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1.  HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer 
Introduction
Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial.
Methods
HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro.
Results
Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, P <0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, P <0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (P = 0.004), but not in HER2-positive/ESR1-negative tumors.
Conclusions
Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group.
Introduction The human epidermal growth factor receptor 2 (HER2) is the prototype of a predictive biomarker for targeted treatment [1-8]. International initiatives have established the combination of immunohistochemistry (IHC) and in situ hybridization as the current gold standard [9,10]. As an additional approach determination of HER2 mRNA expression is technically feasible in formalin-fixed paraffin-embedded (FFPE) tissue [11-13]. Crosstalk between the estrogen receptor (ER) and the HER2 pathway has been suggested based on cell culture and animal models [14]. Consequently, the 2011 St Gallen panel has pointed out that HER2-positive tumors should be divided into two groups based on expression of the ER [15].
A retrospective analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 study has suggested that mRNA levels of HER2 and ESR1 might be relevant for the degree of benefit from adjuvant trastuzumab. By subpopulation treatment effect pattern plot (STEPP) analysis in ER-positive tumors, benefit from trastuzumab was shown to be restricted to those with higher levels of HER2 mRNA (S Paik, personal communication, results summarized in [15]).
In our study we evaluated this hypothesis in the neoadjuvant setting in a cohort of 217 patients from the neoadjuvant GeparQuattro trial [5]. All patients had been HER2- positive by local pathology assessment and had received 24 to 36 weeks of neoadjuvant trastuzumab plus an anthracycline/taxane-based chemotherapy. For central evaluation we used three different methods, HER2 IHC, and HER2 silver in situ hybridization (SISH), as well as measurement of HER2 mRNA by quantitative real-time (qRT)-PCR [11].
The primary objective of this analysis was to investigate if pathological complete response (pCR) rate in HER2-positive breast cancer would depend on the level of HER2 mRNA expression, with a separate analysis for HR-positive and -negative tumors. Central evaluation of the HER2 status showed that 27% of the tumors with HER2 overexpression by local pathology were HER2-negative. This enabled us to compare response rates in patients with HER2-positive and -negative tumors as a secondary objective.
doi:10.1186/bcr3384
PMCID: PMC3672694  PMID: 23391338
2.  Breast cancer (metastatic) 
Clinical Evidence  2010;2010:0811.
Introduction
Median survival from metastatic breast cancer is 12 months without treatment, but young people can survive up to 20 years with the disease, whereas in other metastatic cancers this would be considered unusual.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of first-line hormonal treatment? What are the effects of second-line hormonal treatment in women who have not responded to tamoxifen? What are the effects of first-line chemotherapy? What are the effects of first-line chemotherapy in combination with a monoclonal antibody? What are the effects of second-line chemotherapy? What are the effects of treatments for bone metastases? What are the effects of treatments for spinal cord metastases? What are the effects of treatments for cerebral or choroidal metastases? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 77 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: first-line hormonal treatment using anti-oestrogens (tamoxifen), ovarian ablation, progestins, selective aromatase inhibitors, or combined gonadorelin analogues plus tamoxifen; second-line hormonal treatment using progestins or selective aromatase inhibitors; first-line non-taxane combination chemotherapy; first-line taxane-based combination chemotherapy; first-line high- versus low-dose standard chemotherapy; first-line chemotherapy plus monoclonal antibody (bevacizumab, trastuzumab); first-line chemotherapy plus tyrosine kinase inhibitor (lapatinib); second-line taxane-based combination chemotherapy; second-line capecitabine or semi-synthetic vinca alkaloids for anthracycline-resistant disease; second-line chemotherapy plus tyrosine kinase inhibitor (lapatinib); and treatment for bone, spinal, or choroidal metastases using bisphosphonates, intrathecal chemotherapy, radiotherapy (alone or plus corticosteroids) radiation sensitisers, or surgical resection.
Key Points
Median survival from metastatic breast cancer is 12 months without treatment, but young people can survive up to 20 years with the disease, whereas in other metastatic cancers this would be considered very unusual.
Anti-oestrogens (tamoxifen) result in tumour responses in about one third of women with oestrogen receptor-positive metastatic breast cancer when used as first-line treatment, but most women eventually develop resistant disease. Progestins and ovarian ablation may be as effective as tamoxifen as first-line treatment but are associated with more adverse effects, while adding tamoxifen to gonadorelin analogues increases survival and response rates.Selective aromatase inhibitors may be as effective in delaying disease progression as tamoxifen for first-line treatment, and as effective as tamoxifen or progestins as second-line treatment in postmenopausal women, with similar overall survival. The benefit may be greatest in oestrogen receptor-positive women.
Hormonal treatment using tamoxifen or progestins may be preferable to chemotherapy as first-line treatment in women with oestrogen receptor-positive disease.
First-line chemotherapy is associated with an objective tumour response in 40% to 60% of women, of median duration of 6 to 12 months. Complete remission may occur in some women, whereas others show little or no response. First-line classical non-taxane combination chemotherapy, especially those containing anthracyclines, may be more effective than modified regimens and as effective as hormonal treatments in prolonging survival.The optimum duration of chemotherapy is unknown. Increasing the dose may increase serious adverse effects without prolonging survival.
Adding trastuzumab to standard first-line chemotherapy increases response rates and overall survival in women with HER2/neu overexpression, but risks of cardiac function are increased in women also receiving anthracyclines. Adding bevacizumab or lapatinib to standard first-line chemotherapy may also be more effective than standard chemotherapy alone but we cannot be certain as high-quality evidence is still emerging.
Taxane-based chemotherapy may increase tumour response and survival compared with some non-taxane regimens as second-line treatment. No clear benefit has been found in first-line treatment.
We don't know how capecitabine or semisynthetic vinca alkaloids perform as second-line treatment for anthracycline-resistant disease. Adding bevacizumab or lapatinib to capecitabine may also be more effective at increasing response rates and improving quality of life than second-line capecitabine alone, and adding lapatinib may also increase survival, but we cannot be certain as high-quality evidence is still emerging.
Bisphosphonates reduce skeletal complications from bone metastases, while radiotherapy may reduce pain and complications from bone metastases, cranial nerve or spinal cord compression, and in brain or choroidal metastases.
PMCID: PMC3217794  PMID: 21418674
3.  Neoadjuvant Treatment in Patients with HER2-Positive Breast Cancer 
ISRN Oncology  2013;2013:362467.
