EGFR activity in HER-2 over-expressing metastatic breast cancer: evidence for simultaneous phosphorylation of Her-2/neu and EGFR.

Her-2/neu overexpression is an important prognostic parameter in breast cancer patients and has become a response predictor for trastuzumab treatment. Nevertheless, while trastuzumab is highly effective in many Her-2/neu overexpressing tumors, some do not respond. The reason for the differential effect is unknown, but it has been hypothesized that the complex interactions between Her-2/neu and other members of the EGFR family are involved in trastuzumab resistance. We have analyzed the protein expression of Her-2/neu, EGFR, and their activated forms, ptyr-1248 Her-2/neu, ptyr-845 EGFR and ptyr-1173 EGFR, in 57 Her-2/neu overexpressing breast tumors and investigated potential correlations between the receptors. By performing immunohistochemistry on paraffin-embedded tissue sections, we found that ptyr-845 EGFR was significantly co-expressed with Her-2/neu and ptyr-1248 Her-2/neu (p=0.043 and p=0.040, respectively), while ptyr-1173 EGFR was only correlated to Her-2/neu expression (p=0.042). Interestingly, EGFR and its activated forms were all significantly inversely correlated with PgR expression (p=0.011, p=0.033 and p=0.032, respectively), and ptyr-845 EGFR was also inversely correlated with ER expression (p=0.008). While we have previously shown that serum levels of the extracellular component of Her-2/neu are associated with tumoral ptyr-1248 Her-2/neu expression, we did not find a similar relationship between serum EGFR and intratumoral total/activated EGFR. We did, however, observe significantly higher levels of serum EGFR in women with 3+ overexpression of HER-2/neu (p=0.047). Taken together, we have demonstrated the activation pattern of EGFR and Her-2/neu in Her-2/neu overexpressing breast cancer. We suggest that EGFR inhibition might enhance the efficacy of trastuzumab by preventing cross-phosphorylation.

Maintaining bone density in patients undergoing treatment for breast cancer: is there an adjuvant benefit?

Women undergoing treatment for breast cancer often experience a marked decrease in bone mineral density. This decrease is observed with chemotherapy as well as endocrine therapy and is more pronounced and rapid than normal postmenopausal bone loss. Pharmacologic intervention is, therefore, necessary in many cases to preserve bone health and prevent fractures. Many small studies have demonstrated that cancer therapy-induced bone loss (CTIBL) is effectively prevented by bone-targeted therapies, such as bisphosphonates and other inhibitors of bone resorption. Recently, several trials have confirmed the efficacy of bisphosphonates in the prevention of CTIBL in both premenopausal and postmenopausal women with early-stage breast cancer. In addition, concomitant treatment with zoledronic acid 4 mg every 6 months and standard adjuvant endocrine therapy has been reported to significantly improve disease-free survival and decrease disease recurrence in bone as well as other sites compared with standard therapy alone. Zoledronic acid treatment has also decreased residual tumor volume in the neoadjuvant setting. Furthermore, long-term follow-up of a single study in patients with bone marrow micrometastases from breast cancer revealed overall survival benefits for patients receiving clodronate 1600 mg/day compared with placebo; however, combined results from several trials of clodronate are inconclusive. Overall, a large body of evidence is accumulating to support the potential adjuvant benefits of bisphosphonates in the treatment of early-stage breast cancer. Results from ongoing studies are expected to further elucidate the benefits of bisphosphonates in maintaining bone health and improving clinical outcomes in patients with breast cancer.

Factors predicting severe perineal trauma during childbirth: role of forceps delivery routinely combined with mediolateral episiotomy.

OBJECTIVE: Anal sphincter injury and its sequelae are a recognized complication of vaginal childbirth. The aim of the present study was to identify risk factors for third- and fourth-degree perineal tears in patients undergoing either spontaneous or vaginal-assisted delivery by forceps routinely combined with mediolateral episiotomy. STUDY DESIGN: We retrospectively reviewed 5377 vaginal deliveries based on the analysis of the obstetric database and patient records of our department during a 5-year period from 1999 to 2003. Cases and control subjects were chosen randomly and patients' records were reviewed for the following variables: maternal age, parity, gestational age, tobacco use, gestational diabetes or pregnancy-induced hypertension, use of peridural anesthesia, duration of first and second stages of labor, use of mediolateral episiotomy, forceps combined with mediolateral episiotomy, induction of labor, infant head diameter, shoulder circumference, and birth weight. RESULTS: Of 5044 spontaneous vaginal deliveries 32 (0.6%) and of 333 assisted vaginal deliveries 14 (4.2%) patients sustained a perineal defect involving the external sphincter. An univariate analysis of these 46 cases and 155 randomly selected control subjects showed that low parity (P = .003; Mann-Whitney U test), prolonged first and second stages of labor (P = .001, P = .001), high birth weight (P = .031), episiotomy (P = .004; Fisher exact test), and forceps delivery (P = .002) increased the risk for sphincter damage. In multivariate regression models, only high birth weight (P = .004; odds ratio [OR] 1.68, 1.18-2.41, 95% confidence interval [CI]), and forceps delivery combined with mediolateral episiotomies (P < .001; OR 5.62, 2.16-14.62, 95% CI) proved to be independent risk factors. There was a statistical significant interaction of birth weight and head circumference (P = .012; OR 0.99, 0.98-0.99, 95% CI). Although the use of episiotomy conferred an increased risk toward a higher likelihood of severe perineal trauma, it did not reach statistical significance (P = .06; OR 2.15, 0.97-4.76, 95% CI). CONCLUSIONS: In consistence with previous reports, women who are vaginally delivered of a large infant are at a high risk for sphincter damage. Although the rate of these complications was surprisingly low in vaginally assisted childbirth, the use of forceps, even if routinely combined with mediolateral episiotomy, should be minimized whenever possible.