The genomic profile of
            HER2
            ‐amplified breast cancers: the influence of ER status

By the conventional steroid-binding assay method for receptor, 3% of 1,095 primary breast cancers (or 10.6% of 263 premenopausal tumors) were classified as negative for estrogen receptor (ER), but positive for progesterone receptor (PR). The true ER status in this rare group of tumors was further investigated by the enzyme-immunoassay (EIA) or immunocytochemical (ICA) staining method using monoclonal antibodies H222 and D547. Immunoreactive ER was present in nine ER-/PR+ tumors studied, whereas it was not detectable in nine age-matched ER-/PR- tumors. Immunoreactive ER was also present in 24 ER+ breast cancers studied, and was particularly higher in tumors that were PR+. Measurement of immunoreactive ER by monoclonal antibody method provides certain advantages over the conventional dextran-coated charcoal (DCC) method, especially in ER-/PR+ tumors.

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Correlation of an Estrogen Receptor-related Phosphoprotein with Histopathological Features in Breast Cancer

The International Journal of Biological Markers ◽

10.1177/172460088900400206 ◽

1989 ◽

Vol 4 (2) ◽

pp. 95-102

Author(s):

R.M. Tomasino ◽

E. Daniele ◽

R. Nuara ◽

V. Morello ◽

M. Salvato ◽

...

Keyword(s):

Breast Cancer ◽

Monoclonal Antibody ◽

Estrogen Receptor ◽

Breast Carcinoma ◽

Breast Cancers ◽

Histopathological Features ◽

Histological Types ◽

Biological Meaning ◽

Er Status

A series of 65 cases of different histological types of breast carcinoma was investigated for the immunohistochemical location of the estrogen receptor-related, 29 kD phosphoprotein using the ER-D5 monoclonal antibody. The ER-D5 response is heterogeneous in relation to some therapeutic limitations and is correlated with histopathological features of the tumors and survival. The main parameters for evaluation of breast cancers are reviewed, both those that are statistically correlated and those that are not apparently always correlated but are known to have considerable biological meaning, such as the ER-status of tumors.

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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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Breast cancers with stem cell-like features delineate endocrine responsiveness

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.10517 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 10517-10517

Author(s):

A. Rody ◽

T. Karn ◽

C. Solbach ◽

R. Gaetje ◽

R. Diallo ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Lymph Node ◽

Survival Rates ◽

Disease Recurrence ◽

Normal Breast ◽

Endocrine Treatment ◽

Breast Cancers ◽

Er Positive ◽

Er Status

10517 Background: Endocrine responsiveness is one of the most important characteristics of breast cancer. The negative association between expression of the estrogen receptor (ER) and proliferation detected in normal breast is frequently lost in breast cancers leading to receptor independent growth and poor patients’ prognosis. Methods: Microarray analysis of 171 breast cancer samples allowed the discrimination of a KIT+ tumor group by using a set of genes coregulated with the “stem cell factor” receptor KIT. Validation was performed on three independent datasets encompassing 637 samples. Furthermore the response to endocrine treatment only was analyzed in a dataset of 700 patients. Results: KIT+ tumors are transcriptionally related to proposed mammary stem cells. Two types of KIT+ tumors were identified which are characterized by their positive and negative ER status, respectively. The inverse link of ER expression and proliferation is perfectly conserved within the KIT+ tumor groups, while it is uncoupled among half of the KIT-Low ER positive tumors. Those “uncoupled” ER positive tumors with altered ER response are characterized by a prognosis inferior to the ER negative cancers despite an apparent positive ER status (hazard ratio for disease recurrence, 2.07; 95% CI 1.53–2.81; P<0.001). Moreover, the 5 and 10 year survival rates of lymph node negative “uncoupled” tumors are even worse than those of lymph node positive “normal” ER positive cancers. While all ER positive patients seem to profit from endocrine treatment the relative benefit was reduced in uncoupled tumors (21.2 % vs. 31.7 %). Conclusions: The classification of breast cancers according to this biologically based model identified clinical relevant tumor groups whose further characterization will have important implications. Moreover, since the ability to recognize malfunctions in ER pathways largely depends on an appropriate reference system, the KIT+ tumors could allow a dissection of estrogen responsiveness giving crucial insights for prediction of response to endocrine therapy. No significant financial relationships to disclose.

