Regulation of Estradiol Synthesis by Aromatase Interacting Partner in Breast (AIPB).

Estradiol is essential for the development of female sex characteristics and fertility. Postmenopausal women and breast cancer patients have high levels of estradiol. Aromatase catalyzes estradiol synthesis; however, the factors regulating aromatase activity are unknown. We identified a new 22-kDa protein, aromatase interacting partner in breast (AIPB), from the endoplasmic reticulum of human breast tissue. AIPB expression is reduced in tumorigenic breast and further reduced in triple-negative tumors. Like that of aromatase, AIPB expression is induced by nonsteroidal estrogen. We found that AIPB and aromatase interact in nontumorigenic and tumorigenic breast tissues and cells. In tumorigenic cells, conditional AIPB overexpression decreased estradiol, and blocking AIPB availability with an AIPB-binding antibody increased estradiol. Estradiol synthesis is highly increased in AIPB knockdown cells, suggesting that the newly identified AIPB protein is important for aromatase activity and a key modulator of estradiol synthesis. Thus, a change in AIPB protein expression may represent an early event in tumorigenesis and be predictive of an increased risk of developing breast cancer.

Adherence to the National Quality Forum (NQF) breast cancer measures within cancer clinical trials: a review from ACOSOG Z0010.

BACKGROUND: In 2007, the National Quality Forum (NQF) released four performance measures for the treatment of breast cancer. We proposed to study the degree of adherence with these measures among participating institutions in a multi-institutional trial. METHODS: American College of Surgeons Oncology Group (ACOSOG) Z0010 enrolled breast cancer patients onto a phase II trial studying the prognostic significance of bone marrow and sentinel node micrometastases. The current study used chi(2) analyses to determine the degree of adherence with four NQF measures among three institution types: academic, community, and teaching affiliate. RESULTS: The study revealed small but important differences in two measures. Ninety-five percent of patients from teaching affiliated institutions received whole-breast radiation compared to 92% at academic and 91% at community hospitals. Among patients who were underinsured or uninsured, a marked decrease in radiation use was noted in comparison to patients with insurance-85 versus 93%, respectively. The study also revealed a difference among institutional types in patients undergoing excisional biopsy for diagnosis. In teaching-affiliated hospitals, 28.6% underwent excisional biopsy as compared to 36.8 and 37.4% in academic and community hospitals, respectively. There was no statistically significant difference between adherence rates with the remaining two measures. Adjuvant chemotherapy was administered to patients with hormone receptor negative tumors > or =1 cm in size in 79-85% of institutions. Tamoxifen was administered to 79-82% of those patients with hormone receptor-positive cancers. CONCLUSIONS: Among breast cancer patients enrolled onto a multi-institutional clinical trial, we found a high degree of adherence with current consensus standards for adjuvant treatment, despite varied practice environments.

Preoperative Predictive Factors of Positive Margin Status After Breast Conserving Therapy (BCT) with Intraoperative Radiation Therapy (IORT): A Retrospective Study of 400 Patients.

INTRODUCTION: Single-fraction intraoperative radiation therapy (IORT) has emerged as a therapeutic option in patients undergoing breast conserving therapy (BCT) for early stage breast cancer, often eliminating the need for postoperative external beam radiation therapy. However, if a positive margin is encountered after BCT, the patient will ultimately require external beam radiation therapy. The purpose of this study was to identify preoperative factors from patient demographics, preoperative workup, or biopsy results that may be predictive of postoperative margin status. MATERIALS AND METHODS: A retrospective chart review was performed on 396 patients who underwent BCT with IORT. Logistic regression models were utilized for statistical analysis. RESULTS: The majority of studied variables were similar; however, differences were noted for high-grade tumors, in situ status, and progesterone receptor-negative (PR-) tumors. Grade 3 tumors were significantly associated with positive margin status when compared with Grade 1 (odds ratio, 2.30; P = .036). PR- status tumors were found to be approximately 2 times more likely to have a positive margin (P = .028). Patients with in situ (stage 0) status tumors were 1.986 times more likely to have positive margins when compared with those with an invasive tumor (P = .030). CONCLUSIONS: Higher grade PR- tumors are at increased risk of having a positive margin, which should be taken into consideration when considering treatment with IORT.

