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1.  Optimizing the management of her2-positive early breast cancer: the clinical reality 
Current Oncology  2010;17(4):20-33.
Breast cancer positive for her2 (human epidermal growth factor receptor 2) is associated with a poor prognosis for patients with both early-stage and metastatic breast cancer. Trastuzumab has been shown to be effective and is now considered the standard of care for early-stage patients with her2-positive breast cancer. In that population, trastuzumab has been studied in six randomized clinical trials. Overall, use of this agent leads to a significant reduction in risk of disease recurrence and improvement in overall survival. Despite the strong evidence for the use of trastuzumab in managing her2-positive early breast cancer (ebc), a number of clinical controversies remain. The authors of this paper undertook a review of the available scientific literature on adjuvant trastuzumab to produce practical considerations from Canadian oncologists. The panel focused their discussion on five key areas: Management of node-negative disease with tumours 1 cm or smaller in sizeManagement of her2-positive ebc across the spectrum of the disease (that is, nodal and steroid hormone receptor status, tumour size)Timing of trastuzumab therapy with chemotherapy for early-stage disease: concurrent or sequentialTreatment duration of trastuzumab for ebcThe role of non-anthracycline trastuzumab-based regimens
PMCID: PMC2913825  PMID: 20697511
Adjuvant; early breast cancer; her2-positive; node-negative; trastuzumab
2.  Early Breast Cancer in the Older Woman 
The Oncologist  2011;16(4):479-485.
A literature review of recently published trials, reviews, and practice guidelines outlining the surgical and adjuvant management of early breast cancer in older women is presented.
Background.
Women aged ≥65 are generally underrepresented in early breast cancer studies. Therefore, the optimal management of this group of women remains less certain.
Methods.
A literature review of recently published trials, reviews, and practice guidelines outlining the surgical and adjuvant management of early breast cancer in older women was performed.
Results.
Surgery remains as the cornerstone treatment for early breast cancer in the elderly. Adjuvant radiation is generally considered if the projected lifespan is >5 years. Hormone receptor–positive disease is best treated with adjuvant endocrine treatment; aromatase inhibitors and tamoxifen are both options. Evidence for the use of adjuvant chemotherapy and trastuzumab for high-risk disease in the elderly is more limited. Polychemotherapy is still preferred in fit older women. Certain toxicities from systemic treatments can be more pronounced and should be carefully managed. Treatment with systemic agents should be individualized, with consideration of patient preference, performance status, comorbidities, and projected lifespan. Molecular tumor signatures may help better select patients for treatment in the future.
Conclusions.
Age in itself should not be an absolute contraindication to any breast cancer therapy. Comprehensive, multidisciplinary assessment of elderly patients is imperative in evaluating eligibility for beneficial therapies.
doi:10.1634/theoncologist.2010-0279
PMCID: PMC3228114  PMID: 21415085
Breast neoplasms; Aged; Geriatrics; General surgery; Adjuvant chemotherapy; Adjuvant radiation
3.  The Implications of Breast Cancer Molecular Phenotype for Radiation Oncology 
The identification of distinct molecular subtypes of breast cancer has advanced the understanding and treatment of breast cancer by providing insight into prognosis, patterns of recurrence, and effectiveness of therapy. The prognostic significance of molecular phenotype with regard to distant recurrences and overall survival are well established in the literature and has been readily incorporated into systemic therapy management decisions. However, despite the accumulating data suggesting similar prognostic significance for locoregional recurrence, integration of molecular phenotype into local management decision making has lagged. Although there are some conflicting reports, collectively the literature supports a low risk of local recurrence (LR) in the hormone receptor (HR) positive luminal subtypes compared to HR negative subtypes [triple negative (TN) and HER2-enriched]. The development of targeted therapies, such as trastuzumab for the treatment of HER2-enriched subtype, has been shown to mitigate the increased risk of LR. Unfortunately, no such remedy exists to address the increased risk of LR for patients with TN tumors, making it a clinical challenge for radiation oncologists. In this review we discuss the correlation between molecular subtype and LR following either breast conservation therapy or mastectomy. We also explore the possible mechanisms for increased LR in TN breast cancer and radiotherapeutic implications for this population, such as the safety of breast conservation, consideration of dose escalation, and the appropriateness of accelerated partial breast irradiation.
doi:10.3389/fonc.2011.00012
PMCID: PMC3355956  PMID: 22649753
breast; cancer; subtype; local; recurrence; triple; negative; radiotherapy
4.  Ixabepilone development across the breast cancer continuum: a paradigm shift 
The epothilone analog ixabepilone exhibits reduced susceptibility to several important tumor survival mechanisms that limit the efficacy of taxanes and anthracyclines. As a single agent, ixabepilone has shown promise in metastatic breast cancer when anthracyclines, taxanes, or capecitabine have failed; and in early-stage breast cancer that is taxane-naïve or has previously received taxanes in the adjuvant or metastatic setting. Compared with capecitabine alone, ixabepilone used in combination with capecitabine in patients previously treated with and resistant to anthracyclines and taxanes produced a 25% reduction in the risk of disease progression. Triple-negative tumors showed particular susceptibility to this doublet. Ixabepilone has also demonstrated efficacy as first-line therapy in combination with targeted agents such as bevacizumab and trastuzumab. Ongoing investigations should provide insight as to how this agent could be integrated into treatment of early-stage disease. In clinical studies, toxicities with ixabepilone were manageable and reversible through dose reduction or delay, even in patients with extensive or heavily-pretreated disease. Thus, ixabepilone represents a useful addition to the therapeutic options available for advanced breast cancer, and it may extend progression-free survival in patients with limited treatment options.
