Without epithelial–mesenchymal transitions, in which polarized epithelial cells are converted into motile cells, multicellular organisms would be incapable of getting past the blastula stage of embryonic development. However, this important developmental programme has a more sinister role in tumour progression. Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.

Epithelial–mesenchymal transitions in tumour progression

Clinical Trials: A Practical Approach

N A RECENT COLLABORATIVE REanalysis of more than 90% of the world’s epidemiological data on the relationship between menopausal hormone replacement therapy (HRT) and breast cancer risk, it was found that longer durations of recent, but not past, use of HRT increased breast cancer risk, particularly among leaner women and for tumors that were less clinically advanced. 1 Unresolved issues include the extent to which the findings were due to a biological effect of hormones rather than issues of screening and ascertainment. The data were also insufficient to determine whether a combined estrogen-progestin regimen increased risk beyond that associated with estrogen alone. In 1994, we published data on HRT

https://jamanetwork.com/journals/jama/articlepdf/192332/JOC91096.pdf

Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk.

An initial analysis of data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registries shows that the age-adjusted incidence rate of breast cancer in women in the United States fell sharply (by 6.7%) in 2003, as compared with the rate in 2002. Data from 2004 showed a leveling off relative to the 2003 rate, with little additional decrease. Regression analysis showed that the decrease began in mid-2002 and had begun to level off by mid-2003. A comparison of incidence rates in 2001 with those in 2004 (omitting the years in which the incidence was changing) showed that the decrease in annual age-adjusted incidence was 8.6% (95% confidence interval [CI], 6.8 to 10.4). The decrease was evident only in women who were 50 years of age or older and was more evident in cancers that were estrogen-receptor-positive than in those that were estrogen-receptor-negative. The decrease in breast-cancer incidence seems to be temporally related to the first report of the Women's Health Initiative and the ensuing drop in the use of hormone-replacement therapy among postmenopausal women in the United States. The contributions of other causes to the change in incidence seem less likely to have played a major role but have not been excluded.

https://www.nejm.org/doi/pdf/10.1056/NEJMsr070105

The decrease in breast-cancer incidence in 2003 in the United States

The year 2007 marks exactly two decades since Human Epidermal Growth Factor Receptor-2 (HER2) was functionally implicated in the pathogenesis of human breast cancer. This finding established the HER2 oncogene hypothesis for the development of some human cancers. The subsequent two decades have brought about an explosion of information about the biology of HER2 and the HER family. An abundance of experimental evidence now solidly supports the HER2 oncogene hypothesis and etiologically links amplification of the HER2 gene locus with human cancer pathogenesis. The molecular mechanisms underlying HER2 tumorigenesis appear to be complex and a unified mechanistic model of HER2-induced transformation has not emerged. Numerous hypotheses implicating diverse transforming pathways have been proposed and are individually supported by experimental models and HER2 may indeed induce cell transformation through multiple mechanisms. Here I review the evidence supporting the oncogenic function of HER2, the mechanisms that are felt to mediate its oncogenic functions, and the evidence that links the experimental evidence with human cancer pathogenesis.

The oncogene HER2; Its signaling and transforming functions and its role in human cancer pathogenesis

The type 1 tyrosine kinase receptor HER2 (c-erbB2/neu) is associated with resistance to hormone therapy and poor survival in invasive breast cancer, whereas HER4 expression is associated with endocrine responsiveness. Patterns of tyrosine kinase receptor coexpression may aid prediction of recurrence risk after surgery for ductal carcinoma in situ (DCIS). Women who had undergone surgery for pure DCIS were studied. Out of 129 primary tumors, 39 had recurred and 90 had not recurred after 5 years of follow-up. Primary tumors were compared for HER2, HER3, and HER4, estrogen receptor, and Ki67 by immunohistochemistry. HER2 was expressed in 58%, HER3 in 49%, and HER4 in 63% of nonrecurrent DCIS, compared with HER2 expression in 82% (P = 0.008), HER3 expression in 71% (P = 0.04), and HER4 expression in 36% (P = 0.004) in DCIS that subsequently recurred. Dually expressing HER2/4 DCIS was more likely to be estrogen receptor positive than HER2-only-expressing DCIS (73% versus 53%; P = 0.05). HER2 expression was associated with a higher percentage and HER4 expression a significantly lower percentage of proliferating DCIS cells (median, 13.8% versus 8.4%; P = 0.001). Coexpression of HER2 with HER4 was associated with reduced recurrence compared with HER2-only positive DCIS (P = 0.003). This association remained significant when analyzing only high nuclear-grade DCIS (P = 0.015). Low nuclear grade, low proliferation rate and presence of HER4 expression were independent predictors of nonrecurrence. Potentially, HER4 expression may identify women who could avoid radiotherapy after breast-conserving surgery for DCIS.