Mitochondrial metabolic regulation by GRP78.

Steroids, essential for mammalian survival, are initiated by cholesterol transport by steroidogenic acute regulatory protein (StAR). Appropriate protein folding is an essential requirement of activity. Endoplasmic reticulum (ER) chaperones assist in folding of cytoplasmic proteins, whereas mitochondrial chaperones fold only mitochondrial proteins. We show that glucose regulatory protein 78 (GRP78), a master ER chaperone, is also present at the mitochondria-associated ER membrane (MAM), where it folds StAR for delivery to the outer mitochondrial membrane. StAR expression and activity are drastically reduced following GRP78 knockdown. StAR folding starts at the MAM region; thus, its cholesterol fostering capacity is regulated by GRP78 long before StAR reaches the mitochondria. In summary, GRP78 is an acute regulator of steroidogenesis at the MAM, regulating the intermediate folding of StAR that is crucial for its activity.

Endoplasmic Reticulum Stress Enhances Mitochondrial Metabolic Activity in Mammalian Adrenals and Gonads.

The acute response to stress consists of a series of physiological programs to promote survival by generating glucocorticoids and activating stress response genes that increase the synthesis of many chaperone proteins specific to individual organelles. In the endoplasmic reticulum (ER), short-term stress triggers activation of the unfolded protein response (UPR) module that either leads to neutralization of the initial stress or adaptation to it; chronic stress favors cell death. UPR induces expression of the transcription factor, C/EBP homology protein (CHOP), and its deletion protects against the lethal consequences of prolonged UPR. Here, we show that stress-induced CHOP expression coincides with increased metabolic activity. During stress, the ER and mitochondria come close to each other, resulting in the formation of a complex consisting of the mitochondrial translocase, translocase of outer mitochondrial membrane 22 (Tom22), steroidogenic acute regulatory protein (StAR), and 3ß-hydroxysteroid dehydrogenase type 2 (3ßHSD2) via its intermembrane space (IMS)-exposed charged unstructured loop region. Stress increased the circulation of phosphates, which elevated pregnenolone synthesis by 2-fold by increasing the stability of 3ßHSD2 and its association with the mitochondrion-associated ER membrane (MAM) and mitochondrial proteins. In summary, cytoplasmic CHOP plays a central role in coordinating the interaction of MAM proteins with the outer mitochondrial membrane translocase, Tom22, to activate metabolic activity in the IMS by enhanced phosphate circulation.

Breast cancer chemoprevention phase I evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator.

PURPOSE: Arzoxifene, a new selective estrogen receptor modulator with strong breast antiestrogen activity and absence of uterine agonist activity, was explored as a potential chemoprevention agent. We performed a multi-institutional evaluation of arzoxifene in women with newly diagnosed ductal carcinoma in situ or T1/T2 invasive cancer. EXPERIMENTAL DESIGN: In a Phase IA trial, 50 pre- or postmenopausal women were randomized to 10, 20, or 50 mg of arzoxifene daily in the interval between biopsy and re-excision or were enrolled as no-treatment controls. In a Phase IB trial, 76 postmenopausal women were randomized to 20 mg of arzoxifene versus matched placebo. Serum specimens collected at entry and at re-excision were assayed for various hormones and growth factors. Tissue from biopsies (estrogen receptor + and/or progesterone receptor +) and re-excision specimens was evaluated immunohistochemically for proliferation (Ki-67 by MIB-1 and proliferating cell nuclear antigen) and other biomarkers. RESULTS: In both trials, increases in serum sex hormone binding globulin were noted, as were decreases in insulin-like growth factor (IGF)-I and the IGF-I:IGF binding protein-3 ratio (P < 0.007 versus control/placebo). For 45 evaluable women in Phase IA, decreases in proliferation indices were more prevalent for arzoxifene (particularly 20 mg) than for controls. For 58 evaluable women in Phase IB, a decrease in estrogen receptor expression for arzoxifene was observed compared with no change with placebo (P = 0.0068). However, decreases in proliferation indices for arzoxifene were not statistically different from placebo, perhaps due to a confounding effect of stopping hormone replacement therapy before entry. CONCLUSION: Given the favorable side effect profile and the biomarker modulations reported here, arzoxifene remains a reasonable candidate for additional study as a breast cancer chemoprevention agent.

