This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Joensuu, H. Articles by Lundin, J. Search for Related Content PubMed PubMed Citation Articles by Joensuu, H. Articles by Lundin, J.

Amplification of erbB2 and erbB2 Expression Are Superior to Estrogen Receptor Status As Risk Factors for Distant Recurrence in pT1N0M0 Breast Cancer

A Nationwide Population-based Study¹

Departments of Oncology [H. J., M. L., T. S., J. L.] and Surgery [K. v. S.], Helsinki University Central Hospital, FIN-00029 Helsinki; Laboratory of Cancer Genetics, Institute of Medical Technology, University and University Hospital of Tampere, Tampere [J. I.]; Department of Palliative Medicine, Tampere University Hospital, Tampere [K. H.]; Department of Oncology, Kuopio University Hospital, Kuopio [V. K.]; Department of Oncology, Turku University Central Hospital, Turku [L. P.]; Department of Oncology and Radiotherapy, Oulu University Central Hospital University, Oulu [T. T-H.], Finland

	ABSTRACT

Top ABSTRACT Introduction Patients and Methods Results Discussion REFERENCES

 
Purpose: To assess the relative importance of 10 prognostic factors in pT1N0M0 breast cancer (2 cm in diameter, node negative).

Experimental design: Women diagnosed with breast cancer in Finland from 1991 to 1992 were identified from the files of the Finnish Cancer Registry, and individual clinicopathological data were collected from the hospital case records of women living in five regions comprising about one-half of the Finnish population. Of the women with minimum required information available (n = 2842), 852 had unilateral pT₁N₀M₀ cancer. The median follow-up time was 9.5 years, and only 5% had received systemic adjuvant therapy. Estrogen receptor (ER), progesterone receptor, erbB2, p53, and Ki-67 expression was determined from tumor tissue microarrays using immunohistochemistry, and the erbB2 (HER-2) amplification status was determined using chromogenic in situ hybridization.

Results: Primary tumor size 5 mm and histological grade 1 were associated with 100 and 95% (95% confidence interval, 92–98%) 9-year distant disease-free survival, respectively, whereas strong erbB2 expression or the presence of >20% Ki-67-positive cells was associated with >20% risk. ER and progesterone receptor values obtained from the hospital case records or tumor microarrays showed weaker association with outcome than the erbB2 status. Small (10 mm) erbB2-negative cancers were associated with >90% 9-year distant disease-free survival, irrespective of histological grade.

Conclusions: Prognosis of pT₁N₀M₀ breast cancer is generally well defined by the histological grade and primary tumor size. The erbB2 status was superior to ER as a prognostic factor in these tumors.

	Introduction

Top ABSTRACT Introduction Patients and Methods Results Discussion REFERENCES

 
Most node-negative breast cancers with the primary tumor 2 cm (pT₁N₀M₀) do not recur within 20 years of follow-up when treated with locoregional therapy alone and may thus be cured of the disease without any systemic therapy (1 , 2) . Yet, 10–30% of pT₁N₀M₀ cancers treated with locoregional therapy alone eventually recur (1, 2, 3, 4) . Some of these patients are likely to benefit from adjuvant therapy, but, in general, the benefit becomes less the smaller the primary tumor size. pT₁N₀M₀ cancer is becoming increasingly common with the use of mammography, and in some series, 30% of cancers are 1 cm (5) . Hence, pT₁N₀M₀ cancers are not only common but they may also be problematic when the decision regarding the use of adjuvant therapy needs to be made.

The most commonly used recommendations for assessment of the risk of recurrence are probably those proposed by the International Consensus Panel (6) . Recently, this panel classified node-negative breast cancers as "minimal low risk" of recurrence (defined as recurrence risk 10% at 10 years) when all of the following four criteria are met: (a) the primary tumor is <2 cm in diameter; (b) cancer is ER³ and/or PgR positive; (c) histological grade is 1 (well differentiated); and (d) age at presentation is 35. The panel recommends either tamoxifen or no adjuvant systemic therapy given to patients with endocrine-responsive minimal/low-risk cancer, whereas all other cancers with higher risk were recommended to be treated with adjuvant therapies.

