Carolyn M. Kaelin

Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: a pilot study.

PURPOSE Trastuzumab combined with chemotherapy improves outcomes for women with human epidermal growth factor receptor 2 (HER2) overexpressing advanced breast cancer. We conducted a pilot study of preoperative trastuzumab and paclitaxel, followed by surgery and adjuvant doxorubicin and cyclophosphamide chemotherapy in earlier stage breast cancer. PATIENTS AND METHODS Patients with HER2-positive (2+ or 3+ by immunohistochemistry) stage II or III breast cancer received preoperative trastuzumab (4 mg/kg x 1, then 2 mg/kg/wk x 11) in combination with paclitaxel (175 mg/m(2) every 3 weeks x 4). Patients received adjuvant doxorubicin and cyclophosphamide chemotherapy following definitive breast surgery. Clinical and pathologic response rates were determined after preoperative therapy. Left ventricular ejection fraction and circulating levels of HER2 extracellular domain were measured serially. RESULTS Preoperative trastuzumab and paclitaxel achieved clinical response in 75% and complete pathologic response in 18% of the 40 women on study. HER2 3+ tumors were more likely to respond than 2+ tumors (84% v 38%). No unexpected treatment-related noncardiac toxicity was encountered. Four patients developed grade 2 cardiotoxicity (asymptomatic declines in left ventricular ejection fraction). Baseline HER2 extracellular domain was elevated in 24% of patients and declined with preoperative therapy. Immunohistochemical analyses of posttherapy tumor specimens indicated varying patterns of HER2 expression following trastuzumab-based treatment. CONCLUSION Preoperative trastuzumab and paclitaxel is active against HER2 overexpressing early-stage breast cancer and may be feasible as part of a sequential treatment program including anthracyclines. The observed changes in cardiac function merit further investigation. Correlative analyses of HER2 status may facilitate understanding of tumor response and resistance to targeted therapy.

Prospective Study of Wide Excision Alone for Ductal Carcinoma in Situ of the Breast

PURPOSE It has been hypothesized that wide excision alone with margins > or = 1 cm may be adequate treatment for small, grade 1 or 2 ductal carcinoma in situ (DCIS). To test this hypothesis, we conducted a prospective, single-arm trial. METHODS Entry criteria included DCIS of predominant grade 1 or 2 with a mammographic extent of < or = 2.5 cm treated with wide excision with final margins of > or = 1 cm or a re-excision without residual DCIS. Tamoxifen was not permitted. The accrual goal was 200 patients. RESULTS In July 2002, the study closed to accrual at 158 patients because the number of local recurrences met the predetermined stopping rules. The median age was 51 and the median follow-up time was 40 months. Thirteen patients developed local recurrence as the first site of treatment failure 7 to 63 months after study entry. The rate of ipsilateral local recurrence as first site of treatment failure was 2.4% per patient-year, corresponding to a 5-year rate of 12%. Nine patients (69%) experienced recurrence of DCIS and four (31%) experienced recurrence with invasive disease. Twelve recurrences were detected mammographically and one was palpable. Ten were in the same quadrant as the initial DCIS and three were elsewhere within the ipsilateral breast. No patient had positive axillary nodes at recurrence or subsequent metastatic disease. CONCLUSION Despite margins of > or = 1 cm, the local recurrence rate is substantial when patients with small, grade 1 or 2 DCIS are treated with wide excision alone. This risk should be considered in assessing the possible use of radiation therapy with or without tamoxifen in these patients.

Sexual Problems in Younger Women After Breast Cancer Surgery

PURPOSE To examine sexual problems in younger women diagnosed with breast cancer during the first year after surgery and to identify sociodemographic, medical, and psychosocial predictors of sexual problems. PATIENTS AND METHODS Women diagnosed with breast cancer age < or = 50 years completed surveys at three time points: within 24 weeks after initial surgery (baseline), 6 weeks after baseline, and 6 months later. Survey items included the Medical Outcomes Study Sexual Functioning Scale, satisfaction with sex life, feeling sexually attractive, body image, marital satisfaction, quality of life, medical history, symptoms, and sociodemographics. Prediagnosis sexual problems were retrospectively ascertained at the initial survey. RESULTS Analyses included 209 women sexually active at baseline (78.6% of total sample). Sexual problems were significantly greater immediately postsurgery compared with retrospective reports before diagnosis (P < .0001). Although problems gradually decreased over time, they were still greater at 1 year postsurgery than before diagnosis. In multivariate analyses controlling for sexual problems at prediagnosis, vaginal dryness, and lower perceived sexual attractiveness were consistently related to greater overall sexual problems. Chemotherapy was related to sexual problems only at baseline except for women who became menopausal as a result of chemotherapy, who continued to have problems. CONCLUSION Findings substantiate the need to address potential sexual problems related to chemotherapy treatment and menopause among younger breast cancer survivors and to counsel women about possible remedies, particularly for vaginal dryness. Increasing feelings of sexual attractiveness may also help sexual problems, especially among women for whom these feelings were altered by surgery or treatment.

