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Background: The incidence of brain metastases (BrM) has steadily increased over time as women with metastatic breast cancer (MBC) live longer and survive to experience spread of cancer to the central nervous system (CNS). Women with triple negative and HER2+ MBC, which represent 30-40% of the MBC population, are at particularly high risk of BrM. At present, MBC patients are not screened for BrM; rather, they undergo imaging of the brain only after symptoms suggestive of CNS involvement develop. Unfortunately, by the time that patients experience potentially debilitating symptoms of BrM, they often have a significant burden of disease with limited treatment options and a poor prognosis. We hypothesize that early detection of BrM via magnetic resonance imaging (MRI)-based screening may allow for early intervention and, ultimately, improved outcomes for MBC patients. Methods: A multi-centre, open-label prospective phase II study, randomizing 50 women with triple negative or HER2+ MBC to either MRI-based BrM screening or symptom-directed surveillance. Randomization is stratified for tumor subtype. Intervention arm: Contrast-enhanced MRI of the brain at baseline, 4-, 8- and 12-months with concurrent chemical exchange saturation transfer (CEST) imaging, a new metabolic MRI sequence that may detect BrM even earlier than standard MRI. Control arm: Symptom-directed surveillance (brain imaging only if patients develop symptoms suggestive of BrM). All participants complete questionnaires at baseline, 6- and 15-months to assess overall (EORTC QLQ BN20) and neurologic-specific (FACT-BR tools) quality of life (QoL) as well as cancer-related anxiety (NCI PRO-CTCAE). A blood sample is collected for ctDNA analysis at baseline in all patients at diagnosis of BrM, if applicable. Key inclusion criteria: 1) Age ≥18; 2) Triple negative MBC, with metastatic disease diagnosed ≤12 weeks prior to study entry OR HER2+ MBC with no restrictions regarding timeline of diagnosis; 3) No symptoms of BrM or known asymptomatic BrM at study entry. Key exclusion criteria: 1) ECOG>2; 2) Inability to complete an MRI (e.g., claustrophobia). Analyses: The primary goal of this study is to determine the feasibility of a randomized trial of BrM screening versus symptom-directed surveillance in the proposed patient population. The pilot study will be considered “not feasible” if 50% of patients allocated to the control arm are screened for BrM with CT or MRI. Overall survival will be assessed as a secondary endpoint. We will also investigate how screening for BrM influences the detection rate of BrM and explore how subsequent intervention affects both overall and neurologic-specific QoL. Our data will enable a power calculation to determine a sample size for a future, larger trial. 28 of 50 planned patients have enrolled in the study to-date. Citation Format: Katarzyna J Jerzak, Arjun Sahgal, Gregory Pond, Priscilla K Brastianos, Orit Freedman, Gregory Stanisz, Ellen Warner. MRI screening versus symptom-directed surveillance for brain metastases among patients with triple negative or HER2+ metastatic breast cancer: A pilot study (nct03881605) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-07-01.

Advanced Breast Cancer; Efficacy; Margetuximab Cáncer de mama avanzado; Eficacia; Margetuximab Càncer de mama avançat; Eficàcia; Margetuximab Importance ERRB2 (formerly HER2)–positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation. Objective To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC. Design, Setting, and Participants The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019. Interventions Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice. Main Outcomes and Measures Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis. Results A total of 536 patients were randomized to receive margetuximab (n = 266) or trastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. Margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P

