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J F Simpson

Publications and source records attributed to J F Simpson.

At least 19 recordsLinked to original sources
PubMed2002

Predictors of long-term outcome following high-dose chemotherapy in high-risk primary breast cancer.

We report on a predictive model of long-term outcome in 114 high-risk breast cancer patients treated with high-dose chemotherapy between 1989 and 1994. Paraffin-blocks from 90 of the 114 primaries were assessed for the presence of five risk factors: grade, mitotic index, protein expression of p53, HER2/neu, and oestrogen/progesterone receptor status; we could analyse the effect of risk factors in 84 of these 90 tumours. Seven-year relapse-free and overall survival was 58% (95% confidence interval 44-74%) and 82% (95% confidence interval 71-94%) vs 33% (95% confidence interval 21-52%) and 41% (95% confidence interval 28-60%) for patients whose primary tumours displayed > or =3 risk factors vs patients with < or =2 risk factors. For the entire group of 168 high-risk breast cancer patients, inflammatory stage IIIB disease and involved post-mastectomy margins were associated with decreased relapse-free survival and overall survival; patients treated with non-doxorubicin containing standard adjuvant therapy experienced worse overall survival (RR, 2.08; 95% confidence interval 1.04 to 4.16; P=0.04), while adjuvant tamoxifen improved overall survival (RR, 0.65; 95% confidence interval 0.41-1.01; P=0.054). Future trial designs and patient selection for studies specific for high-risk breast cancer patients should include appropriate prognostic models. Validation of such models could come from recently completed randomised, prospective trials.

Adult↗
PubMed2001

Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo.

Aberrrant signaling by the epidermal growth factor receptor [EGFR (HER1, erbB1)] and/or HER2/neu tyrosine kinases is present in a cohort of breast carcinomas. Because HER2 is constitutively phosphorylated in some breast tumors, we speculated that, in these cancers, transmodulation of HER2 may occur via EGFR signaling. To test this possibility, we examined the effect of EGFR-specific kinase inhibitors against the HER2-overexpressing human breast tumor lines BT-474, SKBR-3, MDA-361, and MDA-453. ZD1839 (Iressa) is an ATP-mimetic that inhibits the purified EGFR and HER2 kinases in vitro with an IC(50) of 0.033 and >3.7 microM, respectively. The specificity of ZD1839 against EGFR was confirmed in Rat1 fibroblasts transfected with EGFR or HER2 chimeric receptors activated by synthetic ligands without the interference of endogenous receptors. Treatment of all breast cancer cell lines (except MDA-453) with 1 microM ZD1839 almost completely eliminated HER2 phosphorylation. In contrast, the incorporation of [gamma-(32)P]ATP in vitro onto HER2 receptors isolated from BT-474 cells was unaffected by 1 microM ZD1839. EGFR is expressed by BT-474, SKBR-3, and MDA-361 but not by MDA-453 cells, suggesting that ZD1839-mediated inhibition of the EGFR kinase explained the inhibition of HER2 phosphorylation in vivo. In SKBR-3 cells, ZD1839 exhibited a greater growth-inhibitory effect than Herceptin, a monoclonal antibody against the HER2 ectodomain. In both SKBR-3 and BT-474 cells, treatment with ZD1839 plus Herceptin induced a greater apoptotic effect than either inhibitor alone. Finally, ZD1839 completely prevented growth of BT-474 xenografts established in nude mice and enhanced the antitumor effect of Herceptin. These data imply that EGFR tyrosine kinase inhibitors will be effective against HER2-overexpressing breast tumor cells that also express EGFR and support their use in combination with HER2 antibodies, such as Herceptin, against mammary carcinomas with high levels of the HER2 proto-oncogene.

Animals↗
PubMed2001

No elevation in long-term breast carcinoma risk for women with fibroadenomas that contain atypical hyperplasia.

