Anne M. Wallace

Pain after breast surgery: a survey of 282 women

&NA; Breast surgery is a common procedure performed in women. Many women who undergo breast surgery suffer from ill‐defined pain syndromes. Although there exists a few reports on the incidence of post mastectomy pain, there are no published reports on chronic pain after breast reconstruction. This investigation attempts to characterize the pain after four types of breast surgery: (1) mastectomy, (2) mastectomy with reconstruction, (3) cosmetic augmentation, and (4) breast reduction. A questionnaire was mailed to 479 women who underwent breast surgery at the University of California, San Diego Medical Center between January 1988 and December 1992. A second mailing was sent to women who did not respond to the first mailing. Women were divided into four groups; mastectomy, mastectomy with reconstruction, cosmetic augmentation, and breast reduction. In the mastectomy and mastectomy with reconstruction groups, only women who had a lumpectomy with axillary dissection, a modified radical mastectomy, or a radical mastectomy were used in the study. 59% of the women responded. The incidence of pain occurring at least one year after surgery in the mastectomy + reconstruction group (49%) was significantly higher than the mastectomy (31%) and breast reduction (22%) groups. Thirty‐eight percent of the women with breast augmentation complained of pain. Women who had reconstruction using breast implants had a higher incidence of pain (53%) than those without (30%). The pain incidence in women who had reconstruction without implants was identical to women who had a mastectomy without reconstruction. There was no relationship between the use of silicone or saline implants and pain (22% and 33% respectively). However, the submuscular placement of the implants resulted in a significantly higher incidence of pain (50%) than the subglandular placement (21%). Of the women that reported pain, arm pain was significantly higher in the mastectomy and mastectomy + reconstruction group (56% and 42%, respectively) as compared to the breast reduction group (0%). Most patients reported intermittent pain in all groups. Of the women that reported pain, the mastectomy and mastectomy + reconstruction group had higher pain related to movement (41% and 42%, respectively) than the augmentation and breast reduction groups (15% and 9%, respectively). The peak pain intensity was significantly higher in the augmentation group as compared to the mastectomy group. Our incidence of post mastectomy pain is higher than most reports. The incidence of breast pain is highest in the mastectomy + reconstruction and augmentation groups which is assumed to be secondary to breast implants. Every effort should be made to achieve the best cosmetic result in breast reconstruction which in many cases justifies the use of breast implants. However, these women should be counseled on the possibility of developing chronic pain.

Prognostic Value of Nodal Ratios in Node-Positive Breast Cancer

PURPOSE The American Joint Committee on Cancer staging system for breast cancer was recently updated to reflect the impact of increasing the absolute number of positive lymph nodes on prognosis. However, numerous studies suggest that nodal ratios (absolute number of involved nodes-number of nodes resected) may have greater prognostic value than absolute numbers of involved nodes. Here we examine the data supporting the use of nodal ratios in breast cancer prognosis and consider the potential advantages and disadvantages of including nodal ratios in breast cancer staging. METHODS A systematic review of the literature was conducted using the following search engines: http://www.google.com; Thomsons ISI Web of Science; PubMed. RESULTS In multiple reports from both prospective and retrospectively collected data sets, nodal ratios have been shown to be significant predictors of outcome, including locoregional recurrence and overall survival. These studies span all stages of breast cancer and include various treatments as well as various statistical approaches. CONCLUSION There is considerable data supporting the use of nodal ratios in breast cancer prognosis. A thorough and methodological evaluation of the potential prognostic importance of nodal ratios in large multicenter data sets is merited and is currently being undertaken by the International Nodal Ratio Working Group.

Ras activation in human breast cancer

Genetic ras mutations are infrequent in breast cancer but Ras may be pathologically activated in breast cancer by overexpression of growth factor receptors which signal through Ras. Using a highly sensitive, coupled enzymatic assay, we measured Ras activation in 20 breast cancers, two fibroadenomas, and seven normal breast samples. Ras was highly activated compared to benign tissue in 11 of the 20 cancer; 7 of these 11 cancers expressed both the epidermal growth factor (EGF) and ErbB-2/neu/HER-2 receptors with the remaining four cancers with high Ras activation expressing one of these two receptors. In the other nine cancers, Ras activation was similar to that observed in benign breast tissue with none of these cancers expressing the EGF receptor while one expressed the ErbB-2 receptor. None of the cancers tested had an activating K-ras mutation nor did any of the cancers express a truncated EGF receptor or the c-FMS receptor. The activity of mitogen-activated protein (MAP) kinase was high in the cancers, and reflected the degree of Ras activation. In cultured mammary tumor cell lines, we showed that Ras activation was ligand dependent in cells overexpressing the ErbB-2 receptor. Thus, Ras was abnormally activated in breast cancers overexpressing the EGF and/or ErbB-2 receptors indicating there are sufficient ligands in vivo to activate these receptors, and this work provides a basis for new target-based treatments of this disease.

