S. E. Singletary

Significantly Higher Pathologic Complete Remission Rate After Neoadjuvant Therapy With Trastuzumab, Paclitaxel, and Epirubicin Chemotherapy: Results of a Randomized Trial in Human Epidermal Growth Factor Receptor 2–Positive Operable Breast Cancer

PURPOSE The objective of this study was to determine whether the addition of trastuzumab to chemotherapy in the neoadjuvant setting could increase pathologic complete response (pCR) rate in patients with human epidermal growth factor receptor 2 (HER2) -positive disease. PATIENTS AND METHODS Forty-two patients with HER2-positive disease with operable breast cancer were randomly assigned to either four cycles of paclitaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks. The primary objective was to demonstrate a 20% improvement in pCR (assumed 21% to 41%) with the addition of trastuzumab to chemotherapy. The planned sample size was 164 patients. RESULTS Prognostic factors were similar in the two groups. After 34 patients had completed therapy, the trials Data Monitoring Committee stopped the trial because of superiority of trastuzumab plus chemotherapy. pCR rates were 25% and 66.7% for chemotherapy (n = 16) and trastuzumab plus chemotherapy (n = 18), respectively (P = .02). The decision was based on the calculation that, if study continued to 164 patients, there was a 95% probability that trastuzumab plus chemotherapy would be superior. Of the 42 randomized patients, 26% in the chemotherapy arm achieved pCR compared with 65.2% in the trastuzumab plus chemotherapy arm (P = .016). The safety of this approach is not established, although no clinical congestive heart failure was observed. A more than 10% decrease in the cardiac ejection fraction was observed in five and seven patients in the chemotherapy and trastuzumab plus chemotherapy arms, respectively. CONCLUSION Despite the small sample size, these data indicate that adding trastuzumab to chemotherapy, as used in this trial, significantly increased pCR without clinical congestive heart failure.

Inflammatory breast cancer (IBC) and patterns of recurrence : Understanding the biology of a unique disease

Inflammatory breast cancer (IBC) is the most aggressive manifestation of primary breast cancer. The authors compared the prognostic features of IBC and non‐IBC locally advanced breast cancer (LABC) to gain insight into the biology of this disease entity.

Estrogen Replacement Therapy After Localized Breast Cancer: Clinical Outcome of 319 Women Followed Prospectively

PURPOSE To determine whether estrogen replacement therapy (ERT) alters the development of new or recurrent breast cancer in women previously treated for localized breast cancer. PATIENTS AND METHODS Potential participants (n = 319) in a trial of ERT after breast cancer were observed prospectively for at least 2 years whether they enrolled onto the randomized trial or not. Of 319 women, 39 were given estrogen and 280 were not given hormones. Tumor size, number of lymph nodes, estrogen receptors, menopausal status at diagnosis, and disease-free interval at the initiation of the observation period were comparable for the trial participants (n = 62) versus nonparticipants (n = 257) and for women on ERT (n = 39) versus controls (n = 280). Cancer events were ascertained for both groups. RESULTS Patient and disease characteristics were comparable for the trial participants versus nonparticipants, as well as for the women on ERT versus the controls. One patient in the ERT group developed a new lobular estrogen receptor-positive breast cancer 72 months after the diagnosis of a ductal estrogen receptor-negative breast cancer and 27 months after initiation of ERT. In the control group, there were 20 cancer events: 14 patients developed new or recurrent breast cancer at a median time of 139.5 months after diagnosis and six patients developed other cancers at a median time of 122 months. CONCLUSION ERT does not seem to increase breast cancer events in this subset of patients previously treated for localized breast cancer. Results of randomized trials are needed before any changes in current standards of care can be proposed.