Purpose Despite triple antiemetic therapy use for breast cancer patients receiving emetogenic chemotherapy, nausea remains a clinical challenge. We evaluated adding olanzapine (5 mg) to triple therapy on nausea control in patients at high personal risk of chemotherapy-induced nausea and vomiting (CINV). Methods This multi-centre, placebo-controlled, double-blind trial randomized breast cancer patients scheduled to receive neo/adjuvant chemotherapy with anthracycline-cyclophosphamide or platinum-based chemotherapy to olanzapine (5 mg, days 1–4) or placebo. Primary endpoint was frequency of self-reported significant nausea, repeated for all cycles of chemotherapy. Secondary endpoints included: duration of nausea, overall total control of CINV, Health Related Quality of Life (HRQoL) using FLIE questionnaire, use of rescue mediation and treatment-related adverse events. Results 218 eligible patients were randomised to placebo (105) or olanzapine (113). From days 0–5 following each cycle of chemotherapy, 41.3% (95%CI: 36.1–46.7%) of patients in the placebo group reported significant nausea compared to 27.7% (95%CI: 23.2–32.4%) in the olanzapine group (p = 0.001). Across all cycles of chemotherapy, patients receiving olanzapine experienced a statistically significant improvement in HRQoL (p, Highlights • Double-blind trial evaluated the addition of olanzapine to triple therapy in patients at high personal risk of CINV. • Adding 5 mg olanzapine was associated with significantly improved nausea control with no unexpected toxicities. • Olanzapine plus triple therapy should be considered standard of care for breast cancer patients at high risk of CINV.

The optimal timing of commencing adjuvant endocrine therapy (ET) relative to adjuvant radiotherapy (RT) (i.e. concurrent with or sequential to radiotherapy) remains unknown. A systematic review performed by our team was unable to answer this question due to a lack of high quality, randomized data on concurrent versus sequential ET and RT. Surveys of physicians confirmed this uncertainty and highlighted theoretical concerns for increased side effects with concurrent treatment. Respondents showed keen interest in obtaining real world, randomized data to guide clinical practice. REaCT-RETT is a pragmatic, randomized, non-inferiority trial comparing concurrent and sequential ET and RT in early breast cancer (EBC). The primary endpoint will assess the change in ET side effects at baseline and 3 months post radiation, using the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES), with primary analysis based on an analysis of covariance (ANCOVA). With a sample size of 176 patients (88 per arm), an ANCOVA would have 80% power (α=0.05) to detect effect sizes as small as 0.25 regardless of the correlation with covariates. It is hypothesized that concurrent therapy will be non-inferior to sequential therapy in terms of ET side effects. Secondary endpoints will examine RT toxicity, ET compliance, quality of life, and cost-effectiveness. Patients with HR positive EBC planned to receive both adjuvant ET and RT were eligible. Patients who previously received ET for invasive breast cancer, or RT in the same breast, were excluded. The trial is conducted by The Ottawa Hospital’s (TOH) innovative Rethinking Clinical Trials (REaCT) program (https://react.ohri.ca/) which strives to improve access to patient-centered, pragmatic clinical trials by removing barriers for patients and researchers. Integral features of the program include broad eligibility criteria, a verbal consent model, and pragmatic data collection and assessment procedures. REaCT is the largest pragmatic cancer clinical trials program in Canada, with over 3,200 patients randomized in 18 clinical trials at 15 sites across Canada. REaCT-RETT accrued patients from September 2019 to January 2021. Data collection is ongoing, with final patient follow up expected April 2022. The timing of accrual provided a unique opportunity to adapt in response to restrictions due to the COVID-19 pandemic, which began to impact trial sites in March 2020. The target sample size was met with 262 patients randomized (1:1) across 3 sites in Ontario, 98% from TOH. A mean of 19 patients/month were accrued prior to the pandemic, compared to a mean of 13 patients/month after March 2020. Twenty-two patients were removed due to withdrawal of consent, ineligibility, or physician choice, and the pandemic was not a significant contributing factor. Since March 2020 there have been 772 patient follow ups, of which 47% (364/772) have been virtual. Only 10% (102/1028) of trial mandated appointments have been missed to date. Compliance with baseline and 3-month FACT-ES questionnaires for the primary endpoint in evaluable patients was 90% (215/240) and 83% (198/240), respectively. The pandemic posed several challenges to the REaCT-RETT study including a decline in patient accrual, poor accrual at peripheral sites due to delayed opening, and a rapid switch to virtual patient care. However, the nimble REaCT methodology enabled virtual patient consent and data collection during the pandemic, allowing the trial to continue successfully, with final data expected for presentation summer 2022. Finally, despite the challenges of COVID-19 we have seen that patients and physicians remain interested in research, and we are applying valuable lessons learned to forthcoming REaCT trials to strengthen their performance during and beyond the ongoing pandemic. Citation Format: Sharon F Mc Gee, Mark Clemons, Michelle Liu, Mashari Jemaan Alzahrani, Terry Ng, Arif Awan, Sandeep Sehdev, John Hilton, Jean Michel Caudrelier, Marie France Savard, Lesley Fallowfield, Vikaash Kumar, Orit Freedman, Dean Fergusson, Gregory Pond, Brian Hutton, Jean Marc Bourque. A randomized, pragmatic trial investigating the timing of radiotherapy and endocrine in patients with early stage breast cancer (REaCT-RETT trial) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-01-01.