BACKGROUND: The authors previously showed that women with a fibroadenoma have a relative risk of invasive breast carcinoma of approximately 2.0 compared with women of similar age from the general population. This relative risk approaches 1.0 when family history and proliferative changes in the adjacent parenchyma are removed and rises to > 3.0 if the fibroadenoma has complex histology. The risk for developing breast carcinoma in women with atypical lobular hyperplasia (ALH) and atypical ductal hyperplasia (ADH) or their minimal variants within a fibroadenoma is unknown. METHODS: The authors conducted a long-term, retrospective cohort study of 1834 women with adequate follow-up who presented with fibroadenoma at three local hospitals between 1950 and 1968. Histology was reviewed using established criteria, and the patients were categorized with ALH, ADH, minimal atypia, or no atypia. RESULTS: The overall prevalence of ALH or ADH within fibroadenomas was 0.81%. Minimal or true atypia within a fibroadenoma appeared to be correlated with proliferative disease in the adjacent parenchyma but could not predict for the presence there of well-established atypia. Only 7% of women with well-developed atypia developed invasive carcinoma on follow-up. Three women with minimal atypia developed invasive carcinoma. CONCLUSIONS: In this study of a large cohort of women with fibroadenoma, the authors found that atypia within a fibroadenoma cannot predict for the presence of atypia within adjacent breast parenchyma. They also found that atypia confined to a fibroadenoma does not incur a clinically meaningful risk of future breast carcinoma development greater than that of fibroadenoma alone.

Adolescent↗
PubMed2001

Atypical ductal hyperplasia and ductal carcinoma in situ of the breast associated with perineural invasion.

Perineural invasion is a histologic feature usually diagnostic of invasion in malignancies. In the breast, however, it has been associated with benign lesions such as sclerosing adenosis (SA), complex sclerosing lesion/radial scar (CSL/RS), and ductal carcinoma in situ (DCIS). This article describes perineural invasion associated with atypical ductal hyperplasia (ADH), florid hyperplasia without atypia (FH), and DCIS. All cases with a diagnosis of perineural invasion were selected from a series of 10,000 breast consult cases. Invasive mammary carcinomas were excluded. Fourteen cases of perineural invasion were found and associated with the following diagnoses: ADH (5), DCIS (3), FH (5), and ductal adenoma (1). Nine cases developed in CSL/RS, 4 cases in SA, and 1 case in a previous biopsy site of ductal adenoma; lesions were all less than 3 mm. The glands involving nerves showed cytologic and architectural features of the adjacent ADH, DCIS, and FH. Immunostaining for protein gene product (PGP) 9.5 marked nerves, and smooth muscle actin antibody highlighted the myoepithelial cells around glands. Perineural invasion seen in association with DCIS and ADH, in a background of CSL/RS and SA, may pose difficulty in diagnosis, especially in small biopsy specimens. It should be assessed with care to avoid misinterpretation as invasive mammary carcinoma.

Actins↗
PubMed2001

Core biopsy of the breast with atypical ductal hyperplasia: a probabilistic approach to reporting.

The diagnosis of atypical ductal hyperplasia (ADH) at needle core breast biopsy (NCB) is typically regarded as an indication for surgical excision. Although ADH is an intermediate risk nonobligate precursor lesion, the rationale for further therapy is the result of a reported high prevalence of a concomitant more advanced lesion (typically ductal carcinoma in situ) as the index lesion. To assess whether certain histopathologic features of ADH in NCB are predictive of open biopsy outcomes, the authors correlated the extent and pattern of ADH in 47 core biopsies (11-or 14-gauge) with the subsequent surgical specimen. Extent of ADH on NCB was ascertained by determining the number of large ducts and/or terminal duct-lobular units affected, with involvement of one large duct or one terminal duct-lobular unit representing a single focus, involvement of one duct and one terminal duct-lobular unit as two foci, and so on. Of the 47 cases, ADH was restricted to < or =2 foci in 24 cases (51.1%), confined to 3 foci in 8 cases (17.0%), and involved > or =4 foci in 15 cases (31.9%). The corresponding histopathologic findings at excision were benign lesions without atypia (n = 14), focal residual ADH (n = 13), atypical lobular hyperplasia (n = 3), ductal carcinoma in situ (n = 15), and invasive mammary carcinoma (n = 2). When the number of foci of involvement by ADH on NCB (based on an average of 11.6 cores per case) was correlated with the open biopsy results, all cases of ADH limited to < or =2 foci had no worse lesion on excision, whereas ADH present in > or =4 foci was found to be a strong predictor of a more advanced lesion on excision (p <0.0001, chi2). When histologic pattern was evaluated, all cases of pure micropapillary ADH on NCB showed pure micropapillary ductal carcinoma in situ on excision.

