Michele A. Gadd

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.

Development and treatment of pulmonary metastases in adult patients with extremity soft tissue sarcoma.

ObjectiveThe authors reviewed a series of adult patients with extremily soft tissue sarcoma to determine the incidence of pulmonary metastases and outcome after treatment. MethodsOf 716 patients admitted between January 1983 and December 1990, 135 (19%) had isolated pulmonary metastases as the initial site of distant recurrence. Fifty-eight percent (78 of 135) of the patients were treated surgically, and 83% of them had their tumors completely resected. ResultsThe median survival after complete resection was 19 months; incomplete resection, 10 months; and no operation, 8 months (p = 0.005). The 3-year survival rate after complete resection was 23%, compared with a 2% rate (1 of 57) in those treated nonsurgically (p < 0.001). Factors associated with an increased risk of pulmonary metastases included high tumor grade, tumor size greater than 5 cm, lower extremity site, and histologic type (spindle cell, tendosynovial, and extraskeletal osteosarcoma). Factors associated with complete resectability were the histologic types of spinde cell and extraskeletal osteosarcoma. ConclusionsComplete surgical resection remains the only possibility for cure from pulmonary metastases in soft tissue sarcoma; however, only 11% of the 19% of patients with an extremity sarcoma whose first distant recurrence is in the lung will be alive at 3 years, despite therapy. Complete resection and the development of more effective adjuvant treatments are imperative to improve outcome for this group of patients.

An essential E box in the promoter of the gene encoding the mRNA cap-binding protein (eukaryotic initiation factor 4E) is a target for activation by c-myc.

The mRNA cap-binding protein (eukaryotic initiation factor 4E [eIF4E]) binds the m7 GpppN cap on mRNA, thereby initiating translation. eIF4E is essential and rate limiting for protein synthesis. Overexpression of eIF4E transforms cells, and mutations in eIF4E arrest cells in G, in cdc33 mutants. In this work, we identified the promoter region of the gene encoding eIF4E, because we previously identified eIF4E as a potential myc-regulated gene. In support of our previous data, a minimal, functional, 403-nucleotide promoter region of eIF4E was found to contain CACGTG E box repeats, and this core eIF4E promoter was myc responsive in cotransfections with c-myc. A direct role for myc in activating the eIF4E promoter was demonstrated by cotransfections with two dominant negative mutants of c-myc (MycdeltaTAD and MycdeltaBR) which equally suppressed promoter function. Furthermore, electrophoretic mobility shift assays demonstrated quantitative binding to the E box motifs that correlated with myc levels in the electrophoretic mobility shift assay extracts; supershift assays demonstrated max and USF binding to the same motif. cis mutations in the core or flank of the eIF4E E box simultaneously altered myc-max and USF binding and inactivated the promoter. Indeed, mutations of this E box inactivated the promoter in all cells tested, suggesting it is essential for expression of eIF4E. Furthermore, the GGCCACGTG(A/T)C(C/G) sequence is shared with other in vivo targets for c-myc, but unlike other targets, it is located in the immediate promoter region. Its critical function in the eIF4E promoter coupled with the known functional significance of eIF4E in growth regulation makes it a particularly interesting target for c-myc regulation.

Detection of microscopic melanoma metastases in sentinel lymph nodes

Sentinel lymph node biopsy following radioisotope labeling is a recently developed, minimally invasive surgical staging procedure used in the management of primary cutaneous malignant melanoma. If histologic analysis reveals melanoma metastasis in the sentinel lymph node, completion lymphadenectomy is performed and adjuvant therapy considered. The routine pathologic assessment of the sentinel lymph node consists of bisecting the lymph node along its long axis and histologic examination of one hematoxylin and eosin–stained section of each cut surface.

DOSE-VOLUME ANALYSIS OF RADIOTHERAPY FOR T1N0 INVASIVE BREAST CANCER TREATED BY LOCAL EXCISION AND PARTIAL BREAST IRRADIATION BY LOW-DOSE-RATE INTERSTITIAL IMPLANT

PURPOSE To evaluate the toxicity of partial breast irradiation (RT) using escalating doses of low-dose-rate interstitial implant as the sole adjuvant local therapy for selected T1N0 breast cancer patients treated by wide local excision. The results of a European Organization for Research and Treatment of Cancer study have demonstrated a significant local control benefit using external beam RT to 65 Gy compared with 50 Gy. Thus, the tolerance of escalating doses of partial breast RT should be determined, because this approach may become a standard treatment for patients with early-stage breast cancer. METHODS AND MATERIALS Between 1997 and 2001, 48 patients with T1N0M0 breast cancer were enrolled into an institutional review board-approved Phase I/II protocol using low-dose-rate brachytherapy implants after wide local excision and lymph node staging surgery. Brachytherapy was started 3-4 days after surgery at a dose rate of 50 cGy/h, using (192)Ir sources evenly spaced to cover 3 cm around the resection margins. Typically, 2-3 planes were used, with a median of 14 catheters (range 10-16). The total dose was escalated in three groups: 50 Gy (n = 19), 55 Gy (n = 16), and 60 Gy (n = 13). The implant volume was calculated and used to classify patients into quartiles: 76-127 cm(3) (n = 12), 128-164 cm(3) (n = 12), 165-204 cm(3) (n = 12), and >204 cm(3) (n = 12). Cosmesis, patient satisfaction, treatment-related complications, mammographic abnormalities, rebiopsies, and disease status were recorded at each scheduled patient visit. RESULTS The median follow-up for all patients was 23.1 months (range 2-43). Very good to excellent cosmetic results were observed in 91.8% of patients. Ninety-two percent of patients were satisfied with their cosmetic outcome and said they would choose brachytherapy again over the standard course of external beam RT. Six perioperative complications occurred: two developed bleeding at the time of catheter removal, two had abscesses, one developed a hematoma, and one had a nonhealing sinus tract requiring surgical intervention. Significant fibrosis (moderate-to-severe scarring and thickening of the skin and breast) was noted in only 4 patients; 1 had received 55 Gy and 3 had received 60 Gy. Abnormal posttreatment mammograms were seen in 19 patients. Eight patients underwent rebiopsy for abnormalities found either by mammography or on physical examination; all proved to be fat necrosis or post-RT changes. The rebiopsy rates appeared to correlate with doses >/=55 Gy (6 [75%] of 8 compared with 29 [60%]of 48 overall) and implant volumes >/=128 cm(3) (7 [87.5%] of 8 compared with 36 [75%] of 48 overall). To date, no local, regional, or distant recurrences have been observed. CONCLUSION Low-dose-rate implants up to 60 Gy were well-tolerated overall. With an implant dose of 60 Gy, the incidence of posttreatment fibrosis (25%) appeared to be increased. Only the long-term follow-up of this and other implant studies will allow an understanding of the total radiation dose necessary for tumor control and the volume of breast that requires treatment.