When these recommendations are followed, the question of whether to use or not adjuvant systemic therapy concerns only pT₁N₀M₀ cancer, and the major determinants in this decision making are the hormone receptor status and histological grade. The third factor, age 35 at presentation, is of relatively limited practical significance, because 99% of all breast carcinoma patients are >35 at diagnosis. Before accepting the hypothesis that the ER/PgR status and histological grade are the factors of choice in defining the minimal/low-risk category, these factors should be compared with other potentially efficient prognostic parameters in population-based series.

In the present study, we assessed several clinical, histopathological, and cancer biological factors in pT₁N₀M₀ breast cancer using tumor tissue microarrays. We made an attempt to use the female population of Finland as the starting material, because nation-wide series are likely to be unbiased, and such studies have not been done earlier. Cancer histological type and grade were determined by numerous pathologists and not by few experts, because we were interested to know how these parameters work in prognostication when assessed as part of the routine patient care.

	Patients and Methods

Top ABSTRACT Introduction Patients and Methods Results Discussion REFERENCES

 
Patients.
Five well-defined geographical regions comprising 50% of the Finnish population were selected for the study (Fig. 1) . We identified women diagnosed with breast cancer within these regions in 1991 or 1992 from the files of the Finnish Cancer Registry, which has a coverage approaching to 100%. A computer search identified 2930 women diagnosed with breast cancer in 1991–1992, which constitutes 53% of all 5551 breast cancers diagnosed in Finland.

View larger version (23K): [in this window] [in a new window]   Fig. 1. Five regions that took part in the study in Finland.

Histopathology.
Histological typing and evaluation of the grade components (mitotic count, nuclear pleomorphism, and tubule formation) were done according to the WHO classification (7) , although the criteria used in tumor classification cannot be stated with certainty in retrospect. The main difference between these criteria and those published by Elston and Ellis (8) is that the latter use semiquantitative assessment of tubule formation and define more accurately how to perform mitotic counting. The tumors were classified into three histological types: (a) ductal carcinoma (not otherwise specified, includes apocrine, mixed mucinous, and atypical medullary types); (b) lobular carcinoma (infiltrating lobular carcinoma with variants); and (c) the special histological types (includes tubular, medullary, cribriform, papillary, and pure mucinous carcinomas). More than 50 pathologists performed histological typing and grading at the time of diagnosis.

The longest primary tumor diameter was extracted in most cases from the pathology report (n = 642, 77%) or from the surgery or mammography report. In case of multiple invasive lesions (n = 88, 10%), the diameter of the largest lesion was recorded. ER and PgR status had been determined at the time of diagnosis either by immunohistochemistry (60 and 62%, respectively) or the dextran-coated charcoal method and was classified as positive or negative.

Preparation of Tumor Tissue Microarrays.
Formalin-fixed, paraffin-embedded tumor samples were used for tissue microarrays. Representative tumor regions were first defined from H&E-stained sections and marked. Tumor tissue array blocks were made by punching a 0.6-mm tissue cylinder through a histologically representative area of each "donor" tumor block, which was then inserted into an empty "recipient" tissue array paraffin block using a specific instrument (9) . Three cores were cut from each donor block for the tissue microarray blocks. From the tumor samples available, 19 tissue array blocks were prepared, each containing 50–144 tumor samples. Sections of 5 µm were cut and processed for immunohistochemistry and chromogenic in situ hybridization. Evaluation of the tissue array slides was aided by the use of a computer-controlled and motorized specimen stage (EcoDrive; Märzhauser, Inc., Wetzlar, Germany) installed on an Olympus BX50 microscope.

Immunohistochemistry.
For erbB2 (HER-2) staining, the sections were deparaffinized, followed by antigen retrieval [autoclave treatment at 121°C for 2 min in 10 mM sodium citrate buffer (pH 6.0)]. The primary antibody (CB11; Novocastra Laboratories, Newcastle, United Kingdom) was diluted 1:200 in Powervision blocking solution and incubated overnight at 4°C. An antimouse-peroxidase polymer (30 min at room temperature; Powervision; Immunovision, Inc., Daly City, CA) and diaminobenzidine chromogen were used for visualization. The sections were counterstained with hematoxylin and embedded. A positive and negative control sample (tumors with and without erbB2 amplification in fluorescence in situ hybridization) were included in every staining batch. Evaluation of immunohistochemistry was done using x20 objective magnification. Only "3+"-like strong intensity immunostaining present on the cell membrane of the majority of cancer cells was scored as HER-2 positive.