Approximately 20%–25% of patients with breast cancer demonstrate amplification of the human epidermal receptor type 2 (HER2) gene, resulting in an overexpression of the HER2 receptor. This overexpression is associated with aggressive disease, relatively poor prognosis, and worse clinical outcomes. Neoadjuvant therapy is the standard treatment in patients with locally advanced, inflammatory, or inoperable primary breast cancer. It is generally used to downstage the tumors and therefore to improve surgical options including breast-conserving surgery rather than mastectomy. It has been confirmed that patients with pathological complete response (pCR) to neoadjuvant treatment have better disease-free survival (DFS) and overall survival (OS). Neoadjuvant treatment can also serve as in vivo test of sensitivity to the used therapeutic regimen. The preferred neoadjuvant approach to patients with HER2-positive breast cancer is a sequential anthracycline-taxane-based chemotherapy in combination with trastuzumab. Addition of other anti-HER2 agents has increased pCR rate up to 75% and will probably become a new therapeutic direction. In the first part of this paper, we summarize the information about HER2-positive breast cancer, the various treatment possibilities, and the results of the major neoadjuvant trials. The second part focuses on the data concerning the importance of pCR and the potential risk of cardiotoxicity associated with this treatment.
doi:10.1155/2013/362467
PMCID: PMC3676960  PMID: 23762609
4.  Neoadjuvant therapy of early stage human epidermal growth factor receptor 2 positive breast cancer: latest evidence and clinical implications 
Neoadjuvant therapy in human epidermal growth factor receptor 2 (HER2)-positive breast cancer is exactly the paradigm of targeted therapy and a suitable setting to develop and test rapidly novel therapies in early stages. Moreover, neoadjuvant approaches provide a significant source of tumour tissue to identify molecular heterogeneity and potential predictive biomarkers of response. The addition of trastuzumab to primary chemotherapy revolutionized the treatment of this tumour subtype, increasing pathological complete response rate (pCR) that, even with its limitations, has also been shown to be an early marker of survival in HER2-positive disease. HER2-positive breast cancer is a biological heterogeneous disease with different characteristics and clinical outcomes. Multiple promising anti-HER2 drugs with nonoverlapping mechanisms of action have recently been developed. Combined administration of two different HER2-targeted agents, that is, trastuzumab with lapatinib or pertuzumab, and primary chemotherapy shows enhanced antitumour activity, with an increase in pCR to values never reached in the past. Moreover, results of recent studies show that the combination of targeted therapy alone (dual HER2 blockade with or without endocrine therapy) also has activity in a substantial percentage of patients, eradicating HER2-positive tumours without chemotherapy and with a favourable toxicity profile. It is still necessary to be able to select the appropriate group of patients who can avoid chemotherapy (approximately 25%), and to establish robust predictive biomarkers of response or resistance to the anti-HER2 approach. Neoadjuvant therapy represents an enormous step forward in HER2-positive breast cancer. The results of the most relevant neoadjuvant studies and latest evidence are described in this review, though new questions have emerged.
doi:10.1177/1758834014535650
PMCID: PMC4206611  PMID: 25342988
dual HER2 blockade; early breast cancer; HER2 positive; neoadjuvant therapy; pathological complete response; predictive biomarkers
5.  Clinical Efficacy of Including Capecitabine in Neoadjuvant Chemotherapy for Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2013;8(1):e53403.
Background
Capecitabine has proven effective as a chemotherapy for metastatic breast cancer. Though several Phase II/III studies of capecitabine as neoadjuvant chemotherapy have been conducted, the results still remain inconsistent. Therefore, we performed a meta-analysis to obtain more precise understanding of the role of capecitabine in neoadjuvant chemotherapy for breast cancer patients.
Methods
The electronic database PubMed and online abstracts from ASCO and SABCS were searched to identify randomized clinical trials comparing neoadjuvant chemotherapy with or without capecitabine in early/operable breast cancer patients without distant metastasis. Risk ratios were used to estimate the association between capecitabine in neoadjuvant chemotherapy and various efficacy outcomes. Fixed- or random-effect models were adopted to pool data in RevMan 5.1.
Results
Five studies were included in the meta-analysis. Neoadjuvant use of capecitabine with anthracycline and/or taxane based therapy was not associated with significant improvement in clinical outcomes including: pathologic complete response in breast (pCR; RR = 1.10, 95% CI 0.87–1.40, p = 0.43), pCR in breast tumor and nodes (tnpCR RR = 0.99, 95% CI 0.83–1.18, p = 0.90), overall response rate (ORR; RR = 1.00, 95% CI 0.94–1.07, p = 0.93), or breast-conserving surgery (BCS; RR = 0.98, 95% CI 0.93–1.04, p = 0.49).
Conclusions
Neoadjuvant treatment of breast cancer involving capecitabine did not significantly improve pCR, tnpCR, BCS or ORR. Thus adding capecitabine to neoadjuvant chemotherapy regimes is unlikely to improve outcomes in breast cancer patients without distant metastasis. Further research is required to establish the condition that capecitabine may be useful in breast cancer neoadjuvant chemotherapy.
doi:10.1371/journal.pone.0053403
PMCID: PMC3536736  PMID: 23301067
6.  XeNA: Capecitabine Plus Docetaxel, With or Without Trastuzumab, as Preoperative Therapy for Early Breast Cancer 
Combinations of capecitabine and a taxane are highly active in metastatic breast cancer, and synergy between capecitabine and docetaxel has also been demonstrated. Such combinations potentially would provide a promising non–anthracycline-based alternative for patients with early breast cancer. Non-anthracycline preoperative regimens are a particularly interesting proposition in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, as they offer less cardiotoxicity and thus can be used concomitantly with preoperative trastuzumab therapy. Capecitabine plus docetaxel (XT) and trastuzumab with XT (HXT) are promising non-anthracycline regimens for the preoperative treatment of women with HER2-negative and HER2-positive breast cancer, respectively. The Xeloda in Neoadjuvant (XeNA) trial, an open-label, multicenter, phase II study, independently assesses the efficacy of preoperative XT in HER2-negative and HXT in HER2-positive breast cancer. A particularly important feature of the XeNA study is the use of pathologic complete response (pCR) plus near pCR (npCR) as the primary endpoint. pCR is associated with long-term survival, and although it is valuable as a surrogate marker, pCR has some limitations. Measurement of residual breast cancer burden (RCB) has been proposed as a more practical alternative to predict survival after preoperative chemotherapy. The combination of RCB-0 and RCB-I (npCR) expands the subset of patients shown to benefit from preoperative chemotherapy, and achievement of pCR or npCR is associated with long disease-free survival. In XeNA, the sum of pCR and npCR will facilitate correlative studies designed to identify patients most likely to benefit from XT and HXT and may expedite the clinical evaluation of these novel preoperative regimens.
PMCID: PMC2581822  PMID: 19002271
Pathologic complete response; Breast-conserving surgery; Taxane; Anthracycline-induced cardiotoxicity
7.  Evaluating the predictive value of biomarkers for efficacy outcomes in response to pertuzumab- and trastuzumab-based therapy: an exploratory analysis of the TRYPHAENA study 
Introduction
Molecular markers that predict responses to particular therapies are invaluable for optimization of patient treatment. The TRYPHAENA study showed that pertuzumab and trastuzumab with chemotherapy was an efficacious and tolerable combination for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the neoadjuvant setting. We analyzed whether particular biomarkers correlated with the responses observed and therefore may predict outcomes in patients given pertuzumab plus trastuzumab.
Methods
We describe the analysis of a panel of biomarkers including HER2, human epidermal growth factor receptor 3 (HER3), epidermal growth factor receptor (EGFR), phosphatase and tensin homolog (PTEN), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) by qRT-PCR, immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), enzyme-linked immunosorbent assay (ELISA), and PCR-based mutational analyses as appropriate. For each marker analyzed, patients were categorized into ‘low’ (generally below median) or ‘high’ (generally above median) subgroups at baseline and post-treatment.