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Tamoxifen, Radiation Therapy, or Both for Prevention of Ipsilateral Breast Tumor Recurrence After Lumpectomy in Women With Invasive Breast Cancers of One Centimeter or Less

Journal of Clinical Oncology ◽

10.1200/jco.2002.11.101 ◽

2002 ◽

Vol 20 (20) ◽

pp. 4141-4149 ◽

Cited By ~ 434

Author(s):

Bernard Fisher ◽

John Bryant ◽

James J. Dignam ◽

D. Lawrence Wickerham ◽

Eleftherios P. Mamounas ◽

...

Keyword(s):

Radiation Therapy ◽

Cumulative Incidence ◽

Breast Tumor ◽

Hazard Rate ◽

Tumor Recurrence ◽

Ipsilateral Breast Tumor Recurrence ◽

Distant Recurrence ◽

Breast Cancers ◽

Ipsilateral Breast ◽

Er Status

PURPOSE: This trial was prompted by uncertainty about the need for breast irradiation after lumpectomy in node-negative women with invasive breast cancers of ≤ 1 cm, by speculation that tamoxifen (TAM) might be as or more effective than radiation therapy (XRT) in reducing the rate of ipsilateral breast tumor recurrence (IBTR) in such women, and by the thesis that both modalities might be more effective than either alone. PATIENTS AND METHODS: After lumpectomy, 1,009 women were randomly assigned to TAM (n = 336), XRT and placebo (n = 336), or XRT and TAM (n = 337). Rates of IBTR, distant recurrence, and contralateral breast cancer (CBC) were among the end points for analysis. Cumulative incidence of IBTR and of CBC was computed accounting for competing risks. Results with two-sided P values of .05 or less were statistically significant. RESULTS: XRT and placebo resulted in a 49% lower hazard rate of IBTR than did TAM alone; XRT and TAM resulted in a 63% lower rate than did XRT and placebo. When compared with TAM alone, XRT plus TAM resulted in an 81% reduction in hazard rate of IBTR. Cumulative incidence of IBTR through 8 years was 16.5% with TAM, 9.3% with XRT and placebo, and 2.8% with XRT and TAM. XRT reduced IBTR below the level achieved with TAM alone, regardless of estrogen receptor (ER) status. Distant treatment failures were infrequent and not significantly different among the groups (P = .28). When TAM-treated women were compared with those who received XRT and placebo, there was a significant reduction in CBC (hazard ratio, 0.45; 95% confidence interval, 0.21 to 0.95; P = .039). Survival in the three groups was 93%, 94%, and 93%, respectively (P = .93). CONCLUSION: In women with tumors ≤ 1 cm, IBTR occurs with enough frequency after lumpectomy to justify considering XRT, regardless of tumor ER status, and TAM plus XRT when tumors are ER positive.

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ER as a predictor of early breast cancer (EBC) outcomes in patients.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.590 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 590-590

Author(s):

Joyce O'Shaughnessy ◽

David M. Loesch ◽

Devchand Paul ◽

Christopher T. Stokoe ◽

John E. Pippen ◽

...

Keyword(s):