Cost-effectiveness of sentinel lymph node biopsy in thin melanomas.

BACKGROUND: Consideration of sentinel lymph node biopsy (SLNB) is recommended for thin melanomas with poor prognostic features; however, few metastases are identified. The purpose of this study was to assess the cost effectiveness of SLNB in this population. METHODS: The prospective melanoma database was reviewed to identify patients with melanomas <1.2 mm thick who had undergone SLNB. Physician and hospital charges were collected from the appropriate billing department. RESULTS: A total of 138 patients were identified over an 8-year period (1994-2002). Two patients with positive SLNs were identified (1.4%), one with a melanoma <1 mm thick. Patient charges for SLNB ranged from $10,096 to $15,223 US dollars, compared with $1000 to $1740 US dollars for wide excision as an outpatient. Using these charges, the cost to identify a single positive SLN would be between $696,600 and $1,051,100 US dollars. The cost for wide excision would be between $69,000 and $120,100 US dollars. Assuming that all patients with a positive SLN would die of melanoma, the cost per life saved would be $627,000 to $931,000 US dollars. CONCLUSIONS: The cost of performing SLNB in this population is great and only a small number will have disease identified that will alter treatment. These data call into question the appropriateness of SLNB for thin melanomas.

Is neoadjuvant therapy the answer to adenocarcinoma of the esophagus?

The conflicting results of randomized studies have led to confusion over the proper management of patients with esophageal adenocarcinoma. Although there is no firm evidence that neoadjuvant chemoradiation improves survival, because of the shortcomings of these trials, this method of treatment is practiced at many centers. Without the results of another multiinstitutional randomized trial, the true answer may never be known.

Trends in breast cancer presentation and care according to age in a single institution.

BACKGROUND: This study sought to determine the differences in presentation and treatment of young women (< or =40 years of age) with breast cancer. METHODS: A prospective database was analyzed for differences in presentation and care in breast cancer patients < or =40 and >40 years of age. RESULTS: The study group consisted of 1685 women. Younger women were more likely to present with a palpable mass, have estrogen receptor/progesterone receptor (ER/PR)-negative tumors, and have more advanced disease at presentation. Although there was no difference in breast conservation rates, younger women were more likely to have postmastectomy reconstruction. Younger women were more likely to receive chemotherapy, even with node-negative tumors less than 1 cm in diameter (37% vs. 13%, P = 0.01). CONCLUSIONS: The presentation of younger women with breast cancer differs from that of older women. Although the surgical management is similar, adjuvant therapy differs, with younger women more likely to be treated with chemotherapy.

Sentinel lymph node biopsy results in less postoperative morbidity compared with axillary lymph node dissection for breast cancer.

BACKGROUND: This study was designed to compare the postoperative morbidity and socioeconomic impact of sentinel lymph node biopsy (SLNB) with axillary lymph node dissection (ALND) in patients with early stage breast cancer. METHODS: A prospective, nonrandomized, controlled study was designed to include patients who underwent breast conservation surgery and SLNB +/- ALND. Group A consisted of patients who had a negative SLNB and did not go on to completion ALND. Group B consisted of patients who underwent a SLNB followed by a completion ALND because either (1) their sentinel node contained cancer or (2) they were within the validation phase of our institution's sentinel lymph node protocol. Patients were evaluated with a questionnaire and underwent a standardized physical examination to determine arm circumference. RESULTS: Data were obtained from 96 patients with a mean follow-up period of 15 months (range 8 to 29). Significant differences were seen in subjective measurements of arm complaints and arm numbness (P <0.001), with fewer complaints reported in group A. The difference in mid-bicep and antecubital fossa circumferences was significant when comparing the ratio of the procedure arm with the nonprocedure arm and when subtracting the nonprocedure arm from the procedure arm (P <0.003 and P <0.016, respectively) in favor of group A. Axillary surgery was performed as an outpatient procedure in 88% of group A patients, compared with 15% in group B (P <0.001). Furthermore, 71% of group A patients returned to "normal activity" in less than 4 days, in comparison with 7% of group B (P <0.001). CONCLUSIONS: SLNB results in less postoperative morbidity in terms of subjective arm complaints and mid-arm swelling. Expeditious return to work or normal activity after SLNB has potentially significant socioeconomic consequences.