PMCID: PMC3004591  PMID: 21188108
ixabepilone; breast cancer; efficacy; metastasis; adjuvant
5.  Advances in First-Line Treatment for Patients with HER-2+ Metastatic Breast Cancer 
The Oncologist  2012;17(5):631-644.
The results of a literature review of well-established and recently published trials, reviews, and ongoing clinical trials examining first-line treatment for human epidermal growth factor receptor 2–positive metastatic breast cancer patients are presented.
Learning Objectives:
After completing this course, the reader will be able to: Discuss the optimal strategies to treat HER-2+ metastatic breast cancer patients in the first-line setting and after recurrence with adjuvant trastuzumab.Identify the current first-line therapeutic options for HER-2+ metastatic breast cancer, including HER-2/hormone receptor copositive tumors.Discuss the most important advances for HER-2+ metastatic breast cancer and the potential of novel anti-HER-2 therapies.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
The prognosis for breast cancer patients overexpressing human epidermal growth factor receptor (HER)-2 has changed with anti–HER-2–targeted therapy. Although anti–HER-2 therapy with trastuzumab and chemotherapy is the standard first-line treatment, the best therapeutic regimen has yet to be defined, and new strategies are evolving.
Methods.
A literature review of well-established and recently published trials, reviews, and ongoing clinical trials addressing first-line treatment for HER-2+ metastatic breast cancer patients was performed.
Results.
Taxanes are the agents most commonly used in combination with trastuzumab, but other chemotherapy drugs, such as anthracyclines, vinorelbine, and gemcitabine and triple-combination therapies including platinum compounds, capecitabine, and taxanes have been studied. The combination of aromatase inhibitors with anti–HER-2 therapies is a new therapeutic option for some patients who coexpress HER-2 and hormone receptors, although its activity observed in randomized clinical trials seems to be inferior to that of chemotherapy plus anti–HER-2 therapies. In addition, new anti–HER-2 therapies have shown activity in HER-2+ tumors, both alone and in combination with trastuzumab.
Conclusions.
Trastuzumab plus chemotherapy is the current standard of care for the upfront treatment of HER-2+ breast cancer patients, though other anti–HER-2–targeting agents may appear as new standards in the upcoming years.
doi:10.1634/theoncologist.2011-0187
PMCID: PMC3360903  PMID: 22523199
Metastatic breast cancer; HER-2+; Trastuzumab; First-line treatment
6.  Long-Term Outcome of Neoadjuvant Endocrine Therapy with Aromatase Inhibitors in Elderly Women with Hormone Receptor-Positive Breast Cancer 
Annals of Surgical Oncology  2014;21:1575-1582.
Background
Aromatase inhibitors (AIs) are more effective than tamoxifen as neoadjuvant endocrine therapy (NET) for hormone receptor (HR)-positive breast cancer. Here we report the surgical and long-term outcome of elderly postmenopausal patients with locally advanced, HR-positive breast cancer treated with preoperative AIs.
Methods
Between January 2003 and December 2012, 144 postmenopausal patients inoperable with breast conservative surgery (BCS) received letrozole, anastrozole, or exemestane as NET. Patients underwent breast surgery and received adjuvant AIs. Adjuvant systemic therapy, chemotherapy and/or trastuzumab, and adjuvant radiotherapy were administered as appropriate, but limited to high-risk patients with few or no comorbidities.
Results
After a median follow-up of 49 months, 4 (3.0 %) patients had local relapse, 18 (12.5 %) had distant metastases, and 24 (17.0 %) died. BCS was performed in 121 (84.0 %) patients. A tumor size <3 cm and human epidermal growth factor receptor 2 (HER2) negativity were predictors of BCS. The achievement of BCS and grade G1 were significantly associated with longer disease-free survival (DFS) (p = 0.009 and p = 0.01, respectively) and overall survival (p = 0.002 and p = 0.005, respectively). Residual tumor ≤2 cm (yT0–yT1) in the longest diameter after NET was also statistically associated with longer DFS (p = 0.005).
Conclusions
The results of this retrospective study indicate that elderly breast cancer patients with a tumor size <3 cm at diagnosis and HER2 negativity have a higher probability of achieving BCS after NET. Moreover, patients treated with BCS and with grade G1 tumor have a reduced risk of recurrence and death in the long-term follow-up.
doi:10.1245/s10434-014-3535-7
PMCID: PMC3975084  PMID: 24522992
7.  Docetaxel for the post-surgery treatment of patients with node-positive breast cancer 
Adjuvant chemotherapy reduces risk of relapse and cancer-related mortality in early stage breast cancer. Over the last decade, taxanes (paclitaxel and docetaxel) have been incorporated into various adjuvant trials and have demonstrated a significant benefit in the management of early stage breast cancer. Clinical trials using combinations of taxanes with targeted therapy have also shown considerable activity in breast cancer. This article reviews the pharmacology of docetaxel, a semi-synthetic taxane, and the clinical trials supporting its use in patients with node-positive breast cancer.