Risk Perceptions and Psychosocial Outcomes of Women With Ductal Carcinoma In Situ: Longitudinal Results From a Cohort Study

BACKGROUND Ductal carcinoma in situ (DCIS) has a generally favorable overall prognosis, with a systemic recurrence rate of approximately 1%, a local recurrence rate after mastectomy of 1%, and a local recurrence rate after breast-conserving treatment of less than 10%. Preliminary studies have suggested that women with DCIS may overestimate their risk of disease recurrence. Few data exist regarding psychosocial outcomes for women with DCIS. METHODS Women in Eastern Massachusetts with newly diagnosed DCIS were asked to participate in a longitudinal study of risk perceptions, psychosocial concerns, and health behaviors. Psychosocial outcomes after DCIS diagnosis and risk perceptions were evaluated at enrollment and at 9 and 18 months. All statistical tests were two-sided. RESULTS Four hundred eighty-seven women with DCIS (64% of eligible participants) completed the enrollment survey. Overall quality of life was good among the women surveyed, and the substantial anxiety at enrollment decreased with time (P < .001). At enrollment, 54% perceived at least a moderate risk for DCIS recurrence in the next 5 years, 68% in their lifetime; 39% perceived at least a moderate risk for invasive cancer in the next 5 years, 53% in their lifetime; and 28% perceived at least a moderate likelihood of DCIS spreading to other places in their body. At 18 months after enrollment, perceived risks had not statistically significantly changed from those at enrollment (P = .38). Anxiety at enrollment was the factor that was most consistently and strongly associated with overestimation of future breast cancer-related risks (perceived moderate or greater risk vs less than moderate risk of DCIS recurring within 5 years: odds ratio [OR] = 4.0, 95% confidence interval [CI] = 1.6 to 9.9, P = .003; of invasive breast cancer within 5 years: OR = 4.3, 95% CI = 1.9 to 9.9, P < .001; and of invasive breast cancer during lifetime: OR = 5.3, 95% CI = 2.0 to 14.3, P < .001). CONCLUSIONS Many women with newly diagnosed DCIS have inaccurate perceptions of the breast cancer risks that they face, and anxiety is particularly associated with these inaccurate perceptions.

HIN-1, a putative cytokine highly expressed in normal but not cancerous mammary epithelial cells

To identify molecular alterations implicated in the initiating steps of breast tumorogenesis, we compared the gene expression profiles of normal and ductal carcinoma in situ (DCIS) mammary epithelial cells by using serial analysis of gene expression (SAGE). Through the pair-wise comparison of normal and DCIS SAGE libraries, we identified several differentially expressed genes. Here, we report the characterization of one of these genes, HIN-1 (high in normal-1). HIN-1 expression is significantly down regulated in 94% of human breast carcinomas and in 95% of preinvasive lesions, such as ductal and lobular carcinoma in situ. This decrease in HIN-1 expression is accompanied by hypermethylation of its promoter in the majority of breast cancer cell lines (>90%) and primary tumors (74%). HIN-1 is a putative cytokine with no significant homology to known proteins. Reintroduction of HIN-1 into breast cancer cells inhibits cell growth. These results indicate that HIN-1 is a candidate tumor suppressor gene that is inactivated at high frequency in the earliest stages of breast tumorogenesis.

The Utility of Ultrasonographically Guided Large-Core Needle Biopsy Results From 500 Consecutive Breast Biopsies

Five hundred ultrasonographically guided large‐core needle breast biopsies of solid masses were performed in 446 women. Histopathologic results were correlated with imaging findings. Ultrasonographically guided large‐core needle biopsy resulted in diagnosis of malignancy (n = 124) or severe atypical ductal hyperplasia (n = 4) in 128 lesions (26%). In the remaining 372 lesions (74%), ultrasonographically guided large‐core needle biopsy yielded benign pathologic results. Follow‐up of more than 1 year (n = 225), results of surgical excision (n = 50), or both were obtainable in 275 (74%) of the benign lesions. No malignancies were discovered at surgical excision or during follow‐up of this group of benign lesions. There were no complications related to large‐core needle biopsy that required additional treatment. Ultrasonographically guided large‐core needle biopsy is a safe and accurate method for evaluating breast lesions that require tissue sampling.