https://clincancerres.aacrjournals.org/content/clincanres/11/6/2163.full.pdf

Absence of HER4 Expression Predicts Recurrence of Ductal Carcinoma In situ of the Breast

The factors controlling epithelial proliferation in ductal carcinoma in situ (DCIS) are unclear. Antiestrogens are effective in the prevention of the majority of estrogen receptor-positive, but not estrogen receptor (ER)-negative breast cancers, which suggests that other factor(s) are promoting proliferation in ER-negative DCIS. Mutated or overexpressed tyrosine kinases are frequently associated with tumor development. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is involved with mitogenesis and is expressed in ER-negative DCIS. We hypothesized that EGFR is central in driving proliferation in ER-negative/EGFR-positive DCIS. The purpose of this study was to establish whether the EGFR tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (Iressa), can reduce epithelial proliferation and increase apoptosis in EGFR-positive DCIS. Breast tissue from 16 women undergoing surgery for DCIS were implanted into 16–32 immunosuppressed mice/experiment (8 xenografts/mouse). Treatment commenced 2 weeks after implantation and consisted of once daily oral gavage with ZD1839 at doses ranging from 10 to 200 mg/kg for 14–28 days; appropriate controls were present. Xenografts were removed on days 14, 21, 28, and 42 after implantation and then assessed for proliferation (LI) by Ki67 immunostaining and apoptosis index (AI) by morphology. All Ps reported are two-sided. Overall, a 56% reduction in epithelial proliferation was seen with Iressa in EGFR-positive DCIS. EGFR-TK inhibition compared with vehicle controls resulted in a fall in Geometric Mean Labeling Index (LI) after 14 days (day 28) of treatment both in ER-negative/EGFR-positive DCIS [6.5% interquartile range (IQR, 3.8–11.1) versus 13.9% (IQR, 12.0–16.3%); F(1,3) = 103; P = 0.002] and ER-positive/EGFR-positive DCIS [4.6% (IQR, 3.9–5.2%) versus 11.7% (IQR, 9.2–15.5); F(1,2) = 32.3; P = 0.03]. EGFR-TK inhibition had similar effects on the “at risk” normal breast epithelium adjacent to DCIS in the treated epithelium LI day 28 [ZD1839 2.2% (IQR, 1.7–3.3%) compared with control 3.8% (IQR, 2.4–5.4%); F(1,14) = 29.2; P = 0.00009] and in addition increased epithelial apoptotic index at day 21 [ZD1839 0.38 (0.23–0.83) compared with control 0.19 (0.1–0.25); F(1,6) = 12.2; P = 0.013]. The effect on epithelial proliferation was still significant after 28 days of treatment [for both DCIS (F1,29) = 24; P = 0.039 and normal breast F(1,6) = 47.3; P = 0.0005]. EGFR-TK inhibition with ZD1839 offers a novel approach to the treatment of EGFR-positive DCIS, regardless of ER status, and provides a potential new chemopreventative approach in patients at high risk of breast cancer.

https://cancerres.aacrjournals.org/content/canres/62/1/122.full.pdf

Effect of epidermal growth factor receptor tyrosine kinase inhibition on epithelial proliferation in normal and premalignant breast.