Results
Correlation of marker subgroups with the achievement of a pathological complete response (pCR) (ypT0/is) was analyzed. HER2 protein and mRNA expression levels were associated with pCR rate in two of the three study arms and the pooled analyses. Correlations of biomarker status with pCR occurred in one individual arm only and the pooled analyses with EGFR and PTEN; however, interpretation of these results is limited by a strong imbalance in patient numbers between the high and low subgroups and inconsistency between arms. We also found no association between expression levels of TOP2A and pCR rate in either the anthracycline-containing or free arms of TRYPHAENA.
Conclusions
According to these analyses, and in line with other analyses of pertuzumab and trastuzumab in the neoadjuvant setting, we conclude that HER2 expression remains the only marker suitable for patient selection for this regimen at present.
Trial registration
The TRYPHAENA study was registered with ClinicalTrials.gov, NCT00976989, on September 14 2009.
doi:10.1186/bcr3690
PMCID: PMC4226982  PMID: 25005255
8.  Anthracycline-free neoadjuvant therapy induces pathological complete responses by exploiting immune proficiency in HER2+ breast cancer patients 
BMC Cancer  2014;14(1):954.
Background
Neoadjuvant Chemotherapy (NC) including trastuzumab induces a high rate of pathological Complete Responses (pCR) in patients with locally advanced HER2-overexpressing Breast Cancer (BC), but is penalized by a severe cardiotoxicity when combined with anthracyclines. A phase II study was designed to assess whether an anthracycline-free NC regimen based on the early addition of trastuzumab to paclitaxel may increase the pCR rate without inducing severe cardiotoxicity in patients with locally advanced HER2-overexpressing BC. Immunomonitoring was performed to assess the contribution of patients’ immunological background to the induction of clinical responses.
Methods
Stage II-III HER2-positive BC patients received 24 weeks paclitaxel and trastuzumab NC, followed by 1 year adjuvant trastuzumab ± hormonal and/or radio-therapy. Assessment of pCR rate was the primary endpoint. A group of HER2-negative BC patients treated with neoadjuvant taxanes and anthracyclines was included. Serum levels of 10 cytokines and the efficiency of trastuzumab-mediated antibody-dependent cell cytotoxicity (ADCC) were monitored in vitro every 3 months.
Results
From July 2006 to February 2013, we enrolled 109 patients including 46 evaluable HER2-positive cases. A pCR rate of 50% was reached and no severe cardiotoxicity occurred. Serum cytokine profiling revealed only an IL-10 decrease (P = 0.02) in patients achieving a partial response, while HER2-negative patients disclosed marked cytokines changes. Compared to the unfavourable F/F genotype, patients carrying the V allele in the FcγRIIIa-158 polymorphism showed a higher efficacy of trastuzumab-ADCC throughout treatment (P ≤0.05).
Conclusions
In the absence of anthracyclines, trastuzumab and paclitaxel induced a high rate of pCR, exploiting the synergy between the immunomodulating properties of these drugs and the retained immunological proficiency of patients with HER2-overexpressing BC.
Trial registration
Trial registration number: NCT02307227, registered on ClinicalTrials.gov (http://www.clinicaltrials.gov, November 26, 2014).
doi:10.1186/1471-2407-14-954
PMCID: PMC4302069  PMID: 25512030
Breast cancer; Neoadjuvant chemotherapy; HER2; Immune response; Trastuzumab
9.  Shift in cytotoxic target from estrogen receptor-positive to estrogen receptor-negative breast cancer cells by trastuzumab in combination with taxane-based chemotherapy 
Oncology Letters  2011;2(2):303-308.
Trastuzumab has shown significant clinical benefits in patients with operable and metastatic HER2-positive breast cancer. However, the biological mechanism of the additional effect of trastuzumab administered in combination with conventional chemotherapy is poorly understood. We performed a retrospective analysis of 55 patients with HER2-positive breast cancer treated with anthracycline and taxane (chemotherapy alone; CT), or trastuzumab in combination with taxane-based chemotherapy (CT+T) for neoadjuvant chemotherapy. We determined the therapeutic efficacies [clinical (CR) and pathological complete responses (pCR)] and changes in the proportion of positive cells for each biomarker pre- to post-neoadjuvant chemotherapy for each treatment regimen. Clinical-CR and quasi-pCR rates defined as the absence of invasive tumors or only a few remaining invasive tumor cells were 6.9 and 31.0% in the CT group and 46.2 and 65.4% in the CT+T group, respectively. In the CT group, the proportion of estrogen receptor (ER)-/progesterone receptor (PgR)-positive cells decreased significantly following treatment (ER, 73.5 vs. 50.9%; P=0.02). Changes in the proportion of ER-/PgR-positive cells were not noted in the CT+T group (ER, 81.9 vs. 80.3%; P=0.61), although a relatively greater decrease in the proportion of Ki-67-positive cells was found in the CT+T group than that in the CT group (−26.5 vs. −13.7%). These findings indicate that CT+T inhibits ER-negative and Ki-67-positive breast cancer cells. In conclusion, trastuzumab sensitized ER-negative proliferative cells to cytotoxic chemotherapy. This finding may indicate an additional clinical effect of trastuzumab when administered in combination with conventional chemotherapy as neoadjuvant chemotherapy for HER2-positive breast cancer.
doi:10.3892/ol.2011.232
PMCID: PMC3410577  PMID: 22866081
trastuzumab; neoadjuvant therapy; estrogen receptor
10.  Non-Pegylated Liposomal Doxorubicin-Cyclophosphamide in Sequential Regimens with Taxanes as Neoadjuvant Chemotherapy in Breast Cancer Patients 
Journal of Cancer  2014;5(6):398-405.
Purpose: Chemotherapy regimens containing anthracyclines and taxanes represent the landmark of neoadjuvant systemic therapy of breast cancer. In advanced breast cancer patients liposomal anthracyclines (LA) have shown similar efficacy and less cardiac toxicity when compared to conventional anthracyclines. We performed this retrospective analysis in order to evaluate the efficacy and tolerability of neoadjuvant regimens including LA outside of clinical trials in routine clinical practice.
Methods: Fifty operable or locally advanced, HER2 negative, breast cancer patients were retrospectively identified in 5 Italian cancer centres. Nineteen patients had received 4 cycles of non-pegylated liposomal doxorubicin (NPLD) and cyclophosphamide, followed by 4 cycles of docetaxel, every 3 weeks. In 25 patients the reverse sequence was employed, and a third subgroup of 6 patients received 4 cycles of NPLD/cyclophosphamide every 3 weeks followed by 4 cycles of weekly carboplatin and paclitaxel.
Results: We observed 10 pathological complete responses (pCR) (20.0%, 95%CI, 9% to 31%), and 35 (70%, 95%CI, 57.3% to 82.7%) partial responses (pPR), whereas no patients progressed onto therapy. In the small subset of triple negative tumors the pCR rate was 37.5%, and in tumors expressing ER and/or PgR it was 16.7%. A pCR rate of 26.5% was observed in tumors with high Ki-67, whereas in tumors with low Ki-67 only one (6.2%) pCR was observed (p=0.14). Treatments were well tolerated. The most common toxicities were myelosuppression and palmar-plantar erytrodysesthesia; 4 asymptomatic and transient LVEF decrease have been recorded, without any case of clinical cardiotoxicity.