Percutaneous removal of benign breast masses using a vacuum-assisted hand-held device with ultrasound guidance.

BACKGROUND: This study evaluates the safety, efficacy, and patient acceptance of a vacuum-assisted, hand-held biopsy device (Mammotome) in percutaneous removal of breast masses using ultrasound guidance. METHODS: A multicenter, nonrandomized study evaluated 124 women with low-risk palpable lesions. Lesions 1.5 cm but

Low-risk palpable breast masses removed using a vacuum-assisted hand-held device.

BACKGROUND: This study evaluates the safety, efficacy, and patient acceptance of a vacuum-assisted, hand-held biopsy device (Mammatome) in the percutaneous removal of breast masses using ultrasound guidance. METHODS: A multicenter, nonrandomized study evaluated 216 women with low-risk palpable lesions. Lesions 1.5 to 3.0 cm in size were removed using an 8-gauge probe. Those lesions <1.5 cm were removed with the 11-gauge probe. Follow-up evaluation was performed at 10 days and 6 months after biopsy. RESULTS: A total of 127 patients had biopsies using the 8-gauge probe, and 89 patients had biopsies using the 11-gauge probe. At 6-month follow-up, 98% of the lesions remained nonpalpable, 73% with no ultrasonographically visible evidence of the original lesion. Most complications were mild and anticipated. Most patients (98%) were satisfied with incision appearance, and 92% of patients would recommend the procedure to others. CONCLUSIONS: Percutaneous removal of palpable benign breast masses using the Mammotome system is feasible and safe, and yields high patient satisfaction. The results at 6 months after biopsy demonstrated the effectiveness of benign lesion removal, with correlative clinical data demonstrating lack of palpability and no need for additional procedures. Continuing evaluation of long-term efficacy is ongoing.

Phase II randomized study of two regimens of sequentially administered mitomycin C and irinotecan in patients with unresectable esophageal and gastroesophageal adenocarcinoma.

BACKGROUND: Based on the observation of topoisomerase-1, upregulation by mitomycin C (MMC), and the phase I antitumor activity of sequential MMC/irinotecan in esophageal cancer, we conducted a phase II evaluation of two schedules of this combination in previously untreated stage III/IV esophageal/gastroesophageal junction adenocarcinomas. PATIENTS AND METHODS: Patients (n = 76) were randomized to either 6 mg/m MMC on day 1 and 125 mg/m irinotecan on days 2 and 9 (arm A) or 3 mg/m MMC on days 1 and 8 and 125 mg/m irinotecan on days 2 and 9 (arm B). Each cycle was repeated every 28 days. Restaging was planned after two cycles, and resections were performed whenever possible. A two-stage Simon minimax design was used for each arm, with a "pick-the-winner" approach based on efficacy. RESULTS: The response rate (complete response + partial response) in 73 evaluable patients was 52% (21 of 40 patients) for arm A and 33% (11/33) for arm B. Moderate or severe toxicity was similar. Twenty-seven patients were resected (20:7, arm A:B). There was one complete pathologic response; five others were node negative. CONCLUSION: Irinotecan/MMC is feasible in esophageal/gastroesophageal junction adenocarcinoma. MMC (6 mg/m) every 28 days for up to six cycles is the recommended modulatory dose for irinotecan in future trials.

Prospective randomized clinical trial comparing intradermal, intraparenchymal, and subareolar injection routes for sentinel lymph node mapping and biopsy in breast cancer.