Background: CTX + dual HER2-targeting monoclonal antibodies (mAb) remains a standard of care for treatment (Tx) of both HER2+ early-stage and MBC. However, when the SOPHIA trial was launched, limited Tx options existed after progression on T, pertuzumab (P), and ado-trastuzumab emtansine. M, an Fc-engineered anti-HER2 mAb, targets the same epitope as T and exerts similar antiproliferative effects. M enhances CD16A-mediated ADCC compared to T. Furthermore, M treatment is associated with increased HER2-specific T- and B-cell responses and increased T-cell clonality compared to baseline. The phase 3 SOPHIA (NCT02492711) study demonstrated PFS benefit of M vs T, both + CTX, in HER2+ MBC pts. M improved PFS over T, with a 24% relative risk reduction (HR .76; 95% CI .59-.98; P=.033; median, 5.8 [95% CI 5.5-7.0] months (mo) vs 4.9 [95% CI 4.2-5.6] mo (Rugo HS, et al. JAMA Oncol 2021), resulting in FDA approval. Median OS after 270 mortality events (2nd interim analysis) was 21.6 mo with M vs 19.8 mo with T (HR .89; 95% CI .69-1.13; P=.33). Here we report final OS after 385 events, as well as updated safety.Methods: Pts with disease progression after ≥2 lines of anti-HER2 Tx, including P, and 1-3 lines of Tx for HER2+ MBC were randomized 1:1 to CTX + either M (15 mg/kg) or T (8 mg/kg loading dose, then 6 mg/kg), both given IV every 3 weeks. Randomization was stratified by number of metastatic sites (≤2, >2), lines of Tx for MBC (≤2, >2), and CTX choice (capecitabine, eribulin, gemcitabine, or vinorelbine). Sequential primary end points were central-blinded review of PFS and OS.Results: The intent-to-treat (ITT) population comprised 536 pts (M, 266; T, 270). At the median follow-up of 20.2 mo among all ITT pts, pts received a median of 7 cycles of M + CTX vs 6 cycles of T + CTX. Median OS after 385 events in the ITT population was 21.6 mo with M vs 21.9 mo with T (HR .95; 95% CI .77-1.17; P=.62; Table). Based on a prespecified, non-α-allocated exploratory analysis, a numerical OS advantage in favor of the M arm was observed in the subgroup of pts homozygous for the CD16A-158F low-affinity allele (median OS, 23.6 vs 19.2 mo; HR .72; 95% CI .52-1.00; nominal P=.05). In contrast, in the small subgroup of CD16A-158V homozygotes, median OS was longer for T vs M (31.1 mo vs 22.0 mo; HR 1.77; 95% CI 1.01-3.12; nominal P=.04). Grade ≥3 adverse events (AE) occurred in 146 pts (55.3%) receiving M vs 141 pts (53.0%) receiving T. Serious AEs were seen in 47 pts (17.8%) receiving M vs 51 pts (19.2%) receiving T. Incidence of infusion-related reactions was higher with M (36 [13.6%]) vs T (9 [3.4%]). Left ventricular dysfunction requiring delay or cessation of M/T administration occurred in 4 pts (1.5%) receiving M and in 7 pts (2.6%) receiving T. Conclusions: The median OS in the ITT population was not statistically different between the 2 arms. An exploratory analysis of CD16A genotyping indicates a numerical OS advantage in favor of M in F homozygous pts, along with a numerical OS advantage in favor of T in V homozygous pts. Safety of M + CTX was similar to previous reports and consistent with M FDA-approved label. Studies of M in HER2+ breast cancer pts with different CD16A allelic variants are warranted, including MARGOT, the neoadjuvant investigator-initiated study on the efficacy of M vs T in pts carrying F-allelic variants of CD16A. Median OSITT analysisPrespecified, non-α-allocated exploratory analysis (n=506)N=536CD16A-158F carriers (F/F and F/V)(n=437)CD16A-158F homozygotes (F/F)(n=192)CD16A-158F/V heterozygotes(n=245)CD16A-158V homozygotes (V/V)(n=69)aM + CTX, mo21.6 (n=266)23.3 (n=221)23.6 (n=102)21.3 (n=119)22.0 (n=37)T + CTX, mo21.9 (n=270)20.8 (n=216)19.2 (n=90)22.0 (n=126)31.1 (n=32)HR (95% CI)0.95 (0.77-1.17)0.86 (0.69-1.08)0.72 (0.52-1.00)0.96 (0.71-1.30)1.77 (1.01-3.12)P value0.620.19b0.05b0.78b0.04bAbbreviations: CTX, chemotherapy; HR, hazard ratio; ITT, intent to treat; M, margetuximab; mo, months; OS, overall survival; T, trastuzumab. Cutoff date: June 14, 2021. aThis subgroup was characterized by an imbalance in poor prognostic features. bNominal P value. Citation Format: Hope Rugo, Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Antonino Musolino, Mark D. Pegram, Thomas Bachelot, Gail S. Wright, Cristina Saura, Santiago Escrivá-de-Romaní, Michelino De Laurentiis, Gary N. Schwartz, Timothy Pluard, Francesco Ricci, William Gwin, III, Christelle Levy, Ursa Brown-Glaberman, Jean-Marc Ferrero, Maaike de Boer, Sung-Bae Kim, Katarína Petráková, Denise A. Yardley, Orit Freedman, Erik H. Jakobsen, Einav Nili Gal-Yam, Rinat Yerushalmi, Peter A. Fasching, Emily Ashley, Shengyan Hong, Minori Rosales, William J. Gradishar. Phase 3 SOPHIA study of margetuximab (M) + chemotherapy (CTX) vs trastuzumab (T) + CTX in patients (pts) with HER2+ metastatic breast cancer (MBC) after prior anti-HER2 therapies: Final overall survival (OS) analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-01.