Impact of Preoperative Versus Postoperative Chemotherapy on the Extent and Number of Surgical Procedures in Patients Treated in Randomized Clinical Trials for Breast Cancer

Objective:To determine the effect of preoperative chemotherapy on the volume of tissue excised and the number of breast operations in patients undergoing breast-conserving therapy (BCT). Summary Background Data:Preoperative chemotherapy is increasingly being used for breast cancer and increases rates of BCT. Its impact on the extent of surgery and the number of surgical procedures in BCT has never been fully defined. The extent of surgery in BCT directly affects cosmesis. Methods:We reviewed the records of 509 consecutive patients with T1–T3, N0–N2 breast cancer who were treated in prospective randomized clinical trials of chemotherapy between 1998 and 2005. We analyzed the final surgical procedure (BCT or mastectomy), the number of operations, and, in patients who underwent BCT, re-excision rates, and the total volume of breast tissue excised [4Π/3(width/2 × length/2 × height/2)]. Results:A total of 241 patients underwent BCT, and 268 patients underwent mastectomy. Among BCT patients who had initial tumor size >2.0 cm, patients who received preoperative chemotherapy had significantly smaller volumes of breast tissue excised compared with patients who received postoperative chemotherapy (113 cm3 vs. 213 cm3, P = 0.004). The re-excision rate and total number of breast operations did not significantly differ between the groups. Among BCT patients who had initial tumor size ≤2 cm, preoperative chemotherapy had no impact on volume of breast tissue excised, re-excision rate, or number of breast operations (P > 0.05). Conclusions:Among patients treated with BCT for larger breast tumors, patients treated with preoperative chemotherapy have less extensive resection, with no change in rates of re-excision.

Selective use of sentinel lymph node surgery during prophylactic mastectomy

Patients with invasive cancer identified at the time of prophylactic mastectomy (PM) will require axillary lymph node dissection for staging; therefore, many surgeons advocate sentinel lymph node (SLN) surgery at the time of PM. The current study investigates the invasive cancer rate in PM and evaluates factors associated with invasive cancer to guide SLN surgery use.

Neoadjuvant chemotherapy in women with invasive breast carcinoma: conceptual basis and fundamental surgical issues

Historically, radical surgery was the only potentially curative treatment for cancer. Recently, neoadjuvant chemotherapy, also termed preoperative, induction, or primary chemotherapy, has assumed an increasingly important role in the management of several solid-organ malignancies, including cancers of the breast, bone, head and neck, bladder, esophagus, and lung. In breast cancer, the use of postoperative, or adjuvant, chemotherapy is inextricably linked to the improved outcomes seen over the past several decades. Neoadjuvant chemotherapy has become the standard of care for patients with locally advanced breast cancer and has rapidly come to the forefront among potential treatments for patients with earlier-stage operable disease.

DOC-2/hDab-2 inhibits ILK activity and induces anoikis in breast cancer cells through an Akt-independent pathway

DOC-2/hDab-2 was identified due to the loss of its expression in primary ovarian cancer cells. It is believed that loss of DOC-2/hDab-2 expression is one of the early events of ovarian malignancy. These results suggest a function of DOC-2/hDab-2 as a tumor suppressor. However, it is not clear how DOC-2/hDab-2 negatively regulates cancer cell growth. In this report, we demonstrate that DOC-2/hDab-2 expression in breast cancer cells resulted in sensitivity to suspension-induced cell death (anoikis). This event was associated with the down-regulation of the integrin-linked kinase (ILK) activity. Since ILK is a key factor in regulating the cellular signaling in responding to the extracellular signals through adhesion molecules like integrins, our results indicate that DOC-2/hDab-2 may prevent tumor growth and invasion by modulating the anti-apoptotic ILK pathway.