Adult↗
PubMed2001

Pathology of preinvasive and excellent prognosis breast cancer.

We review recent reports on breast cancer and its predictors, emphasizing the clinical utility of tissue samples from patients. We highlight indicators of increased cancer risk and lesions without metastatic capacity at time of detection, but of sufficient risk of attaining metastatic capacity that treatment is mandated ( ie, ductal carcinoma in situ ). Emphasized are histologic features of importance in stratification of ductal carcinoma in situ. We also review invasive lesions with little capacity for metastatic behavior and indicators of low malignant potential. Included are several papers reviewing the usefulness of histologic grading, emphasizing mitotic counts. Also, the continuing utility of recognizing some special and unusual types of breast cancer is detailed. Sentinel lymph node evaluation by histology is included because some minimal or artifactual findings in lymph nodes can mimic true metastases.

Artifacts↗
PubMed2000

Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells.

HER2/neu (erbB-2) overexpression has been causally associated with tamoxifen resistance in human breast cancer cells. Forced expression of HER2 in MCF-7 breast cancer cells resulted in mitogen-activated protein kinase (MAPK) hyperactivity and tamoxifen resistance. Inhibition of HER2 and MAPKs with AG1478 and U0126, respectively, as well as dominant-negative MEK-1/2 constructs restored the inhibitory effect of tamoxifen on estrogen receptor (ER)-mediated transcription and cell proliferation. Both AG1478 and U0126 also restored the tamoxifen-mediated association of ER with nuclear receptor corepressor (N-CoR) in the antiestrogen-resistant MCF-7 cells. Treatment with a combination of tamoxifen and a HER2 kinase inhibitor reduced tumor MAPK activity and markedly prevented growth of HER2-overexpressing MCF-7 xenografts in athymic mice. Thus, blockade of HER2 and MAPK signaling may enhance tamoxifen action and abrogate antiestrogen resistance in human breast cancer.

Animals↗
PubMed2000

Blockade of the epidermal growth factor receptor tyrosine kinase suppresses tumorigenesis in MMTV/Neu + MMTV/TGF-alpha bigenic mice.

Overexpression of ErbB-2/Neu has been causally associated with mammary epithelial transformation. Here we report that blockade of the epidermal growth factor receptor (EGFR) kinase with AG-1478 markedly delays breast tumor formation in mouse mammary tumor virus (MMTV)/Neu + MMTV/transforming growth factor alpha bigenic mice. This delay was associated with inhibition of EGFR and Neu signaling, reduction of cyclin-dependent kinase 2 (Cdk2) and mitogen-activated protein kinase (MAPK) activities and cyclin D1, and an increase in the levels of the Cdk inhibitor p27(Kip1). In addition, BrdUrd incorporation into tumor cell nuclei was prevented with no signs of tumor cell apoptosis. These observations prompted us to investigate the stability of p27. Recombinant p27 was degraded rapidly in vitro by untreated but not by AG-1478-treated tumor lysates. Proteasome depletion of the tumor lysates, addition of the specific MEK1/2 inhibitor U-0126, or a T187A mutation in recombinant p27 all prevented p27 degradation. Cdk2 and MAPK precipitates from untreated tumor lysates phosphorylated recombinant wild-type p27 but not the T187A mutant in vitro. Cdk2 and MAPK precipitates from AG-1478-treated tumors were unable to phosphorylate p27 in vitro. These data suggest that increased signaling by ErbB receptors up-regulates MAPK activity, which, in turn, phosphorylates and destabilizes p27, thus contributing to dysregulated cell cycle progression.

Animals↗
PubMed2000

Induction of cytotoxic T cells and their antitumor activity in mice transgenic for carcinoembryonic antigen.