Gastric-type endocervical adenocarcinoma is an uncommon aggressive type of endocervical adenocarcinoma that is not associated with human papillomavirus (HPV). At present, this tumor is classified under the spectrum of mucinous carcinoma of the uterine cervix. The clinical stage of gastric-type endocervical adenocarcinoma at the time of diagnosis is usually more advanced compared to the HPV-associated endocervical adenocarcinoma. Widespread dissemination to unusual sites, such as omentum, peritoneum, and distant organs, can be present. Owing to its rare incidence, diagnostic dilemmas, and aggressive behavior, clinical management can be challenging. In this study, we aimed to elucidate the molecular characteristics of these tumors by using next-generation sequencing (NGS) to assess 161 unique cancer-driver genes for single-nucleotide and copy-number variations, gene fusions, and insertions/deletions within gastric-type endocervical adenocarcinoma tumors. In total, 92 variants were detected across the 14 samples tested (7 variants on average per tumor). TP53 was the most recurrently mutated gene followed by MSH6, CDKN2A/B, POLE, SLX4, ARID1A, STK11, BRCA2, and MSH2. Abnormal p53 expression was observed in nine cases by immunohistochemistry, of which TP53 variants were present in four cases. MDM2 gene amplification in 12q15 (69202190-69233452) locus was seen in two cases that express normal p53 levels by immunohistochemistry. Four cases had STK11 null (frameshift/nonsense) variants, three of which were previously reported in Peutz-Jeghers syndrome. Overall, genes that are implicated in DNA damage, repair, cell cycle, Fanconi anemia pathway, and the PI3K-AKT signaling pathways were found to be mutated. Of note, genes known to have acquired and/or inherited variants in endometrial tumors were enriched within our cohort. In conclusion, our study shows the genetic heterogeneity of gastric-type endocervical adenocarcinoma with some potentially actionable molecular alterations, which highlights the importance of further molecular characterization for better identification of this rare entity, and hence better clinical management.