Immunostaining for ERs was done on adjacent tissue array sections using the monoclonal antibody 6F11 (Novocastra Laboratories; dilution 1:500) and for PgRs using the antibody 312 (Novocastra; dilution 1:500). Immunostaining was considered as positive, when 10% of the cancer cells showed staining. p53 was immunostained with the DO7 antibody (Novocastra) at a dilution of 1:500 and Ki-67 using the MM-1 antibody (Novocastra; dilution 1:1000). Ki-67 and p53 staining were classified into three categories: (a) negative (no positively staining cancer cell nuclei found); (b) borderline (20% nuclei positive); or (c) positive (>20% of cancer cell nuclei stained). Because there was no significant difference in outcome between patients who had either negative or borderline staining, these groups were combined in further analyses.

Chromogenic in Situ Hybridization.
As described in more detail elsewhere (10) , the microarray slides were deparaffinized and incubated in 0.1 M Tris-HCl (pH 7.3) at 92°C for 10 min, followed by cooling for 20 min at room temperature. Enzymatic digestion was done by applying 100 µl of digestion enzyme onto the slides (Digest-All III solution; Zymed, Inc., San Francisco, CA). After dehydration, a ready-to-use digoxigenin-labeled HER-2/neu DNA probe (Zymed) was applied on the slides. The sections were denatured on a thermal plate, and hybridization was carried out overnight at 37°C. The HER-2/neu probe was detected by means of sequential incubations with mouse antidigoxigenin (diluted 1:300; Roche Biochemicals, Mannheim, Germany), antimouse-peroxidase polymer (Powervision+; Immunovision, Inc.), and diaminobenzidine chromogen. The tissue sections were lightly counterstained with hematoxylin and embedded. A positive and negative control sample (tumors with and without HER-2 amplification in fluorescence in situ hybridization) were included in every hybridization batch. The sections were evaluated using a x40 dry objective. Amplification was defined as more than or equal to six signals per nucleus in >50% of cancer cells or when large gene copy clusters were seen.

Statistical Analysis.
Life tables were calculated according to the Kaplan-Meier method. DDFS was computed from the date of diagnosis to occurrence of metastases outside the locoregional area or to death from breast cancer, whichever came first. Breast cancer-specific survival was calculated from the date of diagnosis to death from breast cancer. Patients who died from an intercurrent cause were censored at the date of death. Survival curves were compared with the Log-rank test. Multivariate survival analyses were performed using the following covariates: (a) grade (well differentiated, 0; moderately or poorly differentiated, 1, because moderately and poorly differentiated cancers had similar outcome); (b) ER and PgR status (positive or borderline, 0; negative, 1); (c) erbB2 immunostaining (negative, 0; positive, 1); (d) erbB2 amplification status (no amplification, 0; amplification, 1); (e) histological type (lobular or special, 0; ductal, 1; the lobular and special types were associated with similar outcome); and (f) tumor size in millimeters as a continuous variable. The final multivariate model was constructed using backward Cox stepwise proportional hazards regression, and a P of 0.05 was adopted as the limit for inclusion of a covariate. All Ps are two sided.

	Results

Top ABSTRACT Introduction Patients and Methods Results Discussion REFERENCES

 
Frequency, Characteristics, and Outcome.
Of the 1208 node-negative cancers, 852 (70.5%) had a primary tumor 20 mm (pT₁N₀M₀). This was 46% of all breast cancers with histologically examined axillary nodes (n = 1854). The estimated 10-year DDFS was 87%, and breast cancer-specific survival was 90% (Fig. 2) .

View larger version (10K): [in this window] [in a new window]   Fig. 2. Breast cancer-specific DDFS of 852 patients with pT1N0M0 breast cancer. The 9-year DDFS is 88%.

Patients with cancer with erbB2 overexpression or erbB2 amplification had 72–73% 9-year DDFS, irrespective of the method of analysis, and tumors with a high proportion of Ki-67- or p53-positive cells were associated with 20% risk for distant recurrence within 9 years after diagnosis (Table 2) . On the other hand, tumor ER content was not significantly associated with outcome when either the original ER status or the microarray-derived ER content was entered in the survival analysis (Fig. 3) . A negative PgR status was marginally associated with poor outcome in univariate analyses.

View larger version (28K): [in this window] [in a new window]   Fig. 3. DDFS by histological grade, ER content, erbB2 protein expression, and erbB2 amplification status. Left panels, tumor diameter 1–10 mm; right panels, 11–20 mm.