In order to develop immunotherapy strategies that are based on eliciting immune responsiveness to the self-antigen, human carcinoembryonic antigen (CEA), we examined whether cytotoxic T lymphocyte (CTL) activity against CEA could be elicited in CEA-transgenic and nontransgenic mice. CEA-transgenic [C57BL/ 6-TGN(CEAGe)18FJP] and nontransgenic mice were primed with CEA-transfected syngeneic fibroblasts in combination with Corynebacterium parvum. Spleen cells from immunized mice were cultured with irradiated syngeneic MC-38 colon carcinoma cells transfected with CEA (MC-38.CEA) as stimulators prior to the measurement of CTL activity. Primed nontransgenic spleen cells showed augmented CTL activity against MC-38.CEA cells as compared with control parental MC-38 cells, nontransfected or transfected with vector only. Moreover, primed CEA transgenic spleen cells showed augmented CTL activity against MC-38.CEA cells that was similar to that observed in nontransgenic mice. All CTL clones derived from either transgenic or nontransgenic mice showed cross-reactivity with MC-38 cells expressing the CEA-related antigen, nonspecific cross-reacting antigen, but not biliary glycoprotein. CEA-specific CTL clones were not identified. Adoptive transfer of cloned CTL resulted in inhibition of MC-38.CEA but not MC-38.BGP tumor growth. Tumor cures were elicited in mice treated with a combination of cloned CTL and cyclophosphamide. Histopathological examination of CEA-expressing colons from either immunized mice or recipients of cloned CTL did not reveal any autoimmune reactions. These studies demonstrate that CTL recognizing cross-reactive class I epitopes on the CEA molecule can be induced in transgenic mice. The expression of these epitopes on tumor cells creates effective targets for CTL in vivo without inducing adverse reactions in CEA-expressing normal tissues. Since anti-CEA CTL have been generated in humans, CEA-transgenic mice may be a useful model to study vaccines that are based on CTL effector mechanisms.

Animals↗
PubMed2000

Historical and epidemiologic background of human premalignant breast disease.

Premalignant breast disease in humans is a concept that admits to a broad range of elements and possible determinants predicting the likelihood of developing breast cancer. Most of these elements are relative, such as the risk of breast cancer for women that is 130 times that of men and peaks at a younger age by about 10 years. Breast cancer is clearly a stochastic, multifactorial process that evolves over many years in which we must make predictions by likelihood. This review will present the most specially defined and reliably proven of these elements, highlighting anatomic and molecular factors.

Biomarkers, Tumor↗
PubMed2000

Loss of expression of transforming growth factor beta type II receptor correlates with high tumour grade in human breast in-situ and invasive carcinomas.

AIMS: Loss of transforming growth factor beta type II receptor (TGFbeta-RII) expression has been associated with resistance to TGFbeta-mediated inhibition of cell proliferation and tumour progression. We investigated whether the expression of TGFbeta-RII is related to the progression of human breast cancer and whether there is a correlation between TGFbeta-RII expression and phenotypic markers of biological aggressiveness. METHODS AND RESULTS: Immunohistochemical methods were used to detect TGFbeta-RII in archival breast samples including benign proliferative lesions, ductal carcinoma in situ (DCIS) and invasive mammary carcinomas (IMC). Neoplastic cells showed reduced expression of TGFbeta-RII in comparison to the normal breast tissue and benign lesions. There was a significant inverse correlation between loss of TGFbeta-RII expression and tumour grade within both DCIS (P = 0.004) and IMC (P = 0.001) groups. There was an inverse correlation between TGFbeta-RII expression and both mitotic count (P = 0.001) and clinical stage (P = 0.004). Oestrogen receptor (P = 0.07) and lymph node status (P = 0.10) were not significantly associated with TGFbeta-RII expression. CONCLUSIONS: These data indicate that decreased expression of TGFbeta-RII may contribute to breast cancer progression and is related to a more aggressive phenotype in both in-situ and invasive carcinomas.

Adult↗
PubMed2000

Androgen receptor CAG repeat lengths in ductal carcinoma in situ of breast, longest in apocrine variety.