Background: Bone-targeted agent such as bisphosphonates (BPs) can reduce skeletal complications from bone metastases but have no effect on either disease progression or survival. Despite substantial variability in the frequency and severity of skeletal complications, patients are empirically treated with BPs at the same dose and schedule irrespective of their individual risk. Materials and Methods: A pilot, randomized, non-inferiority trial was conducted. Patients with low-risk bone metastases (serum C-telopeptide [CTx] Results: Fifty-four patients were approached, 44 provided consent and 38 were eligible for randomization. Median age was 55 (range 29–77) and mean baseline CTx was 319ng/L (range 10–526). Thirty-five participants (92%) completed the trial, 2 withdrew consent and one participant died. Fourteen control group participants (73.7%) and 13 experimental group participants (68.4%) maintained CTx in the low risk range (test for two proportions p=0.64). All patients not maintaining CTx in the low risk range showed evidence of both visceral and bone progression. Compared to the control group, there was a trend towards increasing CTx with time in the experimental group (p=0.10). There was no significant difference in BAP (p=0.37), BPI (p=0.21) or FACT-BP scores (p=0.59) between the two groups. Over the 48 week follow-up, two skeletal events were observed in each group. Conclusions: Randomized trials of de-escalated BP therapy in women with low-risk bone metastases are feasible. Twelve-weekly pamidronate appears non-inferior to 3–4 weekly treatment. Larger trials are required to assess whether; 1) increasing CTx levels with de-escalated therapy will lead to higher rates of skeletal complications and 2) whether BP should be given every 3–4 weeks in patients with progressive visceral and bone disease. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-16-08.

At present, there is no gold standard test for the investigation of ovarian function in pre-menopausal breast cancer patients who develop amenorrhea after chemotherapy. Clinical, biochemical and biophysical investigations continue to be utilized in clinical practice, despite concerns regarding their predictive value for menopause. The resulting uncertainty about a woman's actual menopausal status has important consequences for patient management. These include choice of appropriate endocrine therapy, assessment of residual ovarian function and its effect on breast cancer recurrence, fertility issues and the prediction of the likelihood of conception. It is hoped that the development of novel surrogates may allow clinicians to more accurately assess menopausal status and thereby facilitate tailored and individualised therapy for this common group of patients.

Background: Approximately 1/3 of patients with metastatic breast cancer (MBC) and bone disease will sustain a skeletal related event (SRE) despite use of a bisphosphonate; there is therefore an urgent unmet need in this large population to better assess individual SRE risk and develop more effective bone protective agents. Using novel tools to assess bone quality may help guide individual patient treatment choices as well as future trial design. Materials and Methods: Women with MBC and bone metastases were recruited. Baseline bone assessments were performed using dual-energy X-ray absorptiometry (DXA) [areal bone mineral density (BMD) and vertebral fracture assessment (VFA)], high-resolution peripheral quantitative computed tomography (HR-pQCT), and serum markers of bone turnover [serum CTX and bone-specific alkaline phosphatase (BAP)]. Risk factors for osteoporosis and fractures were then recorded. Results: 49 baseline assessments were completed. Mean age and body mass index were 53.6 (range 30-80) and 27 (range 17-45) respectively. One in four women had an ECOG 2-3, and 24% had a clinical fracture since the diagnosis of MBC. 94% had estrogen positive disease, 11% were HER2+. 53% had prior radiation therapy to bone; 90% received bisphosphonate therapy. Bone assessments are outlined in the Table. Vertebral compression deformity (VCD) using the novel technique of VFA was most strongly associated with clinical fracture (p = 0.003). Discussion: Prospective evaluation of individual SRE risk will enable improved patient-centred care and allow more rational use of bone targeted therapies. VFA is a novel tool that may better inform treatment decisions and choice of agents in women with MBC. Future follow-up of these patients will help determine the optimal assessment modality. Bone quantity and quality assessments Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-08.