Adaptive Randomization of Veliparib–Carboplatin Treatment in Breast Cancer

BACKGROUND The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin. METHODS In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. RESULTS With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib-carboplatin was greater than that of the control. CONCLUSIONS The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

Phase I Trial of Adoptive Immunotherapy With Cytolytic T Lymphocytes Immunized Against a Tyrosinase Epitope

PURPOSE To study distribution and toxicity of cytolytic T lymphocytes (CTLs) against a single melanoma epitope. PATIENTS AND METHODS CD8(+) T cells obtained by leukapheresis from 10 patients with disseminated HLA-A2.1(+), tyrosinase-positive melanomas were immunized in vitro against tyrosinase(369-377) (YMNGTMSQV). Drosophila cells transduced with HLA-A2.1, CD80, and CD54 (intracellular adhesion molecule-1) were used for priming, followed by two rounds of immunization with mononuclear cells as antigen-presenting cells. 1 x 10(8) CTL were infused intravenously (IV) on day 1. CTL frequency was measured by limiting dilutions in five patients. (111)In labeling and scintigraphy measured distribution of CTL in next five. Five days later, 1 x 10(8) CTLs were infused on 4 successive days to both groups. Immunohistology of response was judged by biopsies. RESULTS Infusions were nontoxic. CTLs were undetectable in the blood, going to lungs within 5 minutes. At 4, 24, and 72 hours, they were found in liver and spleen. Lesions were visualized by scintiscans in one responding patient where two subcutaneous nodules were noted at 4 and 24 hours. A second patient had a partial response and remains alive with disease 2 years later. CD8(+) T cells were found in lesions of responders, associated with the presence of HLA-A2 molecules and tyrosinase. Two nonresponders without tyrosinase and HLA-A2 molecules had a paucity of CD8(+) T cells in their lesions. Whether the CD8(+) T cells in lesions of responders were those we had reinfused is uncertain. CONCLUSION CTLs immunized against a single melanoma epitope were nontoxic but did not specifically localize to tumor sites. Nevertheless, two patients had disease regression. Additional therapeutic studies with specifically immunized CTL seem justified.

Lymphoseek: a molecular radiopharmaceutical for sentinel node detection.

Background: Lymphoseek is a new radiopharmaceutical that accumulates in lymphatic tissue by binding to a receptor that resides on the surface of macrophage cells. We conducted a phase I clinical trial in which Lymphoseek was compared with filtered [99mTc]sulfur colloid (fTcSC) for sentinel node detection in patients with breast cancer.Methods: Twelve women (42–71 years) with breast cancer were randomly assigned to a 3-hour imaging protocol with peritumoral/subdermal injections (.5 mCi) of either Lymphoseek (1 nmol; molecular weight, 28 kDa; diameter, .007 μm) or .2 μm of fTcSC. Serial images were acquired for 180 minutes. Sentinel nodes, excised within 4.2 to 7.3 hours of administration, were assayed in a dose calibrator.Results: The receptor-binding agent, Lymphoseek, exhibited a significantly (P = .0025) faster injection site clearance (rate, .255 ± .147/hour; fTcSC rate, .014 ± .018/hour); the mean Lymphoseek clearance half-time was 2.72 ± 1.57 hours compared with 49.5 ± 38.5 hours for fTcSC. The primary sentinel node uptake of Lymphoseek (range, .02%–1.12%; mean, .55% ± .43%) and fTcSC (range, .00%–1.93%; mean, .65% ± .63%) did not differ (P = .75). Lymphoseek exhibited a lower mean number of sentinel nodes per study (n = 1.3) than fTcSC (n = 1.7) and a higher concordance with Lymphazurin.Conclusions: The molecular receptor-binding agent Lymphoseek demonstrated faster injection site clearance and equivalent primary sentinel node uptake when compared with fTcSC.

Abstract S5-02: Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL

Background: I-SPY 2 is a multicenter, phase 2 screening trial using adaptive randomization within biomarker subtypes to evaluate a series of novel agents/combinations when added to standard neoadjuvant therapy (paclitaxel q wk x 12, doxorubicin & cyclophosphamide q 2-3 wk x 4, T/AC) vs. T/AC (control arm) for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. Our goal is to identify/graduate regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient biomarker-linked Phase 3 neoadjuvant trial. Experimental regimens can “graduate” in at least 1 of 10 possible signatures defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP), with a maximum number of 120 total patients enrolled. We report final efficacy results of the oral PARP inhibitor veliparib (V, ABT-888) in combination with carboplatin (carbo), 1 of 7 experimental regimens evaluated in the trial to date. Methods: Women with tumors ≥2.5 cm by clinical exam and ≥2 cm by imaging are eligible for screening. Tumors that are MP low/HR+/HER2- are ineligible for randomization. MRI scans (baseline, 3 weeks after start of therapy, at completion of weekly T, and prior to surgery) were used in a longitudinal statistical model to improve the efficiency of adaptive randomization. V+carbo was assigned to HER2- tumors only, which limits its possible signatures to: all HER2-, HR+/HER2-, HR-/HER2-. For these 3 signatures we provide estimated pCR rates with associated 95% Bayesian probability intervals for V+carbo and concurrently randomized controls. Analysis is intent to treat with patients who switched to non-protocol therapy regarded as non-pCRs. For each signature we provide probabilities of superiority for V+carbo over control and Bayesian predictive probabilities of success in a neoadjuvant Phase 3 trial equally randomized between V+carbo and control. Results: When V+carbo met the 85% predictive probability criterion in HR-/HER2- and all HER2-, this regimen graduated and accrual to V+carbo was stopped. V+carbo was assigned to 72 patients, and there were 62 concurrently randomized controls (44 HER2- controls). The following table shows final results based on available pCR information. Two patients assigned to V+carbo withdrew consent during treatment and are not included in the table. Conclusion: Adaptive randomization successfully identified a biomarker signature for V+carbo on the basis of a modest number of patients. V+carbo has graduated with a triple-negative (TN) breast cancer signature, and is the subset recommended for this regimen9s subsequent development. There is a suggestion that HR+/HER2- tumors benefit little from this regimen and inclusion of tumors in this subset would therefore dilute its effect in a subsequent trial. Analyses are currently underway to define additional biomarkers that may be predictive of response. The I-SPY 2 standing trial mechanism efficiently evaluates agents/combinations in biomarker-defined patient subsets, with future agents/combinations reported as available. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-02.