Breast Cancer ◽

Adjuvant Chemotherapy ◽

Older Women ◽

Ovarian Function ◽

Premenopausal Women ◽

Age Group ◽

Breast Cancers ◽

Asco 2012 ◽

Low Levels ◽

Er Status

590 Background: Some ER-negative (ER-) breast cancers express low levels of estrogen receptors and approximately 12% express androgen receptors (Traina, T, et al. ASCO, 2012). Whether young premenopausal women (age <40) with ER- breast cancer (BC) who are more likely to retain ovarian function after adjuvant chemotherapy have a worse outcome than older women with ER- disease has not been widely investigated. Methods: We analyzed 2 adjuvant US Oncology BC studies: 99-016, 1830 BC patients randomized to doxorubicin/cyclophosphamide (AC)→Paclitaxel (P) (AC/P) vs AP→weekly P (no cyclophosphamide [C]) (AP/wP); and 01-062, 2611 patients randomized to AC→docetaxel (T) vs AC→T plus capecitabine (XT). ER+ patients received standard endocrine therapy following chemotherapy. Five-year DFS results did not show significant differences between the treatment arms on either study. The outcomes were analyzed for 5-year DFS by age ≤40yrs and >40yrs and by ER status. Results: In the two studies combined, ER- patients ≤40 had a superior DFS (84%) than ER- patients >40 (80%), while ER+ patients ≤40 had a worse 5-yr DFS (83%) than ER+ patients >40 (89%), although these findings were of borderline significance (see Table below). In 99-016, omitting C did not adversely affect outcomes in either age group, regardless of ER status. Conclusions: We did not observe worse outcomes in ER- patients ≤40 years compared to those >40 years in 2 US Oncology adjuvant chemotherapy trials, suggesting no adverse impact of assumed greater ovarian function following adjuvant chemotherapy in patients ≤40yrs. ER+ patients ≤40 had a worse DFS than ER+ patients >40. Omitting C in ER- patients ≤40 or >40 did not adversely affect outcome. [Table: see text]

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A study on the prevalence of HER2 genetic heterogeneity and its impact on breast cancer survival.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.586 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 586-586

Author(s):

Jingshan Ho ◽

Daniel Boon Yeow Chan ◽

Soo-Chin Lee ◽

Evelyn S. C. Koay

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Cancer Survival ◽

Histologic Grade ◽

Breast Cancers ◽

Impact On Survival ◽

Her 2 ◽

Her2 Heterogeneity ◽

Grade 3 ◽

Er Status

586 Background: HER2 heterogeneity (GH) has been described in breast cancer that has conventionally been labeled as HER2 negative (FISH score <2.2). We aimed to ascertain the prevalence of GH in HER2 negative breast cancers and to investigate for any impact on survival. Methods: We reviewed HER2 FISH (Vysis) data for 158 primary breast cancer specimens from 2006-2010 which were 0 – 2+ on immunohistochemistry. HER2:CEP17 ratios were calculated for each of the 60 cells scored and cases were classified as HER2 GH according to the ASCO/CAP guidelines (GH = 5-50% tumor cells with a ratio >2.2). Results: 67% (106/158), 7% (11/158) and 26% (41/158) were HER2 negative, equivocal (FISH ratio 1.8-2.2) and positive respectively. GH was found in 43% and 100% of Her2 negative and HER2 equivocal patients respectively. Of the 117 cases (with FISH score <2.2), HER 2 GH was associated with higher histologic grade (grade 3: 81.8%, 52.3% and 33.3% in HER2 equivocal, negative with GH and negative without GH (p = 0.007). There were no significant associations with ER status or the presence of lymphovascular invasion. The mean overall survival was 63 months (95% CI 43-87), 118 months (95% CI 96-141) and 148 months (95% CI 148-168) for HER 2 equivocal, negative with GH and negative without GH patients respectively (p=0.017). In a subset analysis of HER2 negative (with FISH score <2.2), non metastatic patients, with at least a 4 year follow up period (n=63), mean overall survival was 79 months (95% CI 60-98), 119 months (95% CI 96-143) and 159 months (95% CI 139-180) for HER2 equivocal, negative with GH and negative without GH patients (p=0.034). GH remained a significant factor in the multivariate analysis irrespective of grade, stage and ER status (p=0.046). Conclusions: HER2 GH occurs in 100% of HER2 equivocal and 43% of HER2 negative breast cancers and is associated with higher histologic grade and poorer overall survival, irrespective of grade, stage or hormonal status.

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Universal testing for hormonal status in breast cancer: Are we choosing wisely?