Conclusions: NPLD-cyclophosphamide and taxanes sequential regimens were proven effective and well tolerated in breast cancer patients with contra-indication to conventional anthracyclines undergoing neoadjuvant chemotherapy, even outside of clinical trials in everyday clinical practice.
doi:10.7150/jca.9132
PMCID: PMC4026993  PMID: 24847380
Breast cancer; neoadjuvant chemotherapy; non-pegylated liposomal doxorubicin; retrospective analysis; everyday clinical practice
11.  Bevacizumab Added to Neoadjuvant Chemotherapy for Breast Cancer 
The New England Journal of Medicine  2012;366(4):310-320.
Background
Bevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)–negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response.
Methods
We randomly assigned 1206 patients to receive neoadjuvant therapy consisting of docetaxel (100 mg per square meter of body-surface area on day 1), docetaxel (75 mg per square meter on day 1) plus capecitabine (825 mg per square meter twice a day on days 1 to 14), or docetaxel (75 mg per square meter on day 1) plus gemcitabine (1000 mg per square meter on days 1 and 8) for four cycles, with all regimens followed by treatment with doxorubicin–cyclophosphamide for four cycles. Patients were also randomly assigned to receive or not to receive bevacizumab (15 mg per kilogram of body weight) for the first six cycles of chemotherapy.
Results
The addition of capecitabine or gemcitabine to docetaxel therapy, as compared with docetaxel therapy alone, did not significantly increase the rate of pathological complete response (29.7% and 31.8%, respectively, vs. 32.7%; P = 0.69). Both capecitabine and gemcitabine were associated with increased toxic effects — specifically, the hand–foot syndrome, mucositis, and neutropenia. The addition of bevacizumab significantly increased the rate of pathological complete response (28.2% without bevacizumab vs. 34.5% with bevacizumab, P = 0.02). The effect of bevacizumab on the rate of pathological complete response was not the same in the hormone-receptor–positive and hormone-receptor–negative subgroups. The addition of bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, the hand–foot syndrome, and mucositis.
Conclusions
The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response, which was the primary end point of this study. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00408408.)
doi:10.1056/NEJMoa1111097
PMCID: PMC3401076  PMID: 22276821
12.  Profiling and targeting HER2-positive breast cancer using trastuzumab emtansine 
Purpose
This article reviews the mechanism of action of trastuzumab emtansine (T-DM1), existing clinical data relating to its use for human growth factor receptor 2 (HER2)-positive breast cancer, potential pathways of resistance, and ongoing studies evaluating this novel agent.
Background
The development of HER2-targeted therapies has dramatically improved clinical outcomes for patients with any stage of HER2-positive breast cancer. Although the positive effect of these treatments cannot be overstated, treatment resistance develops in the vast majority of those diagnosed with stage IV HER2-positive breast cancer. Moreover, HER2-directed therapies are most effective when combined with cytotoxic chemotherapy. The need for chemotherapy leads to significant adverse effects and a clear decrease in quality of life for those dealing with a chronic incurable disease. T-DM1 is a recently developed, novel antibody–drug conjugate in which highly potent maytanisinoid chemotherapy is stably linked to the HER2-targeted monoclonal antibody, trastuzumab.
Results
Preclinical and phase 1–3 clinical data support the significant antitumor activity of T-DM1. Importantly, several randomized studies also now demonstrate its clear superiority in terms of tolerability compared with standard chemotherapy-containing regimens. Its role in the treatment of trastuzumab-resistant metastatic breast cancer has now been established on the basis of the results of two phase 3 randomized studies, EMILIA (An Open-label Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine + Lapatinib in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer) and TH3RESA (A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician’s Choice in Patients With HER2-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy). The most common toxicities seen with T-DM1 are thrombocytopenia and an elevation in liver transaminases. Significant cardiac toxicity has not been demonstrated. Both in vitro cell line–based studies as well as exploratory analyses of archived tumor samples from the clinical trials are seeking to understand potential mechanisms of resistance to T-DM1. Ongoing studies are also evaluating the use of T-DM1 in the first-line metastatic, neoadjuvant, and adjuvant settings, as well as in combination with other targeted therapies.
Conclusion
T-DM1 represents the first successfully developed antibody drug conjugate for the treatment of HER2-positive advanced breast cancer.
doi:10.2147/PGPM.S47524
PMCID: PMC4207068  PMID: 25378946
HER2; T-DM1; trastuzumab emtansine; ado-trastuzumab emtansine; metastatic breast cancer; Kadcyla
13.  Association between Pathological Complete Response and Outcome Following Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer Patients 
Journal of Breast Cancer  2014;17(4):376-385.
Purpose
We aimed to determine the rate of pathological complete response (pCR), clinicopathological factors associated with pCR, and clinical outcomes following neoadjuvant chemotherapy in locally advanced breast cancer.
Methods
Medical records of patients who had undergone neoadjuvant chemotherapy for breast cancer between January 2007 and September 2011 were retrospectively reviewed, and the pCR rates were calculated according to three sets of criteria: the National Surgical Adjuvant Breast and Bowel Project (NSABP), the MD Anderson Cancer Center (MDACC), and the German Breast Group (GBG). Tumors were classified as luminal A like, luminal B like, human epidermal growth factor receptor 2 (HER2), or triple-negative. pCR and clinical outcome, including overall survival (OS) and disease-free survival (DFS) rates were analyzed at the median follow-up of 54.2 months.
Results
Of a total of 179 patients who had received neoadjuvant chemotherapy, 167 patients (93.3%) had locally advanced breast cancer and 12 patients (6.7%) had early-stage breast cancer. The majority of patients (152 patients, 89.4%) received anthracycline-based neoadjuvant chemotherapy. The objective clinical response rate was 61.5%, comprising clinical partial response in 5.5% and clinical complete response in 3.9% of patients. Twenty-one (11.7%), 20 (11.2%), and 17 patients (9.5%) achieved pCR according to NSABP, MDACC, and GBG definitions, respectively. pCR rates, as defined by NSABP, according to breast cancer subtype were 4.4%, 9.7%, 24.2%, and 19.2% in luminal A like, luminal B like, HER2, and triple-negative subtypes, respectively. Patients who achieved pCR had significantly better DFS (5-year DFS rates, 80% vs. 53%, p=0.030) and OS (5-year OS rates, 86% vs. 54%, p=0.042) than those who did not.
Conclusion
The pCR rate following neoadjuvant chemotherapy for breast cancer in Thai women attending our institution was 11.7%; pCR was more frequently observed in HER2 and triple-negative breast tumor subtypes. Patients who achieved pCR had significantly improved survival.
doi:10.4048/jbc.2014.17.4.376
PMCID: PMC4278058  PMID: 25548587
Antineoplastic combined chemotherapy protocols; Breast neoplasms; Neoadjuvant therapy; Surgery; Treatment outcome
14.  Precision medicine and personalized breast cancer: combination pertuzumab therapy 
Trastuzumab (Herceptin), a monoclonal antibody directed against the human epidermal growth-factor receptor 2 (HER2), is the poster child for antibody-based targeted therapy in breast cancer. Pertuzumab, another humanized monoclonal antibody, binds to a different domain of HER2 and prevents the formation of HER2:HER3 dimers, which is the most potent heterodimer in the HER family. The combination of trastuzumab and pertuzumab has synergistic activity, and is associated with improved clinical outcomes. The US Food and Drug Administration (FDA) approved pertuzumab in combination with trastuzumab-based chemotherapy originally as first-line therapy for metastatic HER2-positive breast cancer in 2012, and more recently as neoadjuvant therapy for localized disease in 2013. Pertuzumab is the first neoadjuvant drug to receive accelerated approval by the FDA based on pathological complete response as the primary end point. In this article, we review the mechanism of action, pharmacokinetics, clinical efficacy, safety, and current role of pertuzumab in the management of breast cancer, as well as ongoing clinical trials and future directions regarding the utility of pertuzumab as a personalized therapeutic option for HER2-positive breast cancer. In the coming years, we anticipate increased utilization of neoadjuvant trials for drug development, biomarker discovery, and validation, and envision conduct of personalized breast cancer clinics in which therapies will be routinely selected based on genetic alterations in the tumor. Regardless of the targeted therapy combinations employed based on tumor genomic profile, trastuzumab and pertuzumab will likely continue to form the backbone of the personalized regimen for HER2-positive breast cancer.