BACKGROUND: Multiple injection routes, including intradermal (ID), intraparenchymal (IP), and subareolar (SA), are used for 99mTc-sulfur colloid administration for sentinel lymph node (SLN) mapping and biopsy in breast cancer. The aim of this study was to compare localization by ID, IP, and SA injection routes based on preoperative lymphoscintigraphy and intraoperative identification. METHODS: Four hundred prospectively randomized breast cancers underwent SLN mapping and biopsy. RESULTS: Preoperative lymphoscintigraphy demonstrated localization to the axilla in 126/133 (95%) ID, 82/132 (62%) IP, and 96/133 (72%) SA (P < 0.001 ID vs. IP and ID vs. SA; P = 0.081 IP vs. SA), with a mean duration of preoperative lymphoscintigraphy of 139 +/- 18 minutes. Mean time to first localization when localization was demonstrated on preoperative lymphoscintigraphy was 8 +/- 14 minutes for ID, 53 +/- 49 for IP, and 22 +/- 29 for SA (P < 0.001 ID vs. IP and ID vs. SA; P = 0.003 IP vs. SA). Intraoperative identification of a SLN at the time of SLN biopsy was successful in 133/133 (100%) ID, 121/134 (90%) IP, and 126/133 (95%) SA (P < 0.001 ID vs IP; P = 0.014 ID vs. SA; P = 0.168 IP vs. SA), with a mean time from injection of 99mTc-sulfur colloid to start of SLN biopsy of 288 +/- 71 minutes. Mean intraoperative time to harvest the first SLN was 9 +/- 4 minutes for ID, 13 +/- 6 for IP, and 12 +/- 6 for SA (P < 0.001 ID vs. IP and ID vs. SA; P = 0.410 IP vs. SA). CONCLUSIONS: The ID injection route demonstrated a significantly greater frequency of localization, decreased time to first localization on preoperative lymphoscintigraphy, and decreased time to harvest the first SLN. This represents the first prospective randomized clinical trial to confirm superiority of the ID route for administration of 99mTc-sulfur colloid during SLN mapping and biopsy in breast cancer.

Ablative approaches to the minimally invasive treatment of breast cancer.

With the improvements in imaging techniques that have allowed the earlier detection of smaller breast cancers and the desire for improvements in cosmetic outcome, a number of minimally invasive techniques for the treatment of early stage breast cancers are being investigated. Ablative therapies, including laser ablation, focused ultrasound, microwave ablation, radiofrequency ablation, and cryoablation, have been described. All of these techniques have shown promise in the treatment of small cancers of the breast; however, additional research is needed to determine the efficacy of these techniques when they are used as the sole therapy and to determine the long-term local recurrence rates and survival associated with these treatment strategies.

Sentinel node skills verification and surgeon performance: data from a multicenter clinical trial for early-stage breast cancer.

OBJECTIVE: Marked variations in sentinel lymph node dissection (SLND) technique have been identified, and definitive qualifications for SLND performance remain controversial. Based on previous reports and expert opinion, we predicted that 20 to 30 cases of SLND with axillary lymph node dissection (ALND) would enable surgeons to identify sentinel lymph nodes (SLN). SUMMARY BACKGROUND DATA: In 1999, the American College of Surgeons Oncology Group initiated a prospective trial, Z0010, to evaluate micrometastatic disease in the SLN and bone marrow of women with early-stage breast cancer. Eligible patients included women with biopsy-proven T1/T2 breast cancer and clinically negative lymph nodes who were candidates for lumpectomy and SLND. METHODS: Participating surgeons were required to document 20 to 30 SLNDs followed by immediate ALND with failure rates less than 15%. Prior fellowship or residency training in SLND provided exemption from skill requirements. Data for 5237 subjects and 198 surgeons were available for analysis. RESULTS: Surgeons from academic (48.4%), community (28.6%), or teaching-affiliated (19.8%) institutions qualified with 30 SLND + ALND cases (64.6%), 20 cases (22.2%), or exemption (13.1%). Participants used blue dye + radiocolloid in 79.4%, blue dye alone in 14.8%, and radiocolloid alone in 5.7% of cases, achieving a 98.7% SLN identification rate. Patient factors associated with increased SLND failure included increased body mass index and age, whereas tumor location, stage, and histology, presence of nodal metastases, and number of positive nodes were not. Surgeon accrual of fewer than 50 patients was associated with increased SLND failure; however, SLND technique, specific skill qualification, and institution type were not. CONCLUSIONS: Using a standard skill requirement, surgeons from a variety of institutions achieved an acceptably low SLND failure rate in the setting of a large multicenter trial, validating the incorporation of SLND into clinical practice.