Initial clinical experience with the Strut-Adjusted Volume Implant (SAVI) breast brachytherapy device for accelerated partial-breast irradiation (APBI): first 100 patients with more than 1 year of follow-up.

PURPOSE The Strut-Adjusted Volume Implant (SAVI; Cianna Medical, Aliso Viejo, CA) is a multichannel single-entry brachytherapy device designed to allow dose modulation to minimize normal tissue dose while simultaneously maximizing target coverage. This is the first report on the initial 102 patients with nearly 2 years of median follow-up. METHODS AND MATERIALS One hundred two patients were treated at two institutions. Data were collected on eligibility and dosimetry and followed for toxicity and recurrence. RESULTS The median follow-up is 21 months. Overall dosimetry is outstanding (median percent of target volume receiving 90% of the prescription dose was 95.9%, volume of target receiving 150% of the prescription dose was 27.8 mL, and volume of target receiving 200% of the prescription dose was 14.0 cm(3)). No devices were pulled prior to treatment completion. For patients with a skin bridge of less than 7 mm, the maximum median skin dose was 280 cGy (median percent of target volume receiving 90% of the prescription dose was 95.2%, volume of target receiving 150% of the prescription dose was 25.8 cm(3) and volume of target receiving 200% of the prescription dose was 12.7 mL). For patients with both chest wall and skin of less than 7 mm, the maximum median lung dose was 205 cGy with simultaneous skin dose of 272 cGy. The rate of telangiectasia was 1.9%. Grade 1 hyperpigmentation developed in 10 patients (9.8%) and Grade 2 fibrosis in 2 patients (1.9%). There were 2 symptomatic seromas and 2 cases of asymptomatic fat necrosis (1.9%). Of the patients, 27% were not eligible for MammoSite balloon brachytherapy (Hologic, Inc., Marlborough, MA) and 5% were not eligible for any balloon brachytherapy. The recurrence rate was 1%. CONCLUSIONS The SAVI appears to safely allow an increase in eligibility for APBI over balloon brachytherapy or three-dimensional conformal radiation, highlighting the outstanding device flexibility to maximize the target dose and minimize the normal tissue dose. The device was well tolerated by patients.

The Neoadjuvant Model is Still the Future for Drug Development in Breast Cancer

The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDAs draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach. Clin Cancer Res; 21(13); 2911–5. ©2015 AACR.

Preclinical studies of [99mTc]DTPA-mannosyl-dextran☆☆

We report the preclinical testing of a synthetic receptor-binding macromolecule, [(99m)Tc]DTPA-mannosyl-dextran (36 kDa, 8 DTPA and 55 mannosyl units per dextran, K(D) = 0.12 nM), for sentinel node detection. Nonclinical safety studies included cardiac pharmacology safety studies, acute toxicology and pathology studies at 50 and 500 times the scaled human dose in both rats and rabbits after foot pad administration, and perivascular irritation studies in rabbits following intra-muscular administration at 100 and 1000 times the scaled human dose. Biodistribution studies in rabbits at 15 m, 1 h, and 3 h indicated that [(99m)Tc]DTPA-mannosyl-dextran cleared the hind foot pad with a biological half-life of 2.21 +/- 0.27 h. Other than mild hepatocyte hypertrophy in rabbits, no abnormalities in toxicology or pathology were found. Intravenous administration had no effect on survival, any clinical observations, electrocardiograms, or blood pressures. Intramuscular injection had no effect on survival, clinical observations, injection site observations, or injection site histopathology. The estimated absorbed radiation dose to the affected breast was 0.15 mGy/MBq and the effective dose was 1.06 x 10(-2) mSv/MBq. This preclinical study demonstrates that [(99m)Tc]DTPA-mannosyl-dextran has no toxicities and has an acceptable biodistribution and radiation dose.