Adjuvant therapy of melanoma with interferon-alpha-2b is associated with mania and bipolar syndromes: Gabapentin may serve as a mood stabilizer

The use of a high dose regimen of interferon‐alpha‐2b (IFN) has recently been demonstrated to benefit patients with resected high risk melanoma. The incidence of melanoma is rising rapidly, and the use of this regimen is becoming increasingly common. IFN has been associated with numerous psychiatric side effects.

Proton therapy for breast cancer after mastectomy: early outcomes of a prospective clinical trial.

PURPOSE Dosimetric planning studies have described potential benefits for the use of proton radiation therapy (RT) for locally advanced breast cancer. We report acute toxicities and feasibility of proton delivery for 12 women treated with postmastectomy proton radiation with or without reconstruction. METHODS AND MATERIALS Twelve patients were enrolled in an institutional review board-approved prospective clinical trial. The patients were assessed for skin toxicity, fatigue, and radiation pneumonitis during treatment and at 4 and 8 weeks after the completion of therapy. All patients consented to have photographs taken for documentation of skin toxicity. RESULTS Eleven of 12 patients had left-sided breast cancer. One patient was treated for right-sided breast cancer with bilateral implants. Five women had permanent implants at the time of RT, and 7 did not have immediate reconstruction. All patients completed proton RT to a dose of 50.4 Gy (relative biological effectiveness [RBE]) to the chest wall and 45 to 50.4 Gy (RBE) to the regional lymphatics. No photon or electron component was used. The maximum skin toxicity during radiation was grade 2, according to the Common Terminology Criteria for Adverse Events (CTCAE). The maximum CTCAE fatigue was grade 3. There have been no cases of RT pneumonitis to date. CONCLUSIONS Proton RT for postmastectomy RT is feasible and well tolerated. This treatment may be warranted for selected patients with unfavorable cardiac anatomy, immediate reconstruction, or both that otherwise limits optimal RT delivery using standard methods.

Perception of breast cancer risk among women in breast center and primary care settings: Correlation with age and family history of breast cancer

BACKGROUND A great deal of information about breast cancer risk is available to the public. The accuracy of impressions formed from this information is unknown. METHODS A total of 750 women attending a breast center and 112 women attending a primary care office completed written surveys of their perceptions of average population risk, personal lifetime risk, and personal 10-year risk of getting breast cancer. Data sufficient to apply the Gail model were obtained, and a calculated estimate of risk was generated. Ratios of perceived to calculated risk were correlated with the respondents age, family history of breast cancer, and location in a breast center or primary care office. RESULTS Women in both practice settings overestimated population risk by more than twofold. Eighty percent overestimated personal lifetime risk by more than 50% and 35% by more than fivefold. Only 7% significantly underestimated risk. Ten-year risk estimates were even more inaccurate, with 69% overestimating risk by more than fivefold, 46% by more than 10-fold, and 17% by more than 20-fold. Results from a primary care population were nearly identical. Women at the extremes of age were most inaccurate in estimating risk. It was surprising that family history had little impact on perception of personal risk. CONCLUSIONS Women in both breast center and primary care settings have a fals:ly high perception of both short-term and long-term breast cancer risk. Health care providers should recognize these misconceptions and be aware that many women may benefit from risk counseling.

Gamma probe guided biopsy of the sentinel node in malignant melanoma: a multicentre study

Sentinel lymph node biopsy was attempted in 336 patients with clinically node-negative cutaneous melanoma. All patients were injected with technetium-99m labelled radio-colloid, with 108 patients simultaneously receiving vital blue dye for sentinel node identification. Sentinel lymph nodes were identified in 329 patients, giving a technical success rate of 97.9%. Metastatic disease was identified in 39 (11.9%) of the patients in whom sentinel nodes were found. Patients with negative sentinel nodes were observed and patients with positive sentinel nodes underwent comprehensive lymph node dissection. The presence of metastatic disease in the sentinel nodes and primary tumour depth by Breslow or Clark levels were joint predictors of survival based on Cox proportional hazards modelling. Disease recurrences occurred in 26 (8.8%) patients with negative sentinel lymph nodes, with isolated regional recurrences as the first site in 10 (3.4%). No patients with Clark level II primary tumours were found to have positive sentinel nodes or disease recurrences. One patient with a thin (< 0.75 mm) Clark level III primary had metastatic disease in a sentinel node. Patients with metastases confined to the sentinel nodes had similar survival rates regardless of the number of nodes involved