BACKGROUND: Vitamin D deficiency has potential roles in breast cancer etiology and progression. Vitamin D deficiency has also been associated with increased toxicity from bisphosphonate therapy. The optimal dose of vitamin D supplementation is unknown, but daily sunlight exposure can generate the equivalent of a 10,000-IU oral dose of vitamin D3. This study therefore aimed to assess the effect of this dose of vitamin D3 in patients with bone metastases from breast cancer. METHODS: Patients with bone metastases treated with bisphosphonates were enrolled into this single-arm phase 2 study. Patients received 10,000 IU of vitamin D3 and 1000 mg of calcium supplementation each day for 4 months. The effect of this treatment on palliation, bone resorption markers, calcium metabolism, and toxicity were evaluated at baseline and monthly thereafter. RESULTS: Forty patients were enrolled. No significant changes in bone resorption markers were seen. Despite no change in global pain scales, there was a significant reduction in the number of sites of pain. A small but statistically significant increase in serum calcium was seen, as was a significant decrease in serum parathyroid hormone. Treatment unmasked 2 cases of primary hyperparathyroidism, but was not associated with direct toxicity. CONCLUSIONS: Daily doses of 10,000 IU vitamin D3 for 4 months appear safe in patients without comorbid conditions causing hypersensitivity to vitamin D. Treatment reduced inappropriately elevated parathyroid hormone levels, presumably caused by long-term bisphosphonate use. There did not appear to be a significant palliative benefit nor any significant change in bone resorption. Cancer 2010. © 2010 American Cancer Society.

The potential for synergistic interactions between anticancer drugs has been used to justify combinations of agents in clinical trials. However, most combinations of targeted agents and chemotherapies have been tested in the clinic without previous systematic evaluation of their potential benefit. Preclinical studies may help in the identification of synergistic or antagonistic interactions. For antineoplastic therapies, these studies may reveal synergy or antagonism of the drug combinations. Synergy occurs when two agents given together produce higher antitumoral activity than the sum of each individual drug. This represents the ideal setting for the development of combinations of targeted agents and chemotherapies. On the other side, certain drug combinations have shown adverse results, indicative of an antagonistic effect. In this article, we review the preclinical molecular bases that justify approved combinations of targeted agents with chemotherapy including examples of synergistic and antagonistic combinations. We also discuss scenarios for rational associations of targeted agents based on biological data and propose strategies that may improve the success of combinations of anticancer agents.

Purpose Decisions about treatment for women with metastatic breast cancer are usually based on the estrogen (ER), progesterone (PgR), and human epidermal growth factor receptor 2 (HER2) status of the primary tumor. Retrospective data suggest that discordance between primary and metastatic lesions leads to detrimental outcome. This prospective study investigated receptor status of primary tumors and metastases in the same patient and assessed the impact of discordance on patient management and survival. Patients and Methods Biopsies of suspected metastases were analyzed for ER, PgR, and HER2. Primary tumors and metastases were analyzed using similar methodology. The treating oncologist indicated a treatment plan before and after biopsy to determine whether the result influenced management. Patients were followed up for progression or death. Results Of 121 women undergoing biopsy, 80% could be analyzed for receptor status. Discordance in ER, PgR, and HER2 between the primary and the metastasis was 16%, 40%, and 10%, respectively. Biopsy led to a reported change of management in 14% of women (95% CI, 8.4% to 21.5%). Fine-needle aspiration and biopsy of bone led to reduced ability to analyze receptors. After a median follow-up of 12 months, there were no trends for an association between receptor discordance and either time to treatment failure or overall survival. Conclusion Biopsy of metastases is technically feasible. Clinicians alter immediate management in one of seven patients on the basis of results of the biopsy, and discordance is not then associated with detrimental effects on outcome. Tissue confirmation should be considered in women with breast cancer and suspected metastatic recurrence.

Despite many large randomised trials assessing adjuvant endocrine treatment for postmenopausal breast cancer patients, the optimal endocrine strategy remains unknown. Neoadjuvant endocrine studies provide the opportunity to model an appropriate study design in a more expeditious manner. Several large adjuvant trials are exploring sequential aromatase inhibitor (AI) strategies. The present study compared the effect of two sequences of AI use – steroidal (exemestane (E)) and nonsteroidal (anastrozole (A)) – on serological and pathological biomarkers, when given in the neoadjuvant setting to patients with locally advanced breast cancer.

Fulvestrant use in heavily pretreated patients with metastatic breast cancer is associated with highly variable responses. The present study aimed to characterize the benefit of fulvestrant therapy and to develop a prediction model for clinical benefit in this setting.