PMCID: PMC2504077  PMID: 18728853
docetaxel; node-positive breast cancer; post-surgery treatment; taxanes
8.  Does Use of the Adjuvant! Model Influence Use of Adjuvant Therapy Through Better Risk Communication? 
Adjuvant! is a model that provides recurrence and mortality risk predictions for patients with breast cancer considering adjuvant therapies. Although low-risk patients who saw Adjuvant! chose adjuvant therapy less frequently, whether this was because of educational or other aspects of the decision aid is unknown. The authors explored whether Adjuvant! affects choice of therapy through increased patient knowledge. A subset of data were analyzed from a cluster randomized trial in which oncology practices in 2 major United States cities were randomly assigned to use either Adjuvant! or an informational pamphlet to educate patients. Of 405 patients, 48 were low-risk, with 28 assigned to the decision aid and 20 to the pamphlet. Among the low-risk patients, using frequency tables and Fisher exact tests, the authors explored whether Adjuvant! was associated with more accurate patient estimates of survival; whether accuracy was associated with treatment choice; and whether, after controlling for accuracy, any remaining association was seen between Adjuvant! and treatment choice. Adjuvant! was associated with more accurate estimates of baseline prognosis compared with the pamphlet (57% vs. 25%; P = .04). Patients who had more accurate estimates of baseline prognosis were less likely to choose adjuvant therapy (62% vs. 89%; P = .04). After controlling for accuracy, no statistically significant association was found between the use of Adjuvant! and adjuvant therapy (P = .59 and P = .11 for inaccurate and accurate patients, respectively). Adjuvant! seems to influence patient choice through educational rather than other means of persuasion. However, many patients held inaccurate risk perceptions after viewing Adjuvant!.
PMCID: PMC3528013  PMID: 21715722
Risk communication; shared decision-making; decision aids; Adjuvant!; breast cancer; patient education
9.  Adjuvant bisphosphonates in endocrine-responsive breast cancer: what is their place in therapy? 
Recent advances in the treatment of early breast cancer have improved clinical outcomes and prolonged survival, especially in women with endocrine-responsive disease. However, cancer therapies including cytotoxic chemotherapy, ovarian suppression, and aromatase inhibitors can drastically reduce circulating estrogen, increasing bone loss and fracture risk. Because most women with early breast cancer will live for many years, it is important to protect bone health during cancer therapy. Several recent clinical trials combining adjuvant endocrine therapy with bisphosphonates have demonstrated efficacy for preventing cancer treatment-induced bone loss in pre- and postmenopausal women with early breast cancer. The largest body of evidence supporting the use of adjuvant bisphosphonates comes from studies with zoledronic acid; however, studies with risedronate, ibandronate, and denosumab (a biologic agent) have also demonstrated efficacy for preventing bone loss. Adding zoledronic acid to endocrine therapy prevents bone loss and improves bone mineral density (BMD). In addition, preclinical studies suggest that bisphosphonates have direct and indirect antitumor activity, such as inducing tumor cell apoptosis, reducing tumor cell adhesion and invasion, reducing angiogenesis, activating immune responses, and synergy with chemotherapy agents, among others. Clinical trials have demonstrated significantly improved disease-free survival in patients receiving adjuvant endocrine therapy plus zoledronic acid compared with endocrine therapy alone. Ongoing studies will further define the role of adjuvant bisphosphonates in maintaining bone health and improving clinical outcomes. The available evidence suggests that pre- and postmenopausal patients may receive clinical benefit from including bisphosphonates as part of their adjuvant treatment regimen for endocrine-responsive early breast cancer.
doi:10.1177/1758834009344594
PMCID: PMC3126000  PMID: 21789117
adjuvant; antitumor; bisphosphonates; bone loss; breast cancer; disease recurrence; endocrine responsive; zoledronic acid
10.  Matters of the heart: cardiac toxicity of adjuvant systemic therapy for early-stage breast cancer 
Current Oncology  2008;15(Suppl 1):S16-S29.
Breast cancer remains the most common malignancy in women. Since the late 1980s, significant advances have been made in the treatment of this cancer. Those advances, particularly the ones in the adjuvant setting, have led to declines in the mortality associated with breast cancer. But another result has been treatments that are more complex and that potentially carry more toxicity. One key toxicity related to the adjuvant therapy of breast cancer is cardiac toxicity. Some of the agents commonly used for the treatment of breast cancer, including anthracyclines, trastuzumab, and possibly even aromatase inhibitors, have been associated with cardiac toxicity. The present article reviews the current understanding of cardiac toxicity risk and strategies to minimize cardiac morbidity associated with cytotoxic chemotherapy, trastuzumab therapy, and hormonal therapy with aromatase inhibitors for early-stage breast cancer.