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.6583 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 6583-6583

Author(s):

Taylor Maxwell Goller ◽

Javier De Luca-Johnson ◽

Hibba tul Rehman ◽

Abiy Berhie Ambaye

Keyword(s):

Breast Cancer ◽

False Negative ◽

Nuclear Grade ◽

Breast Cancers ◽

Test Results ◽

Newly Diagnosed ◽

The Us ◽

Er Positive ◽

False Negative Test ◽

Er Status

6583 Background: Characterizing estrogen receptor (ER) and progesterone receptor (PR) status has long been standard practice with newly diagnosed breast cancers. ER and PR expression suggests a more favorable prognosis and predicts tumor responsiveness to hormonal therapy. However, this testing comes with considerable cost. At our institution, the Medicare reimbursement rate for a single ER/PR assay is $310. With over 300,000 newly diagnosed breast cancers in the US each year, the total cost of ER/PR testing is close to 100 million dollars. Furthermore, the 2010 American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) guidelines suggest that up to 20% of ER/PR testing worldwide may be inaccurate with potential for false negative results. A falsely negative result could lead clinicians to not offer treatment with hormonal therapies. The purpose of this study was to investigate whether nuclear grade could be used to predict ER status, thus saving cost and reducing the potential for false negative test results and the inappropriate withholding of beneficial treatment. Methods: A retrospective analysis of prospectively collected data from the University of Vermont Breast Cancer Database identified all newly diagnosed breast cancers of any histologic type with available data on nuclear grade and ER status (2/2008-10/2016). The relationship between nuclear grade and ER status was analyzed (Table). Results: Nuclear grades 1 and 2 were associated with a significantly higher proportion of ER positive results than high nuclear grades (chi-square test p <.001). Conclusions: Nuclear grade 1 and 2 breast cancers are nearly universally ER positive (99% and 97%, respectively). Thus, ER testing may be redundant in these tumors. Elimination of ER testing in nuclear grade 1 and 2 tumors could save tens of millions of dollars each year in the US alone. It could also reduce the potential for false negative test results and the inappropriate withholding of beneficial treatment. [Table: see text]

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Evaluation of pathologic and genomic characteristics in male breast cancer (MBC) patients.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.1098 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 1098-1098

Author(s):

Damien Mikael Hansra ◽

Eugene R Ahn ◽

John Edward McKnight ◽

Haritha Pabbathi ◽

Cynthia Lynch ◽

...

Keyword(s):