LOCALLY ADVANCED NONINFLAMMATORY BREAST CANCER

Treatment of locally advanced noninflammatory breast cancer has changed markedly over the past 50 years. Haagensens description of the clinical signs that define inoperable and operable tumors was the first realization that radical surgery alone could not cure the majority of women with locally advanced disease. Studies of the use of local therapy alone (surgery or radiation therapy) confirmed that most patients developed both distant metastatic disease and a high rate of local-regional failure. Combination surgery and radiation therapy regimens improved local control but did not influence long-term survival. The advent of successful multimodal regimens incorporating systemic treatment (chemotherapy or chemohormonal therapy) as well as local therapy (surgery and radiation) has significantly improved disease-free and overall survival as well as local-regional control. The benefits of neoadjuvant and adjuvant chemotherapy regimens have been debated. Neoadjuvant therapy allows clinical and pathologic assessment of tumor response to the chemotherapy regimen. In addition, local-regional control seems to be improved, and reductions in the size of the primary tumor allow breast-preserving procedures, even in patients initially not believed to be candidates for resection. Longer follow-up of these conservatively treated patients will be needed, however, to determine whether local-regional control is preserved.

The effect of under-treatment of breast cancer in women 80 years of age and older

BACKGROUND Several authors have demonstrated a trend toward the under-treatment of elderly and very elderly women with breast cancer. This study was undertaken to determine the impact of under-treatment of breast cancer in women age 80 and older. METHODS A retrospective chart review of all patients 80 years and older with a newly diagnosed breast cancer at the MD Anderson Cancer Center, Houston, TX, between September 1, 1989 and September 1, 2004 was performed. Data extracted from charts included patient demographics, comorbidity, treatments recommended, treatments received, complications of therapy, disease recurrence and disease related death. Treatments undertaken were analyzed in the context of accepted therapy at the time of diagnosis. RESULTS Two hundred twelve patients were identified. The median age was 83.5 years (range 80-97). Overall survival in the entire cohort was 7.28 years with a median follow up of 4 years for patients still alive at the end of the study period. Fifty seven percent of patients were under-treated according to institutional and national guidelines. Women who underwent hormonal therapy only demonstrated decreased disease specific survival (P<0.001 respectively) compared with patients who received multi-modality therapy. Women who underwent partial mastectomy without radiation treatment experienced a significant increase in local regional recurrence (P=0.045). There was an association of increased disease specific survival in patients who had surgical lymph node evaluation compared to those who did not (P=0.04). CONCLUSIONS Outcomes are compromised in very elderly women with breast cancer in whom less than complete combined modality treatment is undertaken. With the previously demonstrated safety of radiation therapy, hormonal therapy and surgery in the very elderly population, multi-modality therapy should not be routinely withheld in patients in this age category.

Lymphatic drainage patterns on early versus delayed breast lymphoscintigraphy performed after injection of filtered Tc-99m sulfur colloid in breast cancer patients undergoing sentinel lymph node biopsy

The axillary lymph node status is the most important predictor of prognosis and aids in breast cancer treatment planning. Patients with breast cancer now frequently undergo sentinel lymph node (SLN) biopsy rather than axillary lymph node dissection to determine the status of the regional lymph nodes. However, the optimal timing of radionuclide injection relative to the timing of SLN biopsy remains controversial. The objective of this study was to compare the lymphatic drainage patterns on lymphoscintigraphy performed at 15 minutes to 4 hours and at 18 to 24 hours after injection of filtered Tc-99m sulfur colloid, and to determine whether, over time, radiocolloid migrates to second-echelon nodes that are not the SLNs. Fifteen women with breast cancer (mean age, 55 years; range, 38–78 years) were scheduled to undergo SLN biopsy after each received an injection of 18.5 MBq (0.5 mCi) filtered Tc-99m sulfur colloid into the breast parenchyma surrounding the tumor or biopsy cavity. Both early (15 minutes to 4 hours after radionuclide injection) and delayed (18–24 hours after radionuclide injection) lymphoscintigraphy was performed in each patient. SLN biopsy was performed, followed by completion axillary lymph node dissection and planned breast surgery. In each patient the patterns of distribution of the radionuclide in the lymph nodes were the same on early and delayed lymphoscintigrams. These findings, that the distributions of radionuclide in lymph nodes are identical on early and delayed images obtained after injection of filtered Tc-99m sulfur colloid, suggest that performing SLN biopsy on the day after injection does not diminish the accuracy of the technique in predicting the potential site of metastasis in the regional lymph nodes in patients undergoing this procedure for breast cancer.