PMCID: PMC2216425  PMID: 18231644
Anthracyclines; trastuzumab; aromatase inhibitors; cardiac toxicity
11.  Adjuvant treatment of breast cancer in postmenopausal women: role of exemestane 
Adjuvant hormonal therapy significantly reduces the risk of recurrence and death following surgery for estrogen receptor (ER)-positive early breast cancer. Previously, the gold standard hormonal therapy was tamoxifen, a selective modulator of the ER. However, large clinical trials conducted over the past decade have defined the efficacy of an alternative class of hormonal agent, namely the third-generation aromatase inhibitors (AIs): exemestane, letrozole, and anastrozole. On the basis of the pivotal International Exemestane Study (IES), exemestane, a steroidal third-generation AI, was licensed for the adjuvant treatment of postmenopausal women with ER-positive early breast cancer following 2–3 years of tamoxifen to complete a total of 5 years of adjuvant hormonal therapy. Here, we consider recent data to emerge primarily from the IES and Tamoxifen Exemestane Adjuvant Multicenter trials and consider their implications for the role of exemestane in the adjuvant treatment of breast cancer.
doi:10.2147/BCTT.S11835
PMCID: PMC3846455  PMID: 24367167
breast cancer; exemestane; aromatase; tamoxifen
12.  Exemestane in early breast cancer: a review 
The adjuvant treatment of women with endocrine-sensitive early breast cancer has been dominated for the last 40 years by tamoxifen. However, the side-effects associated with this therapy have prompted a search for safer and biochemically more selective endocrine agents and led to the development of the third-generation aromatase inhibitors (AIs) anastrozole, letrozole and exemestane. Promising results in advanced disease have paved the way for treating early breast cancer, and AIs are increasingly replacing tamoxifen in the adjuvant setting. Several large, randomized trials with AIs have been completed or are ongoing in women with early-stage breast cancer, documenting the significant impact that these drugs are making on the risk for recurrence of breast cancer. As a result, there is increasing and widespread use of AI therapy for the treatment of early-stage endocrine-responsive breast cancer. This review summarizes the data for exemestane in the adjuvant setting, showing that a switch to exemestane after 2 to 3 years of tamoxifen therapy is associated with a statistically significant survival benefit and is regarded as being sensitive by international and national experts.
PMCID: PMC2643110  PMID: 19337436
early breast cancer; adjuvant setting; endocrine-sensitive; tamoxifen; aromatase inhibitor; exemestane; switch; IES 31; NSABP B-33; TEAM
13.  Association between genomic recurrence risk and well-being among breast cancer patients 
BMC Cancer  2013;13:295.
Background
Gene expression profiling (GEP) is increasingly used in the rapidly evolving field of personalized medicine. We sought to evaluate the association between GEP-assessed of breast cancer recurrence risk and patients’ well-being.
Methods
Participants were Dutch women from 10 hospitals being treated for early stage breast cancer who were enrolled in the MINDACT trial (Microarray In Node-negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy). As part of the trial, they received a disease recurrence risk estimate based on a 70-gene signature and on standard clinical criteria as scored via a modified version of Adjuvant! Online. \Women completed a questionnaire 6–8 weeks after surgery and after their decision regarding adjuvant chemotherapy. The questionnaire assessed perceived understanding, knowledge, risk perception, satisfaction, distress, cancer worry and health-related quality of life (HRQoL), 6–8 weeks after surgery and decision regarding adjuvant chemotherapy.
Results
Women (n = 347, response rate 62%) reported high satisfaction with and a good understanding of the GEP information they received. Women with low risk estimates from both the standard and genomic tests reported the lowest distress levels. Distress was higher predominately among patients who had received high genomic risk estimates, who did not receive genomic risk estimates, or who received conflicting estimates based on genomic and clinical criteria. Cancer worry was highest for patients with higher risk perceptions and lower satisfaction. Patients with concordant high-risk profiles and those for whom such profiles were not available reported lower quality of life.
Conclusion
Patients were generally satisfied with the information they received about recurrence risk based on genomic testing. Some types of genomic test results were associated with greater distress levels, but not with cancer worry or HRQoL.
Trial registration
ISRCTN: ISRCTN18543567
doi:10.1186/1471-2407-13-295
PMCID: PMC3689597  PMID: 23777535
Personalized medicine; Genomic profile; 70-gene signature; Patient-centered care; Breast cancer; Chemotherapy
14.  Treatment of HER2-Positive Metastatic Breast Cancer Following Initial Progression 
Clinical breast cancer  2009;9(Suppl 2):S50-S57.
Significant advances in molecular-targeted therapies have provided more effective and less aggressive forms of therapy for patients with HER2-overexpressing metastatic breast cancers. Despite the initial encouraging results of many therapeutic randomized trials that have been undertaken in this setting, de novo and acquired resistance to trastuzumab, the first anti-HER2 monoclonal antibody to demonstrate significant activity in this setting, can occur. Because recent studies strongly support a role for trastuzumab in not only the management of metastatic disease but also the adjuvant setting for HER2-overexpressing breast cancers, the clinical problem of trastuzumab resistance is becoming increasingly important. Specific recommendations for the optimal treatment of HER2-overexpressing metastatic disease are challenging because considerable advances in the field have been made. This article will review some of the main points to be considered for decision-making in anti-HER2 treatment in the metastatic setting: (1) the benefit of continued trastuzumab after progression on a first-line trastuzumab-containing regimen, (2) novel agents that have been recently added to the plethora of drugs available to treat HER2-overexpressing breast cancers, and (3) molecular mechanisms that contribute to trastuzumab resistance. These issues are imperative in identifying novel therapeutic targets with the goal of increasing the magnitude and duration of response to trastuzumab-based treatment.
doi:10.3816/CBC.2009.s.005
PMCID: PMC3457066  PMID: 19596643
Anthracycline; Antiangiogenesis; Lapatinib; Neratinib; Paclitaxel; Pertuzumab; Trastuzumab
15.  Optimal use of taxanes in metastatic breast cancer 
Current Oncology  2009;16(3):8-20.