Prognostic Categories in pT₁N₀M₀ Breast Cancer.
In general, histological grade alone defined reasonably well the minimal to low-risk category, because patients with well-differentiated cancer had 95% 9-year DDFS survival, irrespective of the tumor size (Table 4) . Tumor size 10 mm was not uniformly associated with a low risk for distant recurrence, because patients with moderately or poorly differentiated cancer had only 88% (81–95%) 9-year DDFS. Additional analysis of this subgroup suggested that patients with small (10 mm) grade 2 or 3 cancer had a high risk for distant recurrence only when erbB2 expression was positive, whereas patients whose cancer was erbB2 negative had >90% 9-year DDFS (Table 4) . When the outcome of cancers with positive and negative erbB2 expression was compared within the subset of grade 2 or 3 cancer and 10 mm, cancers with negative erbB2 staining were associated with better DDFS than those with positive staining (9-year survival 95 versus 67%, P = 0.003; Fig. 4 ). The result remained the same when the erbB2 status was defined by erbB2 amplification (92 versus 67%, P = 0.006). In this subgroup, too, neither the original nor the microarray-derived ER or PgR content was associated with prognosis (for the original ER assays, 87 versus 90%, P = 0.52; for the original PgR assays, 87 versus 90%, P = 0.57; for the microarray-derived ER assays, 92 versus 81%, P = 0.15; for the microarray-derived PgR content, 89 versus 91%, P = 0.63).

View larger version (20K): [in this window] [in a new window]   Fig. 4. DDFS by cancer erbB2 expression (top panel) and erbB2 amplification status (bottom panel) in moderately or poorly differentiated breast carcinomas with the longest primary tumor diameter ranging from 6 to 10 mm.

	Discussion

Top ABSTRACT Introduction Patients and Methods Results Discussion REFERENCES

There is discrepancy regarding the threshold for ER/PgR that defines endocrine-responsive disease, and even tumors with as few as 1% of positive cells may be regarded as potentially endocrine responsive. Because a precise threshold probably does not exist, 10% positive staining cells for either receptor might be considered as a reasonable threshold accepted by most (6) . We used the 10% cutoff in the tumor microarray analyses, but for the hospital case record data, we accepted the original classification as such. The ER status was somewhat inferior to the PgR status as a prognostic factor, which is plausible, because PgR expression is an indicator of an intact ER pathway, and the PgR requires estrogen stimulation for expression (12) .

ErbB2/HER-2, TP53 mutation, and the presence of a high level of cell proliferation have been regarded as factors of uncertain clinical value as prognostic markers (6) . Amplification or overexpression of erbB2 has been considered as a weak to moderate negative prognostic marker, and a recent review considers the clinical utility of this marker unclear (13) . Contrary to our expectations, both erbB2 expression and erbB2 amplification status were strongly associated with outcome, and the erbB2 status was an independent prognostic factor in a multivariate analysis in pT₁N₀M₀ cancer. Interestingly, the erbB2 status and pT defined a low-risk subgroup within the moderately/poorly differentiated cancers (Fig. 4) . The approximate size of this subgroup is 13% of all pT₁N₀M₀ cancers, 9% of all node-negative cancers, and 6% of all breast cancers. The erbB2 status also predicts for response to trastuzumab therapy (13) , which favors its determination in the clinical praxis. Twenty to 30% of breast cancers are erbB2 positive (13) , whereas only 12–13% of all pT₁N₀M₀ cancers stained positively for erbB2 or had amplified erbB2. This may reflect the smaller malignancy potential of the pT₁N₀M₀ breast cancers or the population-based nature of the study (14) .

All prognostic factors of potential interest could not be included in the present analysis. Lymphatic and/or vascular invasion of cancer is sometimes recognized as a feature indicating an increased risk (4 , 15) , but this factor, too, is not uniformly accepted nor included in consensus recommendations (16) . Detection of cancer cells in the bone marrow aspirate at diagnosis has been suggested to predict poor outcome, and one large study found carcinoma cells in the marrow of 23% of patients with T1a breast cancer and in 35% (29) of those with T1b cancer. Because patients with T1a breast cancer have 100% breast cancer-specific survival, many of the positive marrow findings may have little clinical significance in these subgroups, and additional research needs to be carried out until the presence of cytokeratin-positive marrow cells can be accepted as a reliable prognosticator in pT₁N₀M₀ disease.