Treatment outcome after tangential radiation therapy without axillary dissection in patients with early-stage breast cancer and clinically negative axillary nodes

PURPOSE To determine the risk of nodal failure in patients with early-stage invasive breast cancer with clinically negative axillary lymph nodes treated with two-field tangential breast irradiation alone, without axillary lymph node dissection or use of a third nodal field. METHODS AND MATERIALS Between 1988 and 1993, 986 evaluable women with clinical Stage I or II invasive breast cancer were treated with breast-conserving surgery and radiation therapy. Of these, 92 patients with clinically negative nodes received tangential breast irradiation (median dose, 45 Gy) followed by a boost, without axillary dissection. The median age was 69 years (range, 49-87). Eighty-three percent had T1 tumors. Fifty-three patients received tamoxifen, 1 received chemotherapy, and 2 patients received both. Median follow-up time for the 79 survivors was 50 months (range, 15-96). Three patients (3%) have been lost to follow-up after 20-32 months. RESULTS No isolated regional nodal failures were identified. Two patients developed recurrence in the breast only (one of whom had a single positive axillary node found pathologically after mastectomy). One patient developed simultaneous local and distant failures, and six patients developed distant failures only. One patient developed a contralateral ductal carcinoma in situ, and two patients developed other cancers. CONCLUSION Among a group of 92 patients with early-stage breast cancer (typically T1 and also typically elderly) treated with tangential breast irradiation alone without axillary dissection, with or without systemic therapy, there were no isolated axillary or supraclavicular regional failures. These results suggest that it is feasible to treat selected clinically node-negative patients with tangential fields alone. Prospective studies of this approach are warranted.

Nipple Fluid Carcinoembryonic Antigen and Prostate-Specific Antigen in Cancer-Bearing and Tumor-Free Breasts

PURPOSE Mammograms and breast examinations are established methods for early breast cancer detection. Routine mammography screening reduces breast cancer mortality among women ages > or = 50 years, but additional screening methods are needed. We and others have found high levels of carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA) in nipple aspirate fluids (NAFs), but the usefulness for these bio-markers for early breast cancer detection is unknown. PATIENTS AND METHODS NAFs from one or both breasts of 388 women were analyzed for CEA, PSA, and albumin levels. The study included 44 women with newly diagnosed invasive breast cancers, 67 women with proliferative breast lesions (ductal and lobular carcinoma in situ and atypical ductal hyperplasia), and 277 controls without these breast lesions. Analyses were conducted using the log(10)-transformed CEA and PSA levels to normalize the distributions of these tumor markers. RESULTS Nipple fluid CEAs are significantly higher for cancerous breasts than tumor-free breasts (median 1,830 and 1,400 ng/mL, respectively; P <.01). However, at 90% specificity of the assay (CEA = 11,750 ng/mL), the corresponding sensitivity for cancer detection is 32%. CEA levels are not significantly different for breasts with proliferative lesions compared with tumor-free breasts. Nipple fluid PSAs do not differ by tumor status. Analyses of NAF albumin-standardized CEAs and PSAs yield similar results. Nipple fluid CEA and PSA titers are correlated in the affected and unaffected breast of women with unilateral lesions. CONCLUSION Nipple fluid CEAs are higher for breasts with untreated invasive cancers, but the test sensitivity is low. Nipple fluid PSA titers do not seem to be useful for breast cancer detection.

Incidence of major corrective surgery after post-mastectomy breast reconstruction and radiation therapy.

Abstract: To evaluate the likelihood of requiring major corrective surgery (MCS) after modified radical mastectomy (MRM), immediate reconstruction and radiation therapy (RT) to the reconstructed breast. The study population consisted of 62 patients who underwent MRM and immediate breast reconstruction between 1990 and 1999, had postoperative radiation and at least one follow‐up visit or procedure ≥2 months after radiation. Reconstruction consisted of a pedicled transverse rectus abdominis myocutaneous flap in 42 patients, latissimus dorsi flap in five, latissimus dorsi plus implant in six, and implant alone in nine. Median follow‐up time after reconstruction was 13 months (range: 2–58) for non‐implant patients and 10 months (range: 4–57) for implant patients. The primary endpoint was the incidence of major complications requiring MCS. Ten patients (16%) underwent MCS between 1 and 28 months after radiation (median in these patients of 8 months). 4/47 non‐implant patients (9%) underwent MCS, compared to 6/15 implant patients (40%). Of patients followed ≥6 months after RT, 0/38 non‐implant patients underwent MCS within 6 months compared to 3/13 (23%) implant patients (p = 0.01); of patients followed for ≥12 months after RT, the rates of MCS within 12 months were 1/24 (4%) and 2/7 (29%), respectively (p = 0.12). Patients who undergo immediate reconstruction after mastectomy using an implant followed by radiation have a high rate of subsequent MCS. The difference in the rate of MCS between the implant and non‐implant groups is significant in early follow‐up. Patients considering an implant followed by RT should be apprised of this increased risk. Prospective studies of these risks and the cosmetic outcomes are warranted.

Support needs and acceptability of psychological and peer consultation: attitudes of 108 women who had undergone or were considering prophylactic mastectomy

Objective: Prophylactic mastectomy (PM) offers 90% or greater reduction in risk of breast cancer to women at increased hereditary risk. Nonetheless, acceptance in North America is low (0–27%) and 25–50% of women electing surgery report psychological distress and/or difficulty adapting following PM. Most women also report reduced cancer worry postoperatively. Psychological consultation to aid decision‐making and post‐surgical coping is not routinely offered. This retrospective, cross‐sectional study explored interest in and acceptability of psychological consultation for issues related to PM among 108 women who had undergone or were considering surgery.