The role of taxanes in the treatment of breast cancer is becoming increasingly important. In clinical practice, the taxanes are now standard therapy in both early-stage and metastatic breast cancer. Since the 1990s, multiple randomized clinical trials have been evaluating the efficacy of taxanes in the treatment of metastatic breast cancer. These trials have included treatment with taxanes alone or in combination with other chemotherapeutic agents. Pre-existing published guidelines for the use of taxanes in the management of metastatic breast cancer are available. The mandate of the Alberta Cancer Board Provincial Breast Tumour Group Guideline Panel was to consider and adapt the recommendations of the existing guidelines and to develop de novo guidelines to account for current evidence. For this task, the panel used the adapte process, which is a systematic process of guideline adaptation developed by the adapte Collaboration.
The recommendations formulated by the panel included the identification of taxane regimens that could be offered in anthracycline-naïve patients, anthracycline-pretreated or -resistant patients, and patients overexpressing the human epidermal growth factor receptor 2. Potential toxicities and benefits in terms of time to progression, progression-free survival, overall survival, and quality of life were also considered.
PMCID: PMC2695713  PMID: 19526080
Metastatic breast cancer; docetaxel; paclitaxel; nab-paclitaxel; chemotherapy
16.  Chemotherapy for breast cancer in pregnancy: evidence and guidance for oncologists 
It has been estimated that up to 3.8% of breast cancers may be diagnosed in women who are pregnant, with an estimated 1 in 3000–3500 deliveries occurring in women with breast cancer. Owing to the lack of large randomized trials available to guide our clinical practice, our decisions regarding adjuvant systemic management are based on retrospective analyses, case reports and a small number of prospective studies. A tailored approach to treatment is required with careful consideration given at all stages to the needs of the mother and risks to the foetus. Management is critically influenced by the stage of pregnancy, especially the first trimester. Anthracycline-based chemotherapy may be administered during the second and third trimesters, with apparently few short-term implications. Limited data shows the taxanes may also be given with few adverse events at these stages. Weekly fractionation regimens may allow closer monitoring of pregnancy with prompt termination of agents, if necessary. Data concerning the long-term risks of systemic anticancer treatment are limited. All stages of patient management should be discussed within a multidisciplinary team and a clear consensus of treatment options communicated to the mother. Delaying chemotherapy until after delivery may be reasonable in some cases, but where the delay is likely to be prolonged, a decision must be made on the basis of risks versus benefits.
doi:10.1177/1758834010392445
PMCID: PMC3126038  PMID: 21789157
breast cancer; chemotherapy; pregnancy
17.  Chemotherapy in Patients with Anthracycline- and Taxane-Pretreated Metastatic Breast Cancer: An Overview 
Current breast cancer reports  2013;5(1):42-50.
Anthracyclines and taxanes are cytotoxic agents that are commonly used for the treatment of breast cancer, including in the adjuvant, neoadjuvant, and metastatic setting. Each drug class of is associated with cumulative and potentially irreversible toxicity, including cardiomyopathy (anthracyclines) and neuropathy (taxanes). This may either limit the duration of therapy for advanced disease, or prevent retreatment for recurrence if previously used as component of adjuvant or neoadjuvant therapy. Several classes of cytotoxic agents have been evaluated in patients with anthracycline and taxane-pretreated metastatic breast cancer (MBC), including other antitubulins (vinorelbine, ixabepilone, eribulin), antimetabolites (capecitabine, gemcitabine), topoisomerase I inhibitors (irinotecan), platinum analogues (cisplatin, carboplatin), and liposomal doxorubicin preparations. No trials have shown an overall survival advantage for combination chemotherapy in this setting, indicating that single cytotoxic agents should usually be used, expect perhaps in patients with rapidly progressive disease and/or high tumor burden.
doi:10.1007/s12609-012-0097-1
PMCID: PMC3579672  PMID: 23440080
Metastatic breast cancer; MBC; Chemotherapy; Cytotoxic agents; Anthracycline; Taxane; Pretreated; Systemic cytotoxic therapy; Drug resistance
18.  Targeted Therapy for Early and Locally Advanced Breast Cancer 
Breast Care  2010;5(3):144-152.