Objective: To determine the cost to the NHS and the impact on anxiety of a one stop clinic for assessing women with suspected breast cancer. Study design: Randomised controlled trial. Participants: Women aged 35 or over referred with a breast lump. Study setting: Teaching hospital, north west England. Interventions: Women were randomly allocated to attend a one stop clinic or a dedicated breast clinic. Outcome measures: Reduction in mean anxiety from baseline at 24 hours after the first visit and at 3 weeks and 3 months after diagnosis; mean cost per patient. Results: 670 women were randomised. Compared with women who attended the dedicated clinic, patients attending the one stop clinic were less anxious 24 hours after the visit (adjusted mean change in state anxiety −5.7 (95% confidence interval −8.4 to −3.0)) but not at 3 weeks or 3 months after diagnosis. The additional cost to the NHS of a one stop attendance was £32 per woman; this was largely explained by greater cytopathological and radiological staff costs. Conclusion: One stop clinics may not be justified in terms of a reduction in short term anxiety.

https://www.bmj.com/content/bmj/324/7336/507.full.pdf

Costs and benefits of a one stop clinic compared with a dedicated breast clinic: randomised controlled trial

Overexpression and/or activity of c-Src non-receptor tyrosine kinase is associated with progression of several human epithelial cancers including breast cancer. c-Src activity in 'pure' ductal carcinoma in situ (DCIS) was measured to assess whether this predicts recurrence and/or correlates with HER2 expression and other clinical parameters. Activated c-Src levels were evaluated in DCIS biopsies from 129 women, with median follow-up at 60 months. High levels of activated c-Src correlated with HER2 positivity, high tumour grade, comedo necrosis and elevated epithelial proliferation. In univariate analysis, high activated c-Src level associated with lower recurrence-free survival at 5 years (P=0.011). Thus, high c-Src activity may identify a subset of DCIS with high risk of recurrence or progression to invasive cancer where therapeutics targeting c-Src may benefit this patient subset.

/pdf/activated-c-src-in-ductal-carcinoma-in-situ-correlates-with-282aarnfwz.pdf

Activated c-SRC in ductal carcinoma in situ correlates with high tumour grade, high proliferation and HER2 positivity.

BACKGROUND
Breast conserving surgery (BCS) is common practice for unifocal ductal carcinoma in situ (DCIS) less than 4 cm in size, but the extent of tumor free margin width around DCIS necessary to minimize recurrence is unclear.

METHODS
Clinical and pathologic details were recorded from all patients with pure DCIS 1 mm) were divided up into 3 groups for analysis based on margin of normal tissue excised: 1.1–5 mm, 5.1–10 mm, and 10.1–40 mm.

RESULTS
There were 66 patients with close margins (≤ 1 mm), of which 25 cases (37.9%) recurred. The recurrence rates for the 3 clear margin groups ranged from 4.5–7.1%. Median followup was 47 months (range 12–197 mos). Risk of recurrence in the group with close margins was greater than the subgroups with clear margins (P < 0.001); no differences in recurrence was seen between the individual subgroups with clear margins. Nuclear Grade 3 was predictive of recurrence (P = 0.03). Following excision alone, the recurrence rate was 18.6%, compared with 11.1% when radiotherapy was given as adjuvant therapy. Women with clear margins following excision had a recurrence rate of only 8.1%.

CONCLUSION
After BCS for DCIS, close margins were associated with a high risk of local recurrence. Radiotherapy did not compensate for inadequate surgical clearance. Cancer 2001;91:9–16. © 2001 American Cancer Society.

W. Fiona Knox

Papers

Absence of HER4 Expression Predicts Recurrence of Ductal Carcinoma In situ of the Breast

Effect of epidermal growth factor receptor tyrosine kinase inhibition on epithelial proliferation in normal and premalignant breast.

Costs and benefits of a one stop clinic compared with a dedicated breast clinic: randomised controlled trial

Activated c-SRC in ductal carcinoma in situ correlates with high tumour grade, high proliferation and HER2 positivity.

Extent of excision margin width required in breast conserving surgery for ductal carcinoma in situ.