Video abstract
doi:10.2147/PGPM.S37100
PMCID: PMC3977457  PMID: 24715764
pertuzumab; HER2 breast cancer; personalized therapy; precision medicine
15.  T-bet expression in intratumoral lymphoid structures after neoadjuvant trastuzumab plus docetaxel for HER2-overexpressing breast carcinoma predicts survival 
British Journal of Cancer  2011;105(3):366-371.
Background:
In HER2-overexpressing breast cancer, accumulating preclinical evidences suggest that some chemotherapies, like trastuzumab, but also taxanes, are able to trigger a T helper 1 (Th1) anticancer immune response that contribute to treatment success. T helper 1 immune response is characterised by the expression of the transcription factor T-bet in CD4 T lymphocytes. We hypothesised that the presence of such T cells in the tumour immune infiltrates following neoadjuvant chemotherapy would predict patient survival.
Methods:
In a series of 102 consecutive HER2-overexpressing breast cancer patients treated by neoadjuvant chemotherapy incorporating antracyclines or taxane and trastuzumab, we studied by immunohistochemistry the peritumoral lymphoid infiltration by T-bet+ lymphocytes before and after chemotherapy in both treatment groups. Kaplan–Meier analysis and Cox modelling were used to assess relapse-free survival (RFS).
Results:
Fifty-eight patients have been treated with trastuzumab–taxane and 44 patients with anthracyclines-based neoadjuvant chemotherapy. The presence of T-bet+ lymphocytes in peritumoral lymphoid structures after chemotherapy was significantly more frequent in patients treated with trastuzumab–taxane (P=0.0008). After a median follow-up of 40 months, the presence of T-bet+ lymphocytes after neoadjuvant chemotherapy confers significantly better RFS (log-rank test P=0.011) only in patients treated with trastuzumab–taxane. In this population, multivariate Cox regression model showed that only the presence of T-bet+ lymphocytes in peritumoral lymphoid structures after neoadjuvant chemotherapy was independently associated with improved RFS (P=0.04).
Conclusion:
These findings indicate that the tumour infiltration by T-bet+ Th1 lymphocytes following neoadjuvant trastuzumab–taxane may represent a new independent prognostic factor of improved outcome in HER2-overexpressing breast carcinoma.
doi:10.1038/bjc.2011.261
PMCID: PMC3172914  PMID: 21750556
T-bet; breast cancer; HER2; trastuzumab; docetaxel
16.  Breast cancer (metastatic) 
Clinical Evidence  2007;2007:0811.
Introduction
Median survival from metastatic breast cancer is 12 months without treatment, but young people can survive up to 20 years with the disease, whereas in other metastatic cancers this would be considered unusual.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of first-line hormonal treatment? What are the effects of second-line hormonal treatment in women who have not responded to tamoxifen? What are the effects of first-line chemotherapy? What are the effects of first-line chemotherapy in combination with a monoclonal antibody? What are the effects of second-line chemotherapy? What are the effects of treatments for bone metastases? What are the effects of treatments for spinal cord metastases? What are the effects of treatments for cerebral or choroidal metastases? We searched: Medline, Embase, The Cochrane Library and other important databases up to June 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 63 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: anthracycline-based non-taxane combination chemotherapy regimens; bisphosphonates; capecitabine or semisynthetic vinca alkaloids for anthracycline-resistant disease; chemotherapy plus monoclonal antibody (trastuzumab); classical non-taxane combination chemotherapy; combined gonadorelin analogues plus tamoxifen; hormonal treatment with antioestrogens (tamoxifen) or progestins; intrathecal chemotherapy; non-anthracycline-based regimens; non-taxane combination chemotherapy; ovarian ablation; radiation sensitisers; radiotherapy (alone, or plus appropriate analgesia, or plus high-dose corticosteroids); selective aromatase inhibitors; chemotherapy (standard, or high dose); surgical resection; tamoxifen; and taxane-based combination chemotherapy.
Key Points
Median survival from metastatic breast cancer is 12 months without treatment, but young people can survive up to 20 years with the disease, whereas in other metastatic cancers this would be considered very unusual.
Antioestrogens (tamoxifen) result in tumour responses in about a third of women with oestrogen receptor positive metastatic breast cancer when used as first line treatment, but most women eventually develop resistant disease. Progestins and ovarian ablation may be as effective as tamoxifen, while adding tamoxifen to gonadorelin analogues increases survival and response rates.Selective aromatase inhibitors may be as effective as tamoxifen, and more effective than progestins in delaying disease progression as first or second line treatment in postmenopausal women, with similar overall survival. The benefit may be greatest in oestrogen receptor positive women.
Hormonal treatment using tamoxifen or progestins may be preferable to chemotherapy as first line treatment in women with oestrogen receptor positive disease.
First line chemotherapy is associated with an objective tumour response in 40-60% of women, of median duration of 6-12 months. Complete remission may occur in some women, whereas others show little or no response at all. Classical non-taxane combination chemotherapy, especially those containing anthracyclines, may be more effective than modified regimens and as effective as hormonal treatments in prolonging survival.The optimum duration of chemotherapy is unknown. Increasing the dose may increase serious adverse effects without prolonging survival.Taxane based chemotherapy may increase tumour response and survival compared with some non-taxane regimens as second line treatment. No clear benefit has been found in first line treatment.
Adding trastuzumab to standard chemotherapy increases response rates and overall survival in women with HER2/neu overexpression, but risks of cardiac function are increased in women also receiving anthracyclines.
Bisphosphonates reduce skeletal complications from bone metastases, while radiotherapy may reduce pain and complications from bone metastases, cranial nerve or spinal cord compression, and in brain or choroidal metastases.
PMCID: PMC2943771  PMID: 19454050
17.  Comparison of neoadjuvant adriamycin and docetaxel versus adriamycin, cyclophosphamide followed by paclitaxel in patients with operable breast cancer 
Purpose
Neoadjuvant chemotherapy is the standard treatment for patients with locally advanced breast cancer and is increasingly considered for patients with operable disease. Recently, as many clinical trials have demonstrated favorable outcomes of anthracycline-taxane based regimen, this approach has been widely used in the neoadjuvant setting.
Methods
We compared women who received adriamycine and docetaxel (AD) with adriamycin, cyclophosphamide followed by paclitaxel (AC-T) as neoadjuvant chemotherapy. The AD group was scheduled for six cycles of AD (50 mg/m2 and 75 mg/m2, respectively) at a 3-week interval. The AC-T group was scheduled for four cycles of adriamycin and cyclophosphamide (50 mg/m2 and 500 mg/m2, respectively) followed by four cycles of paclitaxel (175 mg/m2) at a 3-week interval.