Bone is the most common site of metastatic spread in breast cancer patients. The use of bisphosphonates (BPs) in women with bone metastases from breast cancer has been shown to reduce the incidence, and delay the onset of, skeletal-related events. Indeed, BPs are now an established standard of care in treating patients with bone metastases. As with many new therapies, once efficacy in the metastatic setting is demonstrated, therapies are tested in the adjuvant setting. There are a number of trials that have tested the hypothesis that BP therapy in women with early breast cancer may not only reduce the development of skeletal metastases but also improve both disease-free and overall survival; recent randomized trials have demonstrated intriguing results regarding the possible anticancer effects of adjuvant BP therapy. Furthermore, interesting signals are filtering through from trials evaluating the role of BPs to prevent cancer-treatment induced bone loss. Many of these trials will be reported in the near future. In this article we review possible subgroups that may benefit from adjuvant treatment with BPs, and ongoing trials that may offer more definitive answers.

Bacteriophage D3112 is a Mu-like temperate transposable phage of Pseudomonas aeruginosa. Genetic mapping and DNA sequence analysis have identified the left end of the phage genome as encoding the transposase enzyme (A) and the lysogenic (c) repressor. The c open reading frame (ORF), located at the leftmost end of the phage genome and transcribed from right to left, has four possible GTG initiation codons. Using site-directed mutagenesis, each of the four GTG codons was modified to GTA, which cannot serve as an initiation codon. Plasmids were constructed expressing either the wild-type repressor ORF or the ORFs containing the mutated GTA codons. When introduced into Pseudomonas aeruginosa, no immunity to superinfection by D3112 was observed when the second GTG had been mutated. Northern blotting analysis demonstrated that the D3112 c repressor is transcribed as a 900-nt mRNA. The promoter region was defined by transcriptional lacZ fusions and primer extension analyses to bp 972–940 from the left end of the phage genome. When the D3112 c repressor was overexpressed and purified as a fusion protein with a C-terminal six-histidine extension (cts15-His6), it showed high affinity for a 261-bp PvuII fragment localized directly upstream of the c repressor ORF. Our results indicate that although D3112 c shows higher amino acid similarity to the λ family of repressors than it does to those of Mu and D108, it appears that its structure and function more accurately reflect an evolutionary ancestry with those from transposable coliphages Mu and D108.

As the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer points out,[1][1] locally advanced breast cancer comprises a heterogeneous group of breast tumours. Because of the complex needs of these patients, including the requirement for combined-modality

With the widespread use of sequential anthracycline/taxane&ndash, based chemotherapy for early-stage breast cancer, clinicians are becoming rapidly aware of toxicities associated with those regimens. Despite the low incidence reported in the literature of significant arthralgia and myalgia with those regimens, it is clinically evident that a substantial proportion of patients develop such toxicities. We performed a pilot study to investigate the extent of this problem. Patients who had received prior adjuvant or neoadjuvant chemotherapy [doxorubicin&ndash, cyclophosphamide followed by paclitaxel (ac-t), doxorubicin&ndash, cyclophosphamide followed by docetaxel (ac-d), or 5-fluourouracil&ndash, epirubicin&ndash, cyclophosphamide followed by docetaxel (fec-d)] completed a retrospective outcomes-based survey. The survey utilized the Functional Assessment of Cancer Therapy&ndash, Taxane Scale, the Memorial Symptom Assessment Scale, and a modified Brief Pain Inventory. Interviews were conducted with 82 patients. Interviewees had received ac-t (43%), fec-d (43%), and ac-d (14%). Pain as a side effect of either the anthracycline or the taxane chemotherapy was reported by 87% of patients. Most of the patients (79%) indicated that their worst pain occurred during the taxane component of treatment. Compared with paclitaxel, docetaxel was reported to cause more pain. Narcotics for pain management were required by 35 of 82 patients (43%). A significant number of patients receiving sequential anthracycline/taxane&ndash, based chemotherapy for early-stage breast cancer experience pain, particularly during the taxane component. Prospective patient-reported outcome assessments are needed to help individualize treatment interventions and to improve symptom management in this population.