Phase II trial of neoadjuvant chemotherapy with docetaxel followed by epirubicin in stage II/III breast cancer.

PURPOSE: In most neoadjuvant chemotherapy regimens, the taxane is administered either in combination with an anthracycline or after an anthracycline-containing regimen. We sought to test the feasibility, safety, and determine the pathological complete response (pCR) rate of administering docetaxel first followed by epirubicin as neoadjuvant chemotherapy in women with clinical stage II, III breast cancer. PATIENTS AND METHODS: Twenty-five women with newly diagnosed clinical stage IIB (n = 10), IIIA (n = 5), or IIIB (n = 10) received 3 cycles of docetaxel 100 mg/M2 intravenously (IV) every 3 weeks followed by 3 cycles of epirubicin 100 mg/M2 IV every 3 weeks. pCR was defined as the absence of invasive cancer in the breast at definitive surgery. RESULTS: The median primary tumor size was 6 cm (range 1-12 cm), and 13 (52%) women had clinically palpable axillary lymph nodes. Patients received 149 of the 150 planned cycles of docetaxel and epirubicin without treatment delays, and only 3 (12%) patients had a dose reduction of docetaxel. Seven (28%) patients experienced febrile neutropenia, and 9 (36%) patients had grade 3 non-hematological toxicities with diarrhea being the most frequent in 3 (12%) patients. Six (24%) patients had pCR in the breast. Analysis of pre- and post-docetaxel biopsies from a subset of patients documented taxane-induced activation of mitogen-activated and stress-activated protein kinase pathways. CONCLUSION: Neoadjuvant docetaxel followed by epirubicin is well tolerated and active in breast cancer. To our knowledge, this is first description of docetaxel-induced activation of mitogen-activated and stress-activated protein kinase pathways in human breast cancer.

Lymphatic mapping in solid neoplasms: state of the art.

BACKGROUND: Lymphatic mapping and sentinel lymph node biopsy is an established technique for the staging and treatment of melanoma. The success of lymphatic mapping in this realm has broadened its application to other solid neoplasms. This update reviews the status of sentinel lymph node biopsy in its most widely cited applications. METHODS: Seminal manuscripts on lymphatic mapping in melanoma, breast, colon, vulvar, cervical, lung, gastric, and head and neck cancers are reviewed. RESULTS: Studies suggest that the application of lymphatic mapping as a staging tool in breast cancer and melanoma is justified when applied by trained surgeons. Additional validation is necessary before sentinel node biopsy is advocated in gynecologic, colon, lung, and head and neck cancer. CONCLUSIONS: As in breast cancer and melanoma, validation of the sentinel node concept in other solid tumors must occur in institutions other than those in which the technique is being developed before it is generally applied to other neoplasms.

Positron emission tomography affects surgical management in recurrent colorectal cancer patients.

BACKGROUND: We determined the effect of positron emission tomography (PET) on surgical decision-making in patients with metastatic or recurrent colorectal cancer. METHODS: A total of 114 patients with advanced colorectal cancer were imaged with computed tomography (CT) and PET scans. The PET and CT scans were independently interpreted before surgery and recorded. RESULTS: Forty-two of the 114 patients had resectable disease on the basis of CT. PET altered therapy in 17 (40%) of these 42 patients on the basis of the following results: extrahepatic disease (n = 9), bilobar involvement (n = 3), thoracic involvement (n = 5), retroperitoneal lymphadenopathy (n = 2), bone involvement (n = 1), and supraclavicular disease (n = 1). In 25 patients with liver metastases only, PET found additional disease in 18 (72%), extrahepatic disease in 11, chest disease in 13, retroperitoneal lymphadenopathy in 4, and bone disease in 3. In five patients, both scans underestimated small-volume peritoneal metastases discovered at laparotomy. CONCLUSIONS: PET altered therapy in 40% of patients. In patients with isolated liver involvement, 72% had more extensive disease that precluded surgical resection. PET scans should be used in the management of patients with recurrent colorectal cancer who are being considered for potentially curative surgery.