the phosphorylation rate of P38MAPK was observed in relation with ER, HER2 or TN status. Significantly higher (P=0.0048) expression of p-AKT tumors was observed in HER2+ tumors. No significant difference in p-MEK1, p-GSK3β and p-S6K expression was evidenced in any other comparisons based on ER and HER2 expression subtypes. Conclusions: Investigation of the expression of multiple phosphorylated signaling proteins can be used as molecular biomarkers for personalized targeted therapy. In ER+ invasive breast cancer, the overexpression of P38MAPK could serve as biomarker for evaluation of P38MAPK inhibitors.

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HER2 targeted therapy and outcome in HER2-equivocal cases after 2018 ASCO/CAP HER2 guideline modification.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14729 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14729-e14729

Author(s):

James Crespo ◽

Hongxia Sun ◽

Jimin Wu ◽

Qingqing Ding ◽

Guilin Tang ◽

...

Keyword(s):

Targeted Therapy ◽

Small Sample ◽

Her2 Status ◽

Breast Cancers ◽

Negative Group ◽

Metastatic Site ◽

Kaplan Meier ◽

Md Anderson

e14729 Background: The best targeted therapeutic approach for HER2-equivocal cases remains unclear. New ASCO/CAP HER2 guidelines are intended to decrease this ambiguity by combining immunohistochemistry and in situ hybridization to resolve equivocal cases as positive or negative. However, the benefit of anti-HER2 therapy in HER2-equivocal cases is unknown. Methods: We retrospectively reviewed patients who visited MD Anderson from April 2017 to March 2018 with equivocal HER2 results based on the 2013 ASCO/CAP guidelines. The population was divided into 2 cohorts according to biopsy origin (primary cohort: biopsy from breast or axilla; recurrent/metastatic cohort: biopsy from recurrent or metastatic site). HER2 status was redefined using the 2018 ASCO/CAP guidelines. OS and PFS were calculated (Kaplan-Meier method) based on redefined HER2 status and use of HER2 targeted therapy. Results: A total of 139 equivocal results were found. Primary cohort had 90 patients (33 received neoadjuvant and 57 adjuvant therapy). HER2 IHC results were 0 (6.6%), 1+ (37.7%), 2+ (50%), 3+ (1.1%), and no IHC (4.4%). 94% of HER2-equivocal results became HER2 negative. Only 5 patients received anti-HER2 therapy, all of them in the HER2-negative group. After median follow-up of 1.91 yrs, 3 deaths and 8 progressions had occurred. There was no statistically significant association between anti-HER2 therapy and OS (p = 0.67) or PFS (p = 0.49). The recurrence/metastatic cohort had 49 cases with equivocal results. HER2 IHC results were 0 (6.1%), 1+ (22.4%), 2+ (26.5%), and no IHC (44.9%). 55% of HER2-equivocal results became HER2 negative, and only 1 patient received anti-HER2 therapy. After median follow-up of 2.96 yrs, 15 deaths and 35 progressions had occurred. There was no statistically significant association between anti-HER2 therapy and OS (p = 0.61) or PFS (p = 0.78). Conclusions: Most HER2-equivocal results were redefined as HER2 negative using the new ASCO/CAP guidelines. Association between anti-HER2 therapy and OS or PFS according to the new HER2 status was not observed. Although this is a small sample with short follow-up, patients with HER2-equivocal breast cancers seem to have clinical behavior similar to HER2-negative breast cancer.

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