Summary
The treatment of patients with breast cancer continues to evolve, with cytotoxic chemotherapy, endocrine therapy, and molecular targeted therapies representing the backbones of modern systemic breast cancer treatment. As we learn better to understand the biology of breast cancer cells, therapies to target specific pathways continue to be developed with the goal of expanding available effective therapy in specific populations. Several targeted drugs with different molecular pathways have achieved approval for metastatic breast cancer, but for early breast cancer trastuzumab is the only one that is currently approved in combination with chemotherapy for adjuvant or neoadjuvant treatment in women with HER2-positive breast cancer. Lapatinib and bevacizumab are both approved for the treatment of metastatic breast cancer and are now investigated in phase III clinical trials testing their effectiveness in the treatment of early breast cancer. In this publication, we review the current status in the treatment of early and locally advanced breast cancer with molecular targeted therapies that are currently approved or in advanced clinical development.
doi:10.1159/000315047
PMCID: PMC2931052  PMID: 20847827
Breast cancer: early, locally advanced; Targeted therapy; HER2; Neoadjuvant therapy; Trastuzumab; Lapatinib; Bevacizumab; Neratinib; T-DM1; Pertuzumab
19.  Trastuzumab in the Adjuvant Treatment of HER2-Positive Early Breast Cancer Patients: A Meta-Analysis of Published Randomized Controlled Trials 
PLoS ONE  2011;6(6):e21030.
Background
Adjuvant trastuzumab therapy has yielded conflicting results for overall survival, concerns about central nervous system (CNS) metastasis, and questions about optimal schedule. Therefore, we carried out a meta-analysis to assess the benefits of concurrent or sequential trastuzumab with adjuvant chemotherapy for early breast cancer patients with HER2-positive tumors.
Methods
Computerized and manual searches were performed to identify randomized clinical trials comparing adjuvant chemotherapy with or without trastuzumab in HER2-positive early breast cancer patients. Odds ratios were used to estimate the association between the addition of trastuzumab to adjuvant chemotherapy and various survival outcomes. The fixed-effects or random-effects model was used to combine data.
Findings
With six eligible studies identified, this analysis demonstrated that patients with HER2-positive breast cancer derived benefit in disease-free survival, overall survival, locoregional recurrence and distant recurrence (all P<0.001) from the addition of trastuzumab to adjuvant chemotherapy, whereas trastuzumab did worse in CNS recurrence as compared to the control group (P = 0.018). Furthermore, concomitant use of trastuzumab significantly lowered the hazard of death (P<0.001) but bore a higher incidence of CNS recurrence (P = 0.010), while statistical significance failed to be discerned for either overall survival (P = 0.069) or CNS metastasis (P = 0.374) between the sequential and observation arms.
Conclusion
This analysis verifies the efficacy of trastuzumab in the adjuvant setting. Additionally, our findings indirectly corroborate the superiority of concurrent trastuzumab to sequential use and also illuminate that prolonged survival is the possible reason for the higher incidence of CNS with trastuzumab versus observation.
doi:10.1371/journal.pone.0021030
PMCID: PMC3111470  PMID: 21695277
20.  Changes in Breast Density and Circulating Estrogens in Postmenopausal Women Receiving Adjuvant Anastrozole 
Factors associated with an increased risk of breast cancer include prior breast cancer, high circulating estrogens, and increased breast density. Adjuvant aromatase inhibitors are associated with a reduction in incidence of contralateral breast cancer. We conducted a prospective, single-arm, single-institution study to determine whether use of anastrozole is associated with changes in contralateral breast density and circulating estrogens. Eligible patients included postmenopausal women with hormone receptor-positive early-stage breast cancer who had completed local therapy, had an intact contralateral breast, and were recommended an aromatase inhibitor as their only systemic therapy. Participants received anastrozole 1 mg daily for 12 months on study. We assessed contralateral breast density and serum estrogens at baseline, 6, and 12 months. The primary endpoint was change in contralateral percent breast density from baseline to 12 months. Secondary endpoints included change in serum estrone sulfate from baseline to 12 months. Fifty-four patients were accrued. At 12 months, compared with baseline, there was a nonstatistically significant reduction in breast density (mean change: −16%, 95% CI: −30 to 2, P = 0.08) and a significant reduction in estrone sulfate (mean change: −93%, 95% CI: −94 to −91, P < 0.001). Eighteen women achieved 20% or greater relative reduction in contralateral percent density at 12 months compared with baseline; however, no measured patient or disease characteristics distinguished these women from the overall population. Large trials are required to provide additional data on the relationship between aromatase inhibitors and breast density and, more importantly, whether observed changes in breast density correlate with meaningful disease-specific outcomes.
doi:10.1158/1940-6207.CAPR-11-0154
PMCID: PMC3700336  PMID: 21885816
21.  The role of neoadjuvant her2-targeted therapies in her2-overexpressing breast cancers 
Current Oncology  2009;16(5):48-57.
Women receiving neoadjuvant systemic therapy for primary operable or inoperable breast cancer can potentially benefit in a number of ways, but the main advantage, which has been consistently demonstrated, is improved tumour resectability. Given the improvement in outcomes with the adjuvant use of trastuzumab in patients with early-stage breast cancer positive for the human epidermal growth factor receptor 2 (her2), questions have been raised about the use of trastuzumab in the neoadjuvant setting. The present paper reviews the currently available data and outlines suggestions from a panel of Canadian oncologists about the use of trastuzumab and other her2-targeted agents in the neoadjuvant setting.
The panel focussed on
the use of trastuzumab and other her2-targeted agents as neoadjuvant therapy in primary operable, locally advanced, and inflammatory breast cancer; andpossible choices of chemotherapeutic regimens with trastuzumab.
The suggestions described here will continue to evolve as data from current and future trials with trastuzumab and other her2-targeted agents emerge.