Results
The responses of chemotherapy were equivalent (overall response rate [AD, 75.7% vs. AC-T, 80.9%; P = 0.566], pathologic complete response [pCR] rate [breast and axilla: AD, 10.8% vs. AC-T, 12.8%; P = 1.000; breast only: AD, 18.9% vs. AC-T, 14.9%, P = 0.623], breast conserving surgery rate [P = 0.487], and breast conserving surgery conversion rate [P = 0.562]). The pCR rate in the breast was higher in the human epidermal growth factor receptor 2 (HER2) positive cases (HER2 positive 33.3% vs. negative 10%, P = 0.002). Although nonhematologic toxicities were comparable, hematologic toxicities were more severe in the AD group. Most women in the AD group suffered from grade 3/4 neutropenia (P < 0.001) and neutropenic fever (P < 0.001).
Conclusion
Tumor responses were not different in various variables between the two groups. However, AC-T was a more tolerable regimen than AD in patients with breast cancer receiving neoadjuvant chemotherapy.
doi:10.4174/jkss.2013.85.1.7
PMCID: PMC3699689  PMID: 23833754
Breast neoplasms; Neoadjuvant therapy
18.  Neoadjuvant Chemotherapy and Targeted Therapy in Breast Cancer: Past, Present, and Future 
Journal of Oncology  2013;2013:732047.
Traditionally, neoadjuvant treatment for breast cancer was preserved for locally advanced and inflammatory disease, converting an inoperable to a surgical resectable cancer. In recent years, neoadjuvant therapy has become an accepted treatment option also for lower tumor stages in order to increase the rate of breast conserving therapy and to reduce the extent of surgery. Furthermore, treatment response can be monitored, and therefore, patient compliance may be increased. Neoadjuvant trials, additionally, offer the opportunity to evaluate new treatment options in a faster way and with fewer patients than large adjuvant trials. Compared to the metastatic setting, the issue of acquired resistance and pretreatments, which may distort treatment efficacy, can be avoided. New trial designs like window-of-opportunity trials or postneoadjuvant trials provide the chance to identify tumor sensitivity or to overcome tumor resistance in early tumor stages. In particular, in HER2-positive breast cancer, the neoadjuvant approach yielded great successes. The dual HER2 blockade with trastuzumab and pertuzumab recently showed the highest pCR rates ever reported. Many new drugs are in clinical testing with the aim to further increase pCR rates. Whether this endpoint really represents a surrogate for long-term outcome is not answered yet and will be discussed in this review.
doi:10.1155/2013/732047
PMCID: PMC3762209  PMID: 24027583
19.  Predictive value of HER2 serum levels in patients treated with lapatinib or trastuzumab – a translational project in the neoadjuvant GeparQuinto trial 
British Journal of Cancer  2012;107(6):956-960.
Background:
We were able to demonstrate a predictive value of serum HER2 (sHER2) in patients receiving trastuzumab in the neoadjuvant GeparQuattro trial. However, the role of sHER2 in patients receiving neoadjuvant therapy (NT) with lapatinib is still unclear.
Methods:
The neoadjuvant GeparQuinto trial compared trastuzumab vs lapatinib in addition to chemotherapy in HER2-positive primary breast cancer patients. The sHER2 levels were measured by enzyme-linked immunosorbant assay in 210 patients, of whom 109 (52%) patients received trastuzumab and 101 (48%) lapatinib at three different time points.
Results:
Twenty-two percent of patients had elevated baseline sHER2 levels (>15 ng ml−1). A decrease of sHER2 levels (>20%) in the trastuzumab and lapatinib-treated group during NT was seen in 44% and 24% of the patients, an increase of sHER2 levels (>20%) was seen in 6% and 41% of patients, respectively. Higher pre-chemotherapy sHER2 levels were associated with higher pathological complete remission (pCR) rates in the entire study cohort (OR 1.8, 95% CI 1.02–3.2, P=0.043). A decline of sHER2 levels (>20%) during NT was a predictor for pCR in the lapatinib-treated patient group (OR: 11.7, 95% CI 1.3–110, P=0.031).
Conclusion:
Results of this study demonstrate that sHER2 levels change differently during NT depending on the anti-HER2 treatment strategy. Elevated baseline sHER2 levels (>15 ng ml−1) and a decrease of sHER2 levels (>20%) early after therapy initiation are both relevant criteria to predict response to lapatinib-based treatment.
doi:10.1038/bjc.2012.353
PMCID: PMC3464767  PMID: 22892393
breast cancer; neoadjuvant therapy; HER2; serum; trastuzumab; lapatinib
20.  Breast cancer (non-metastatic) 
Clinical Evidence  2011;2011:0102.
Introduction
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions after breast-conserving surgery for ductal carcinoma in situ? What are the effects of treatments for primary operable breast cancer? What are the effects of interventions in locally advanced breast cancer (stage 3B)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 83 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding chemotherapy (cyclophosphamide/methotrexate/fluorouracil and/or anthracycline and/or taxane-based regimens), or hormonal treatment to radiotherapy; adjuvant treatments (aromatase inhibitors, adjuvant anthracycline regimens, tamoxifen); axillary clearance; axillary dissection plus sentinel node dissection; axillary radiotherapy; axillary sampling; combined chemotherapy plus tamoxifen; chemotherapy plus monoclonal antibody (trastuzumab); extensive surgery; high-dose chemotherapy; hormonal treatment; less extensive mastectomy; less than whole-breast radiotherapy plus breast-conserving surgery; multimodal treatment; ovarian ablation; primary chemotherapy; prolonged adjuvant combination chemotherapy; radiotherapy (after breast-conserving surgery, after mastectomy, plus tamoxifen after breast-conserving surgery, to the internal mammary chain, and to the ipsilateral supraclavicular fossa, and total nodal radiotherapy); sentinel node biopsy; and standard chemotherapy regimens.
Key Points
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
In women with ductal carcinoma in situ (DCIS), radiotherapy reduces local recurrence and invasive carcinoma after breast-conserving surgery. The role of tamoxifen added to radiotherapy for DCIS remains unclear because of conflicting results.
In women with primary operable breast cancer, survival may be increased by full surgical excision, tamoxifen, chemotherapy, radiotherapy, ovarian ablation, or trastuzumab (in women who over-express HER2/neu oncogene). Incomplete excision may increase the risk of local recurrence, but less-extensive mastectomy that excises all local disease is as effective as radical mastectomy at prolonging survival, with better cosmetic results. Axillary clearance (removal of all axillary lymph nodes) achieves local disease control, but has not been shown to increase survival, and can cause arm lymphoedema. Sentinel lymph node biopsy or 4-node sampling may adequately stage the axilla with less morbidity compared with axillary clearance. Adjuvant tamoxifen reduces the risk of recurrence and death in women with oestrogen-positive tumours. Primary chemotherapy may facilitate successful breast-conserving surgery instead of mastectomy. Adjuvant combination chemotherapy improves survival compared with no chemotherapy, with greatest benefit likely with anthracycline-based regimens at standard doses for 4 to 6 months.Radiotherapy decreases recurrence and mortality after breast-conserving surgery. Post-mastectomy radiotherapy for women who are node-positive or at high risk of recurrence decreases recurrence and mortality. Adjuvant aromatase inhibitors improve disease-free survival compared with tamoxifen, but their effect on overall survival is unclear. Adjuvant taxane-based regimens may improve disease-free survival over standard anthracycline-based therapy.