CAG repeat number in the androgen receptor (AR) has been associated with decreased prostate cancer risk, and AR expression has been found in female breast cancer, often associated with apocrine differentiation. Because trinucleotide expansion can alter gene expression and protein function, we hypothesized that it might occur in breast neoplasms. We used a repeat expansion detection technique to determine CAG repeat lengths in DNA from breast biopsies. Three lesion types were microdissected: fibroadenoma (48 cases), ductal carcinoma in situ (DCIS, 24 cases), and invasive mammary carcinoma (18 cases). The maximum number of CAG repeats in either allele of each patient in these three groups was compared. Microsatellite repeat lengths in DCIS were longer than in fibroadenomas or invasive carcinomas (P= 0.017 comparing DCIS vs invasive carcinomas). Two cases of apocrine DCIS had very long repeat lengths, both exhibiting microsatellite lengths at the longest range of normal (32 and 33). Inherited differences in AR CAG length might influence the transition from DCIS to invasive breast cancer, perhaps by modulating function of AR in breast tissue. AR microsatellite polymorphisms could influence cellular differentiation in DCIS lesions, promoting formation of the apocrine subtype in the presence of longer CAG repeats.

Journal Article↗
PubMed2000

Pathology of preinvasive and excellent-prognosis breast cancer.

Our review of recent developments in breast cancer emphasizes clinical utility of tissue samples from patients. We highlight indicators of increased cancer risk and lesions without metastatic capacity at time of detection (but of sufficient risk of attaining metastatic capacity that treatment is mandated, ie, ductal carcinoma in situ). This review also includes invasive lesions with little capacity for metastatic behavior and indicators of low malignant potential. Histologic criteria for their recognition, as well as biologic and clinical characterization, are discussed. Several papers reviewing the usefulness of histologic grading, emphasizing mitotic counts and definitions of microinvasion, are included.

Breast Neoplasms↗
PubMed2000

Prognostic value of histologic grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189.

PURPOSE: The identification of a subset of patients with axillary lymph node-positive breast cancer with an improved prognosis would be clinically useful. We report the prognostic importance of histologic grading and proliferative activity in a cohort of patients with axillary lymph node-positive breast cancer and compare these parameters with other established prognostic factors. PATIENTS AND METHODS: This Eastern Cooperative Oncology Group laboratory companion study (E4189) centered on 560 axillary lymph node-positive patients registered onto one of six eligible clinical protocols. Flow cytometric (ploidy and S-phase fraction [SPF]) and histopathologic analyses (Nottingham Combined Histologic Grade and mitotic index) were performed on paraffin-embedded tissue from 368 patients. RESULTS: Disease recurred in 208 patients; in 161 (77%), within the first 5 years. Mitotic index and grade were associated with both ploidy and SPF (P </=.01). Within the first 5 years of follow-up, mitotic index (P =.004), grade (P =.004), ploidy (P =. 006), and SPF (P =.05) were associated with time to recurrence; there was also a significant association with survival. The effect of mitotic index was largely a result of the difference between 0 to 2 mitoses/10 high-power fields (HPF; 5-year recurrence of 31%) and more than 2 mitoses/10 HPF (5-year recurrence of 52%). The 0 to 2 mitoses/10 HPF group was independently associated with improved prognosis at 5 years (P =.002) in regression models that included other standard prognostic factors. CONCLUSION: A subset of axillary lymph node-positive patients with improved prognosis may be identified using a lower (< 3 mitoses/10 HPF) mitotic count than is usually performed.

Adult↗
PubMed2000

Benign transport of breast epithelium into axillary lymph nodes after biopsy.

The most important prognostic indicator of distant metastasis in breast cancer is histologic documentation of axillary lymph node metastasis. Controversy exists about the importance of micrometastases (< 0.2 cm), and current pathology practice includes a careful search for their presence. We describe the histologic findings in a series of axillary lymph node dissections taken approximately 2 weeks after breast biopsy. Each case has limited presence of epithelial cells in the subcapsular sinus of a draining lymph node that we attribute to mechanical transport of tumor and/or normal breast epithelium secondary to the previous surgical or needle manipulation. These cells were accompanied by hemosiderin-laden macrophages and damaged RBCs. While the clinical implication of these findings is unknown, we believe that it will be of no clinical significance and have no untoward prognostic effect.

Adult↗