Tumor microarrays allow rapid analysis of biological parameters, but they have also limitations. Tumor heterogeneity cannot be addressed from microarrays unless several tissue cores are prepared from each tumor. However, this may not be a severe limitation, because some common prognostic variables appear to show equally good or better association with outcome when assessed from microarrays than when the same factors are determined from ordinary immunostained slides (Table 2) .⁴ According to one study, one core taken for a tumor tissue array from the original paraffin block represents the ER, PgR, and erbB2 status of the original tumor with 90–95% accuracy, and when three cores are cut from each tumor, the accuracy raises to 98% (17) .

We did not succeed in obtaining the paraffin blocks from all patients for tumor microarray preparation, and some analyses failed technically, which led to loss of microarray data in about one-third of the cases (Table 1) . This is, however, unlikely to alter the conclusions of the study, because DDFS of the patients whose tumor erbB2, ER, or PgR expression could not be studied on the tissue arrays was not different from that of the patients whose tumor tissue was available for these analyses (P = 0.44, 0.50, and 0.37, respectively). Similarly, we found no difference in outcome between the cases where histological grading was or was not available (P = 0.57). On the other hand, patients where the data on the original ER and PgR status were missing had somewhat better outcome than those cases where these data were available (P = 0.02 and 0.03, respectively), which survival difference is likely to result from inability to perform hormone receptor analysis using the dextran-coated charcoal method from the smallest tumors (data not shown).

As in most other published series, tumor size was usually based on the pathology reports. The tumor sizes measured from gross examination and those assessed from microscopic examination have been reported to differ by 3 mm in about one-third of the cases, and therefore, the size of the invasive component of the lesion as determined from microscopic evaluation has been recommended for clinical use (18) .

We conclude that women with pT₁N₀M₀ breast cancer 5 mm have excellent outcome with 10-year DDFS approaching to 100%. Patients with well-differentiated pT₁N₀M₀ cancer form a low-risk group for distant recurrence, irrespective of the tumor size within the pT₁N₀M₀ category. The prognostic influence of ER and PgR was limited in this nationwide study, and other factors, such as the erbB2 status, were more useful. The erbB2 status may be of particular value in defining the patients with low risk for recurrence within the subgroup of patients with moderately or poorly differentiated pT₁N₀M₀ cancer of 6–10 mm in diameter.

	ACKNOWLEDGMENTS

 
We thank laboratory technician Harri Sihto for skillful assistance.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Helsinki University Central Hospital Research Funds (to H. J., J. L.), Academy of Finland (to H. J.), Yamanouchi European Foundation (H. J.), Cancer Society of Finland (to H. J.), and the Finnish Breast Cancer Group (to H. J.).

² To whom requests for reprints should be addressed, at Department of Oncology, Helsinki University Central Hospital, Haartmaninkatu 4, P. O. Box 180, FIN-00029 Helsinki, Finland. Phone: 358-9-471 73208; Fax 358-9-471 74202; E-mail: heikki.joensuu{at}hus.fi

³ The abbreviations used are: ER, estrogen receptor; PgR, progesterone receptor; pT, primary tumor; TNM, Tumor-Node-Metastasis; RR, relative risk; CI, confidence interval; DDFS, distant disease-free survival.

⁴ Unpublished data.

Received 5/ 6/02; revised 10/21/02; accepted 10/22/02.

	REFERENCES

Top ABSTRACT Introduction Patients and Methods Results Discussion REFERENCES

 