Breast Cancer ◽

Primary Tumor ◽

Ductal Carcinoma ◽

Genomic Alteration ◽

Breast Cancers ◽

Genomic Profile ◽

Adult Males ◽

Genomic Alterations ◽

Primary Tumor Site ◽

Metastatic Site

1098 Background: MBC is a rare entity comprising less than 1% of breast cancers [Siegel RL 2017]. Due to the low incidence of MBC, information about the genomic landscape of MBC is lacking. Here we describe detailed pathologic and genomic characteristics of MBC patients. Methods: IRB approval was obtained for a retrospective analysis of archived pathology on patients treated at Cancer Treatment Centers of America. Comprehensive genomic profiling of tumors was derived from Foundation One next generation sequencing. Clinical information was derived from retrospective chart review. Inclusions: adult males with breast cancer with stage IV metastatic disease. Exclusions: Females, stage 0-IIIC disease, missing genomic and pathology information. Results of clinical, pathology and genomic data were summarized. Results: 10 patients met study criteria. Median age: 56 yrs., range 39-61 yrs. Race: 5/10 (50%) Caucasian, 5/10 (50%) African American. Number of prior treatment regimens: mean = 2.6 (range 0-6). Intrinsic subgroup: hormone receptor (HR)+/ HER2- 7/10 (70%), HR+/ HER2+ 2/10 (20%), HR-/ HER2+ 1/10 (10%), triple negative breast cancer (TNBC) 0/10 (0%). Tumor histology: invasive ductal carcinoma 10/10 (100%). Histology grade: poorly differentiated (diff.) 4/10 (40%), moderate diff. 4/10 (40%), well diff. 1/10 (10%), unknown 1/10 (10%). Biopsy site: primary tumor 4/10 (40%), metastatic site 4/10 (40%), liquid biopsy 1/10 (10%). Most frequent genomic alterations: PIK3CA 5/9 (56%), CCND1 4/9 (44%), ZNF703 3/9 (33%), FGF4 3/10 (33%), GATA3 3/9 (33%) FGF 19 3/9 (33%), FGF3 3/9 (33%) Alterations in FGF seen 14/38 (36.8%) of total genomic alterations. Most frequent alterations by primary tumor: ZNF703 3/4 (75%), FGF3 2/4 (50%), FGFR1 2/4 (50%), CCND1 2/4 (50%), FGF19 2/4 (50%), FGF4 2/4 (50%); by metastatic site: PIK3CA 4/5 (80%), GATA 3 2/5 (40%), CCND1 2/5 (40%), FGF3 1/5 (20%), FGF19 1/5 (20%), FGF4 1/5 (20%). Genomic alteration by histologic subgroup; HR+ HER2- PIK3CA 3/6 (50%), CCND1 3/6 (50%), FGF4 3/6 (50%), ZNF703 3/6 (50%), FGF19 3/6 (50%), FGF3 3/6 (50%); HR+/ HER2+: PIK3CA 2/2 (100%), CCND1 1/2 (50%), GATA3 1/2 (50%), MLL3 1/2 (50%); TNBC: BRCA2 1/1 (100%), BARD1 1/1 (100%). Microsatellite status was stable in 6/6 (100%) of patients. Conclusions: MBC patients display a heterogeneous variety of complex genomic alterations. Mutations in FGF genes were most commonly observed. Other common alterations seen in this series include PIK3CA, CCND1, ZNF703, and GATA3. Furthermore, the genomic profile of primary tumor site differed from the genomic profile of the metastatic site.

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Estrogen Receptor Status by Immunohistochemistry Is Superior to the Ligand-Binding Assay for Predicting Response to Adjuvant Endocrine Therapy in Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.1999.17.5.1474 ◽

1999 ◽

Vol 17 (5) ◽

pp. 1474-1474 ◽

Cited By ~ 1385

Author(s):

Jennet M. Harvey ◽

Gary M. Clark ◽

C. Kent Osborne ◽

D. Craig Allred

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Clinical Outcome ◽

Ligand Binding ◽

Endocrine Therapy ◽

Binding Assay ◽

Adjuvant Endocrine Therapy ◽

Ligand Binding Assay ◽

Breast Cancers ◽

Er Status

PURPOSE: Immunohistochemistry (IHC) is a newer technique for assessing the estrogen receptor (ER) status of breast cancers, with the potential to overcome many of the shortcomings associated with the traditional ligand-binding assay (LBA). The purpose of this study was to evaluate the ability of ER status determination by IHC, compared with LBA, to predict clinical outcome—especially response to adjuvant endocrine therapy—in a large number of patients with long-term clinical follow-up. PATIENTS AND METHODS: ER status was evaluated in 1,982 primary breast cancers by IHC on formalin-fixed paraffin-embedded tissue sections, using antibody 6F11 and standard methodology. Slides were scored on a scale representing the estimated proportion and intensity of positive-staining tumor cells (range, 0 to 8). Results were compared with ER values obtained by the LBA in the same tumors and to clinical outcome. RESULTS: An IHC score of greater than 2 (corresponding to as few as 1% to 10% weakly positive cells) was used to define ER positivity on the basis of a univariate cut-point analysis of all possible scores and disease-free survival (DFS) in patients receiving any adjuvant endocrine therapy. Using this definition, 71% of all tumors were determined to be ER-positive by IHC, and the level of agreement with the LBA was 86%. In multivariate analyses of patients receiving adjuvant endocrine therapy alone, ER status determined by IHC was better than that determined by the LBA at predicting improved DFS (hazard ratios/P = 0.474/.0008 and 0.707/.3214, respectively) and equivalent at predicting overall survival (0.379/.0001 and 0.381/.0003, respectively). CONCLUSION: IHC is superior to the LBA for assessing ER status in primary breast cancer because it is easier, safer, and less expensive, and has an equivalent or better ability to predict response to adjuvant endocrine therapy.

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