PMCID: PMC2768514  PMID: 19862361
Neoadjuvant; breast cancer; her2-targeted therapy; trastuzumab
22.  Cost-effectiveness of a 21-gene recurrence score assay versus Canadian clinical practice in women with early-stage estrogen- or progesterone-receptor-positive, axillary lymph-node negative breast cancer 
BMC Cancer  2012;12:447.
Background
A 21-gene recurrence score (RS) assay may inform adjuvant systematic treatment decisions in women with early stage breast cancer. We sought to investigate the cost effectiveness of using the RS-assay versus current clinical practice (CCP) in women with early-stage estrogen- or progesterone-receptor-positive, axilliary lymph-node negative breast cancer (ER+/ PR + LN- ESBC) from the perspective of the Canadian public healthcare system.
Methods
We developed a Markov model to project the lifetime clinical and economic consequences of ESBC. We evaluated adjuvant therapy separately in post- and pre-menopausal women with ER+/ PR + LN- ESBC. We assumed that the RS-assay would reclassify pre- and post-menopausal women among risk levels (low, intermediate and high) and guide adjuvant systematic treatment decisions. The model was parameterized using 7 year follow up data from the Manitoba Cancer Registry, cost data from Manitoba administrative databases, and secondary sources. Costs are presented in 2010 CAD. Future costs and benefits were discounted at 5%.
Results
The RS-assay compared to CCP generated cost-savings in pre-menopausal women and had an ICER of $60,000 per QALY gained in post-menopausal women. The cost effectiveness was most sensitive to the proportion of women classified as intermediate risk by the RS-assay who receive adjuvant chemotherapy and the risk of relapse in the RS-assay model.
Conclusions
The RS-assay is likely to be cost effective in the Canadian healthcare system and should be considered for adoption in women with ER+/ PR + LN- ESBC. However, ongoing assessment and validation of the assay in real-world clinical practice is warranted.
doi:10.1186/1471-2407-12-447
PMCID: PMC3488327  PMID: 23031196
Breast cancer; Chemotherapy; Cost-effectiveness; 21-gene recurrence score assay
23.  Progress on BIG 1-02/IBCSG 27-02/ NSABP B-37, A Prospective Randomized Trial of Evaluating Chemotherapy after Local Therapy for Isolated Locoregional Recurrences of Breast Cancer 
Annals of surgical oncology  2008;15(11):3227-3231.
Background
The utility of chemotherapy for women who experience a locoregional recurrence after primary treatment of early breast cancer remains an open question. An international collaborative trial is being conducted by the BIG, IBCSG, and NSABP to determine the effectiveness of cytotoxic therapy for these patients, either alone or in addition to selective use of hormonal therapy and trastuzumab.
Methods
The trial population includes women who have had a previous diagnosis of invasive breast cancer treated by mastectomy or breast-conserving surgery, but subsequently develop an isolated local and/or regional ipsilateral invasive recurrence. Excision of all macroscopic tumor without evidence of systemic disease is required for study entry. Patients are randomized to receive chemotherapy or no chemotherapy; type of chemotherapy is not protocol-specified. Radiation, hormonal therapy, and trastuzumab are given as appropriate. The primary endpoint is disease-free survival. Quality of life measurements are collected at baseline, and then at 9 and 12 months. The accrual goal is 977 patients.
Results
This report describes the characteristics of the first 99 patients. Sites of recurrence at study entry were: breast (56%), mastectomy scar/chest wall (35%), and regional lymph nodes (9%). Two-thirds of patients have estrogen-receptor positive recurrences.
Conclusion
This is the only trial actively investigating the question of “adjuvant” chemotherapy in locally recurrent breast cancer. The case mix of accrual to date indicates a broad representation of this patient population.
doi:10.1245/s10434-008-0129-2
PMCID: PMC2576492  PMID: 18784962
breast cancer recurrence; locoregional breast cancer; IBTR; clinical trials; clinical research; adjuvant therapy
24.  Clinical practice guidelines for the care and treatment of breast cancer: 15. Treatment for women with stage III or locally advanced breast cancer 
Objective
To define the optimal treatment for women with stage III or locally advanced breast cancer (LABC).
Evidence
Systematic review of English-language literature retrieved from MEDLINE (1984 to June 2002) and CANCERLIT (1983 to June 2002). A nonsystematic review of the literature was continued through December 2003.
Recommendations
· The management of LABC requires a combined modality treatment approach involving surgery, radiotherapy and systemic therapy.
Systemic therapy: chemotherapy
Operable tumours
· Patients with operable stage IIIA disease should be offered chemotherapy. They should receive adjuvant chemotherapy following surgery, or primary chemotherapy followed by locoregional management.
· Chemotherapy should contain an anthracycline. Acceptable regimens are 6 cycles of FAC, CAF, CEF or FEC. Taxanes are under intense investigation.
Inoperable tumours
· Patients with stage IIIB or IIIC disease, including those with inflammatory breast cancer and those with isolated ipsilateral internal mammary or supraclavicular lymph-node involvement, should be treated with primary anthracycline-based chemotherapy.
· Acceptable chemotherapy regimens are FAC, CAF, CEF or FEC. Taxanes are under intense investigation.