In women with locally advanced breast cancer, radiotherapy may be as effective as surgery or tamoxifen at increasing survival and local disease control. Adding tamoxifen or ovarian ablation to radiotherapy increases survival compared with radiotherapy alone, but adding chemotherapy may not reduce recurrence or mortality compared with radiotherapy alone.We don't know if chemotherapy alone improves survival in women with locally advanced breast cancer as we found few trials.
PMCID: PMC3217212  PMID: 21718560
21.  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
22.  The Role of Targeted Agents in the Treatment of Metastatic Breast Cancer 
Breast Care  2010;5(3):134-141.
Summary
To date, blockade of growth factor receptors is the mainstay of targeted therapy in metastatic breast cancer (mBC). Monoclonal antibodies such as trastuzumab and bevacizumab represent the first generation of molecular-based therapies. Both the HER2 inhibitors and the vascular endothelial growth factor (VEGF) antagonists have shown synergism with a broad spectrum of established cytotoxins, thus being approved for first-line treatment of mBC in combination with taxanes. As a next step, tyrosine kinase inhibitors (TKIs) have been integrated into daily routine as an alternative approach for targeting HER2: The dual HER1/2 inhibitor lapatinib demonstrated activity in trastuzumab-pretreated mBC patients in combination with capecitabine. Furthermore, chemotherapy-free regimens (trastuzumab or lapatinib plus aromatase inhibitors) have been identified as additional options for hormone receptor (HR)- and HER2-positive patients. Recently published data indicate that a combination of two biologicals such as lapatinib and trastuzumab can be effective as a treatment beyond trastuzumab related progression. Multitarget TKIs have the potential to inhibit several signaling pathways involved in breast cancer-related angiogenesis. Until now, they have failed to show a clear benefit in mBC. On the other hand, poly(ADP-ribose) polymerase (PARP) inhibition, mediated by a new class of small molecules, is an interesting area of investigation. Future directions of research in HER2-positive breast cancer focus on the evaluation of novel antibodies (pertuzumab, T-DM1), and irreversible TKIs (neratinib, BIBW 2992) and inhibitors of HER2-related downstream signaling (mTOR, TORC 1/2, PI3K/Akt) and of receptor cross-talk (IGFR).
doi:10.1159/000314996
PMCID: PMC2931051  PMID: 20847826
Breast cancer, metastatic; Anti-angiogenesis; Antibody; PARP inhibition; Multitargeting
23.  Preoperative/Neoadjuvant Therapy in Pancreatic Cancer: A Systematic Review and Meta-analysis of Response and Resection Percentages 
PLoS Medicine  2010;7(4):e1000267.
Jörg Kleef and colleagues systematically reviewed studies on neoadjuvant therapy and tumor response, toxicity, resection, and survival percentages in pancreatic cancer and suggest that patients with locally nonresectable tumors should be included in neoadjuvant protocols.
Background
Pancreatic cancer has an extremely poor prognosis and prolonged survival is achieved only by resection with macroscopic tumor clearance. There is a strong rationale for a neoadjuvant approach, since a relevant percentage of pancreatic cancer patients present with non-metastatic but locally advanced disease and microscopic incomplete resections are common. The objective of the present analysis was to systematically review studies concerning the effects of neoadjuvant therapy on tumor response, toxicity, resection, and survival percentages in pancreatic cancer.
Methods and Findings
Trials were identified by searching MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from 1966 to December 2009 as well as through reference lists of articles and proceedings of major meetings. Retrospective and prospective studies analyzing neoadjuvant radiochemotherapy, radiotherapy, or chemotherapy of pancreatic cancer patients, followed by re-staging, and surgical exploration/resection were included. Two reviewers independently extracted data and assessed study quality. Pooled relative risks and 95% confidence intervals were calculated using random-effects models. Primary outcome measures were proportions of tumor response categories and percentages of exploration and resection. A total of 111 studies (n = 4,394) including 56 phase I–II trials were analyzed. A median of 31 (interquartile range [IQR] 19–46) patients per study were included. Studies were subdivided into surveys considering initially resectable tumors (group 1) and initially non-resectable (borderline resectable/unresectable) tumors (group 2). Neoadjuvant chemotherapy was given in 96.4% of the studies with the main agents gemcitabine, 5-FU (and oral analogues), mitomycin C, and platinum compounds. Neoadjuvant radiotherapy was applied in 93.7% of the studies with doses ranging from 24 to 63 Gy. Averaged complete/partial response probabilities were 3.6% (95% CI 2%–5.5%)/30.6% (95% CI 20.7%–41.4%) and 4.8% (95% CI 3.5%–6.4%)/30.2% (95% CI 24.5%–36.3%) for groups 1 and 2, respectively; whereas progressive disease fraction was estimated to 20.9% (95% CI 16.9%–25.3%) and 20.8% (95% CI 14.5%–27.8%). In group 1, resectability was estimated to 73.6% (95% CI 65.9%–80.6%) compared to 33.2% (95% CI 25.8%–41.1%) in group 2. Higher resection-associated morbidity and mortality rates were observed in group 2 versus group 1 (26.7%, 95% CI 20.7%–33.3% versus 39.1%, 95% CI 29.5%–49.1%; and 3.9%, 95% CI 2.2%–6% versus 7.1%, 95% CI 5.1%–9.5%). Combination chemotherapies resulted in higher estimated response and resection probabilities for patients with initially non-resectable tumors (“non-resectable tumor patients”) compared to monotherapy. Estimated median survival following resection was 23.3 (range 12–54) mo for group 1 and 20.5 (range 9–62) mo for group 2 patients.
Conclusions
In patients with initially resectable tumors (“resectable tumor patients”), resection frequencies and survival after neoadjuvant therapy are similar to those of patients with primarily resected tumors and adjuvant therapy. Approximately one-third of initially staged non-resectable tumor patients would be expected to have resectable tumors following neoadjuvant therapy, with comparable survival as initially resectable tumor patients. Thus, patients with locally non-resectable tumors should be included in neoadjuvant protocols and subsequently re-evaluated for resection.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pancreatic cancer is the fourth leading cause of cancer-related deaths worldwide. It begins when a cell in the pancreas (an organ lying behind the stomach that produces digestive enzymes and hormones such as insulin that controls blood sugar levels) acquires genetic changes that allow it to grow uncontrollably and, sometimes, to spread around the body (metastasize). Because pancreatic cancer rarely causes any symptoms early in its development, it is locally advanced in more than a third of patients and has already metastasized in another half of patients by the time it is diagnosed. Consequently, on average, people die within 5–8 months of a diagnosis of pancreatic cancer. At present, the only chance for cure is surgical removal (resection) of the tumor, part of the pancreas, and other nearby digestive organs. This procedure—the Whipple procedure—is only possible in the fifth of patients whose tumor is found when it is small enough to be resectable, and even in these patients, the cure rate associated with surgery is less than 25%, although radiotherapy or chemotherapy after surgery (adjuvant therapy) can be beneficial.
Why Was This Study Done?