1. Rosen P. P., Groshen S., Kinne D. W., Norton L. Factors influencing prognosis in node-negative breast carcinoma: analysis of 767 T1N0M0/T2N0M0 patients with long-term follow-up. J. Clin. Oncol., 11: 2090-2100, 1993.[Abstract/Free Full Text]
2. Joensuu H., Pylkkänen L., Toikkanen S. Late mortality from pT1N0M0 breast carcinoma. Cancer (Phila.), 85: 2183-2189, 1999.[CrossRef][Medline]
3. Chen Y-Y., Schnitt S. J. Prognostic factors for patients with breast cancers 1 cm and smaller. Breast Cancer Res. Treat., 51: 209-225, 1998.[CrossRef][Medline]
4. Leitner S. P., Swern A. S., Weinberger D., Duncan L. J., Hutter R. V. Predictors of recurrence for patients with small (one centimeter or less) localized breast cancer (T1a,bN0M0). Cancer, 76: 2266-2274, 1995.[CrossRef][Medline]
5. Cady B., Stone M. D., Schuler J. G., Thakur R., Wanner M. A., Lavin P. T. The new era in breast cancer. Invasion, size, and nodal involvement dramatically decreasing as a result of mammographic screening. Arch. Surg., 131: 301-308, 1996.[Abstract]
6. Goldhirsch A., Glick J. H., Gelber R. D., Coates A. S., Senn H. J. Meeting highlights: International Consensus Panel on the treatment of primary breast cancer. J. Clin. Oncol., 19: 3817-3827, 2001.[Free Full Text]
7. World Health Organization. . Histological typing of breast tumours, Ed. 2 World Health Organization Geneva, Switzerland 1981.
8. Elston C. W., Ellis I. O. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology, 19: 403-410, 1991.[Medline]
9. Kononen J., Bubendorf L., Kallioniemi A., Bärlund M., Schraml P., Leighton S., Torhorst J., Mihatsch M. J., Sauter G., Kallioniemi O. P. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat. Med., 4: 844-847, 1998.[CrossRef][Medline]
10. Tanner M., Gancberg D., Di Leo A., Larsimont D., Rouas G., Piccart M. J., Isola J. Chromogenic in situ hybridization: a practical alternative for fluorescence in situ hybridization to detect HER-2/neu oncogene amplification in archival breast cancer samples. Am. J. Pathol., 157: 1467-1472, 2000.[Abstract/Free Full Text]
11. Joensuu H., Toikkanen S. Comparison of breast carcinomas diagnosed in the 1980’s with those diagnosed in the 1940s to 1960s. Br. Med. J., 303: 155-158, 1991.
12. Horowitz K. B., McGuire W. L. Predicting response to endocrine therapy in human breast cancer: a hypothesis. Science (Wash. DC), 189: 726-727, 1975.[Abstract/Free Full Text]
13. Yamauchi H., Stearns V., Hayes D. F. When is a tumor marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer. J. Clin. Oncol., 19: 2334-2356, 2001.[Abstract/Free Full Text]
14. Eppenburger-Castori S., Kueng W., Benz C., Caduff R., Varga Z., Bannwart F., Fink D., Dieterich H., Hohl M., Muller H., Paris K., Schoumacher F., Eppenberger U. Prognostic and predictive significance of ErbB-2 breast tumor levels measured by enzyme immunoassay. J. Clin. Oncol., 19: 645-656, 2001.[Abstract/Free Full Text]
15. Goldhirsch A., Glick J. H., Gelber R. D., Senn H. J. Meeting highlights: International Consensus Panel on treatment of primary breast cancer. J. Natl. Cancer Inst. (Bethesda), 90: 1601-1608, 1998.[Free Full Text]
16. Braun S., Pantel K., Muller P., Janni W., Hepp F., Kentenich C. R., Gastroph S., Wischnik A., Dimpfl T., Kindermann G., Riethmuller G., Schlimok G. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I. II, or III breast cancer. N. Engl. J. Med., 342: 525-533, 2000.[Abstract/Free Full Text]
17. Camp R. L., Charette L. A., Rimm D. L. Validation of tissue microarray technology in breast carcinoma. Lab. Invest., 80: 1943-1949, 2000.[Medline]
18. Abner A. L., Collins L., Peiro G., Recht A., Come S., Shulman L. N., Silver B., Nixon A., Harris J. R., Schnitt S. J., Connolly J. L. Correlation of tumor size and axillary lymph node involvement with prognosis in patients with T1 carcinoma. Cancer (Phila.), 83: 2502-2508, 1998.[CrossRef][Medline]

This article has been cited by other articles:

				H. Sihto, J. Lundin, T. Lehtimaki, M. Sarlomo-Rikala, R. Butzow, K. Holli, L. Sailas, V. Kataja, M. Lundin, T. Turpeenniemi-Hujanen, et al. Molecular Subtypes of Breast Cancers Detected in Mammography Screening and Outside of Screening Clin. Cancer Res., July 1, 2008; 14(13): 4103 - 4110. [Abstract] [Full Text] [PDF]