· Patients with stage IIIB or IIIC disease who respond to primary chemotherapy should be treated until the response plateaus or to a maximum of 6 cycles (minimum 4 cycles). Patients with stage IIIB disease should then undergo definitive surgery and irradiation. The locoregional management of patients with stage IIIC disease who respond to chemotherapy should be individualized. In patients with stage IIIB or IIIC disease who achieve maximum response with fewer than 6 cycles, further adjuvant chemotherapy can be given following surgery and irradiation. Patients whose tumours do not respond to primary chemotherapy can be treated with taxane chemotherapy or can proceed directly to irradiation followed by modified radical mastectomy, if feasible.
Systemic therapy: hormonal therapy
Operable and inoperable tumours
· Tamoxifen for 5 years should be recommended to pre- and postmenopausal women whose tumours are hormone responsive.
Locoregional management
Operable tumours
· Patients with stage IIIA disease should receive both modified radical mastectomy (MRM) and locoregional radiotherapy if feasible. They may be managed with MRM followed by chemotherapy and locoregional radiotherapy, or chemotherapy first followed by MRM and locoregional radiotherapy. Breast-conserving surgery is currently not a standard approach.
· Locoregional radiotherapy should be delivered to the chest wall and to the supraclavicular and axillary nodes. The role of internal mammary irradiation is unclear.
Inoperable tumours
· Patients with stage IIIB disease who respond to chemotherapy should receive surgery plus locoregional radiotherapy.
· The locoregional management of patients with stage IIIC disease who respond to chemotherapy is unclear and should be individualized.
· Patients whose disease remains inoperable following chemotherapy should receive locoregional radiotherapy with subsequent surgery, if feasible.
Validation
The authors' original text was revised by members of the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. Subsequently, feedback was provided by 9 oncologists from across Canada. The final document was approved by the steering committee.
Sponsor
The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer was convened by Health Canada.
Completion date
December 2003.
doi:10.1503/cmaj.1030944
PMCID: PMC359433  PMID: 15023926
25.  Adjuvant hormonal therapy for stage I endometrial cancer 
Current Oncology  2008;15(3):126-135.
Question
What is the role of hormonal therapy as adjuvant therapy in patients with stage i endometrial cancer?
Perspectives
There is little consensus on the role of adjuvant treatment for patients with stage i endometrial cancer. Although the use of hormonal therapy has been established in advanced disease, less agreement has emerged concerning the benefits of adjuvant hormonal therapy for patients with early-stage disease. The objective of the present evidence series was to review the existing literature on the role of hormonal therapy as adjuvant therapy in patients with stage i endometrial cancer.
Outcomes
Reports were sought that included at least one of the following outcomes: overall survival, disease-free survival, recurrence (local, or distant, or both), adverse effects, and quality of life. Because of the potential for long-term adverse effects with adjuvant hormonal treatment in this patient population, especially with regard to thromboembolic or cardiovascular events, the rates of non-cancer-related death were also of interest.
Methodology
The medline, embase, and Cochrane Library databases were systematically searched for randomized controlled trials, practice guidelines, systematic reviews, and meta-analyses. The resulting evidence informed the development of the clinical practice guideline. The systematic review with meta-analyses and practice guideline were approved by the Report Approval Panel of the Program in Evidence-Based Care, and by the Gynecology Cancer Disease Site Group (dsg).
Results
Nine randomized trials and one published meta-analysis comparing adjuvant hormonal therapy with no adjuvant therapy in women with stage i endometrial cancer constituted the evidence base. One trial reported a statistically significant survival benefit with adjuvant progestogen as compared with no further treatment (97% vs. 69%, p < 0.001). In that trial, the treatment group had a higher number of patients with less myometrial invasion, and a lower number of patients with advanced-stage disease. These differences in baseline characteristics between the randomized groups were considered to be clinically important. In addition, the results of that trial were not consistent with those of other trials, and the trial was a source of statistical heterogeneity when data were pooled across trials.
In two of the nine randomized trials, statistically significant recurrence-free benefits were detected with adjuvant hormonal therapy as compared with no further therapy. In one trial, the difference between the rates of recurrence was 16%; however, the methodologic concerns related to that that trial limited its relevance. In the other trial, the difference between the rates of recurrence was 5%. In that trial, patients were at a high risk of recurrence. None of the remaining seven randomized trials reported any significant difference in recurrence rates between treatment groups.
The meta-analysis identified in the literature detected no statistically significant recurrence-free or overall survival benefit associated with adjuvant hormonal therapy as compared with no adjuvant therapy [odds ratio (or): 1.05; 95% confidence interval (ci): 0.88 to 1.24). Those results are consistent with the results of the meta-analysis in the present report, which included an additional two trials (or: 1.10; 95% ci: 0.91 to 1.34).
Practice Guideline
Target Population
This clinical recommendation applies to women with newly diagnosed stage i endometrial cancer.
Recommendation
The available evidence does not demonstrate any benefit for adjuvant hormonal therapy. The use of hormonal therapy is not recommended as adjuvant treatment for patients with stage i endometrial cancer.
PMCID: PMC2442763  PMID: 18596890
Adjuvant hormonal therapy; stage i endometrial cancer; early-stage endometrial cancer

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