For patients whose tumor has metastasized, palliative chemotherapy to slow down tumor growth and to minimize pain is the only treatment option. But, for the many patients whose disease is locally advanced and unresectable at diagnosis, experts think that “neoadjuvant” therapy might be helpful. Neoadjuvant therapy—chemotherapy and/or radiotherapy given before surgery—aims to convert unresectable tumors into resectable tumors by shrinking the visible tumor and removing cancer cells that cannot be seen with the naked eye. Randomized phase III trials—studies in which groups of patients are randomly assigned to different interventions and specific outcomes measured—are the best way to determine whether an intervention has any clinical benefits, but no randomized phase III trials of neoadjuvant therapy for unresectable pancreatic cancer have been undertaken. Therefore, in this systematic review (a study that uses predefined criteria to identify all the research on a given topic) and meta-analysis (a statistical method for combining the results of several studies), the researchers analyze data from other types of studies to investigate whether neoadjuvant therapy for pancreatic cancer provides any clinical benefits.
What Did the Researchers Do and Find?
In their systematic review, the researchers identified 111 studies involving 4,394 patients in which the effects of neoadjuvant chemotherapy and/or radiotherapy on tumor response, tumor resectability, and patient survival had been investigated. They subdivided the studies into two groups: group 1 studies included patients whose tumors were considered resectable on preoperative examination, and group 2 studies included patients whose tumors were borderline resectable or unresectable. In their meta-analysis, the researchers found that similar percentages of the tumors in both groups responded to neoadjuvant therapy by shrinking or regressing and that about a fifth of the tumors in each group grew larger or metastasized during neoadjuvant therapy. In the group 1 studies, three-quarters of the tumors were resectable after neoadjuvant therapy (a decrease in the proportion of tumors that could be treated surgically) whereas in the group 2 studies, a third of the tumors were resectable after neoadjuvant therapy (an increase in the proportion of tumors that could be treated surgically). After resection, the average survival time for group 1 patients was 23.3 months, a similar survival time to that seen in patients treated with surgery and adjuvant therapy. The average survival time for group 2 patients after resection was 20.5 months.
What Do These Findings Mean?
The finding that the average survival time after neoadjuvant therapy and surgery in patients whose tumor was judged resectable before neoadjuvant therapy was similar to that of patients treated with chemotherapy and/or radiotherapy after surgery suggests that for patients with resectable tumors, neoadjuvant therapy will not provide any clinical benefit. By contrast, the finding that a third of patients initially judged unresectable were able to undergo resection after neoadjuvant therapy and then had a similar survival rate to patients judged resectable before neoadjuvant treatment strongly suggests that patients presenting with locally advanced/unresectable tumors should be offered neoadjuvant therapy and then re-evaluated for resection. Randomized trials are now needed to confirm this finding and to determine the optimum neoadjuvant therapy for this group of patients.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000267.
The US National Cancer Institute provides information for patients and health professionals about all aspects of pancreatic cancer (in English and Spanish), including a booklet for patients
The American Cancer Society also provides detailed information about pancreatic cancer
The UK National Health Service and Cancer Research UK include information for patients on pancreatic cancer on their Web sites
MedlinePlus provides links to further resources on pancreatic cancer (in English and Spanish)
Pancreatica.org, PancreaticDuct.org, and the Pancreatic Cancer Action Network give more information to pancreatic cancer patients, their families, and caregivers
doi:10.1371/journal.pmed.1000267
PMCID: PMC2857873  PMID: 20422030
24.  PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib 
BMC Cancer  2011;11:248.
Background
Human epidermal growth factor receptor 2 (HER2) is the most crucial ErbB receptor tyrosine kinase (RTK) family member in HER2-positive (refered to HER2-overexpressing) breast cancer which are dependent on or "addictive" to the Phosphatidylinositol-3-kinase (PI3K) pathway. HER2-related target drugs trastuzumab and lapatinib have been the foundation of treatment of HER2--positive breast cancer. This study was designed to explore the relationship between PI3K pathway activation and the sensitivity to lapatinib in HER2--positive metastatic breast cancer patients pretreated with anthracyclins, taxanes and trastuzumab.
Methods
Sixty-seven HER2-positive metastatic breast cancer patients were recruited into a global lapatinib Expanded Access Program and 57 patients have primary tumor specimens available for determination of PI3K pathway status. PTEN status was determined by immunohistochemical staining and PIK3CA mutations were detected via PCR sequencing. All patients were treated with lapatinib 1250 mg/day continuously and capecitabine 1000 mg/m2 twice daily on a 2-week-on and 1-week-off schedule until disease progression, death, withdrawal of informed consent, or intolerable toxicity.
Results
PIK3CA mutations and PTEN loss were detected in 12.3% (7/57) and 31.6% (18/57) of the patients, respectively. Twenty-two patients with PI3K pathway activation (defined as PIK3CA mutation and/or PTEN expression loss) had a lower clinical benefit rate (36.4% versus 68.6%, P = 0.017) and a lower overall response rate (9.1% versus 31.4%, P = 0.05), when compared with the 35 patients with no activation. A retrospective analysis of first trastuzumab-containing regimen treatment data showed that PI3K pathway activation correlated with a shorter median progression-free survival (4.5 versus 9.0 months, P = 0.013).
Conclusions
PIK3CA mutations occur more frequently in elder patients for HER2-positive breast cancer. PIK3CA mutations and PTEN loss are not mutually exclusive. PI3K pathway activation resulting from PTEN loss or PIK3CA mutations may lead to drug resistance to lapatinib and trastuzumab (http://ClinicalTrials.gov number, NCT00338247).
doi:10.1186/1471-2407-11-248
PMCID: PMC3141770  PMID: 21676217
25.  Loss of HER2 Amplification Following Trastuzumab-based Neoadjuvant Systemic Therapy and Survival Outcomes 
Purpose
To evaluate HER2 status in residual tumor identified at the time of surgery in patients not achieving a pathologic complete response (pCR) and to determine the impact of alterations in HER2 status on recurrence-free survival (RFS).
Experimental Design
Clinicopathologic data for patients with HER2-overexpressing breast cancer receiving neoadjuvant therapy with a taxane, anthracycline and concomitant trastuzumab between 2004 and 2007 were reviewed. Surgical specimens for patients achieving less than a pCR were assessed to determine if there was enough residual tissue to evaluate post-treatment HER2 status. RFS was determined using the Kaplan-Meier method and compared by the log rank statistic.
Results
A pCR was achieved in 72 (50.7%) of the 142 patients. Residual tumor was sufficient to assess post-treatment HER2 status in 25 patients. FISH performed on pre-treatment specimens confirmed HER2-amplification prior to beginning therapy. Eight (32.0%) post-treatment tumors were found to be HER2-negative by FISH. At a median follow-up of 37 months (range 8–56 months), the RFS was significantly better for patients with tumors that retained HER2 amplification (87.5% vs. 50%, p=0.04).
Conclusion
High pCR rates are achieved in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab in combination with anthracyclines and taxanes. One-third of patients with significant residual disease lose HER2 amplification and this change is associated with poor RFS. Residual tumor identified at the time of surgery should be reassessed for HER2 status and novel adjuvant therapy strategies need to be studied in this population.
doi:10.1158/1078-0432.CCR-09-1735
PMCID: PMC2788123  PMID: 19920100
breast cancer; HER2/neu; neoadjuvant chemotherapy; trastuzumab

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