				E. Azambuja, V. Durbecq, D. D. Rosa, M. Colozza, D. Larsimont, M. Piccart-Gebhart, and F. Cardoso HER-2 overexpression/amplification and its interaction with taxane-based therapy in breast cancer Ann. Onc., February 1, 2008; 19(2): 223 - 232. [Abstract] [Full Text] [PDF]

				L. Harris, H. Fritsche, R. Mennel, L. Norton, P. Ravdin, S. Taube, M. R. Somerfield, D. F. Hayes, and R. C. Bast Jr American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer J. Clin. Oncol., November 20, 2007; 25(33): 5287 - 5312. [Abstract] [Full Text] [PDF]

				R. I. Aqeilan, V. Donati, E. Gaudio, M. S. Nicoloso, M. Sundvall, A. Korhonen, J. Lundin, J. Isola, M. Sudol, H. Joensuu, et al. Association of Wwox with ErbB4 in Breast Cancer Cancer Res., October 1, 2007; 67(19): 9330 - 9336. [Abstract] [Full Text] [PDF]

				E. O. Hanrahan, V. Valero, A. M. Gonzalez-Angulo, and G. N. Hortobagyi Prognosis and Management of Patients With Node-Negative Invasive Breast Carcinoma That Is 1 cm or Smaller in Size (stage 1; T1a,bN0M0): A Review of the Literature J. Clin. Oncol., May 1, 2006; 24(13): 2113 - 2122. [Abstract] [Full Text] [PDF]

				A. Urruticoechea, I. E. Smith, and M. Dowsett Proliferation Marker Ki-67 in Early Breast Cancer J. Clin. Oncol., October 1, 2005; 23(28): 7212 - 7220. [Abstract] [Full Text] [PDF]

				N. Linder, J. Lundin, J. Isola, M. Lundin, K. O. Raivio, and H. Joensuu Down-Regulated Xanthine Oxidoreductase Is a Feature of Aggressive Breast Cancer Clin. Cancer Res., June 15, 2005; 11(12): 4372 - 4381. [Abstract] [Full Text] [PDF]

				T. T. Junttila, M. Sundvall, M. Lundin, J. Lundin, M. Tanner, P. Harkonen, H. Joensuu, J. Isola, and K. Elenius Cleavable ErbB4 Isoform in Estrogen Receptor-Regulated Growth of Breast Cancer Cells Cancer Res., February 15, 2005; 65(4): 1384 - 1393. [Abstract] [Full Text] [PDF]

				H. Sihto, M. Sarlomo-Rikala, O. Tynninen, M. Tanner, L. C. Andersson, K. Franssila, N. N. Nupponen, and H. Joensuu KIT and Platelet-Derived Growth Factor Receptor Alpha Tyrosine Kinase Gene Mutations and KIT Amplifications in Human Solid Tumors J. Clin. Oncol., January 1, 2005; 23(1): 49 - 57. [Abstract] [Full Text] [PDF]

				Y. Kun, L. C. How, T. P. Hoon, V. B. Bajic, T. S. Lam, A. Aggarwal, H. G. Sze, W. S. Bok, W. C. Yin, and P. Tan Classifying the estrogen receptor status of breast cancers by expression profiles reveals a poor prognosis subpopulation exhibiting high expression of the ERBB2 receptor Hum. Mol. Genet., December 15, 2003; 12(24): 3245 - 3258. [Abstract] [Full Text] [PDF]

				R. Nahta and F. J. Esteva HER-2-Targeted Therapy: Lessons Learned and Future Directions Clin. Cancer Res., November 1, 2003; 9(14): 5078 - 5084. [Abstract] [Full Text] [PDF]

				W. P. Carney, R. Neumann, A. Lipton, K. Leitzel, S. Ali, and C. P. Price Potential Clinical Utility of Serum HER-2/neu Oncoprotein Concentrations in Patients with Breast Cancer Clin. Chem., October 1, 2003; 49(10): 1579 - 1598. [Abstract] [Full Text] [PDF]

				J. S. Ross, J. A. Fletcher, G. P. Linette, J. Stec, E. Clark, M. Ayers, W. F. Symmans, L. Pusztai, and K. J. Bloom The HER-2/neu Gene and Protein in Breast Cancer 2003: Biomarker and Target of Therapy Oncologist, August 1, 2003; 8(4): 307 - 325. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Joensuu, H. Articles by Lundin, J. Search for Related Content PubMed PubMed Citation Articles by Joensuu, H. Articles by Lundin, J.