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PubMed | Breast Unit, Medical University of Graz, University of Bristol, U.S. Center for Disease Control and Prevention and 4 more.
Type: Journal Article | Journal: The Lancet. Oncology | Year: 2016

Breast cancer is the leading cause of cancer death among women worldwide, and increasingly, randomised controlled trials of this disease are measuring the health-related quality of life of these patients. In this systematic Review, we assess the adequacy of methods used to report health-related quality of life (HRQOL) from 49 eligible randomised controlled trials of advanced breast cancer. We compare our findings with those from the literature to investigate whether the standard of HRQOL reporting in this field has changed. We conclude that the overall reporting of HRQOL has improved, but some crucial aspects remain problematic, such as the absence of HRQOL research hypotheses and the overemphasis on statistical rather than clinical significance. Additionally, new challenges are arising with the emergence of novel treatments and the advent of personalised medicine, and improved HRQOL tools are required to cover the range of side-effects of newer therapies.

PubMed | Italian National Cancer Institute, Genentech, Breast International Group, French Institute of Health and Medical Research and 2 more.
Type: Journal Article | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2016

Estrogen receptor-positive (ER+) breast cancers (BCs) constitute the most frequent BC subtype. The molecular landscape of ER+ relapsed disease is not well characterized. In this study, we aimed to describe the genomic evolution between primary (P) and matched metastatic (M) ER+ BCs after failure of adjuvant therapy.A total of 182 ER+ metastatic BC patients with long-term follow-up were identified from a single institution. P tumor tissue was available for all patients, with 88 having matched M material. According to the availability of tumor material, samples were characterized using a 120 mutational hotspot qPCR, a 29 gene copy number aberrations (CNA) and a 400 gene expression panels. ESR1 mutations were assayed by droplet digital PCR. Molecular alterations were correlated with overall survival (OS) using the Cox proportional hazards regression models.The median follow-up was 6.4 years (range 0.5-26.6 years). Genomic analysis of P tumors revealed somatic mutations in PIK3CA, KRAS, AKT1, FGFR3, HRAS and BRAF at frequencies of 41%, 6%, 5%, 2%, 1% and 2%, respectively, and CN amplification of CCND1, ZNF703, FGFR1, RSF1 and PAK1 at 23%, 19%, 17%, 12% and 11%, respectively. Mutations and CN amplifications were largely concordant between P and matched M (>84%). ESR1 mutations were found in 10.8% of the M but none of the P. Thirteen genes, among which ESR1, FOXA1, and HIF1A, showed significant differential expression between P and M. In P, the differential expression of 18 genes, among which IDO1, was significantly associated with OS (FDR < 0.1).Despite the large concordance between P and matched M for the evaluated molecular alterations, potential actionable targets such as ESR1 mutations were found only in M. This supports the importance of characterizing the M disease. Other targets we identified, such as HIF1A and IDO1, warrant further investigation in this patient population.

Saini K.S.,Breast International Group | Saini K.S.,Free University of Colombia | Taylor C.,King's College London | Ramirez A.-J.,King's College London | And 14 more authors.
Annals of Oncology | Year: 2012

Background: The optimal management of patients with breast cancer (BC) requires the expertise of specialists from different disciplines. This has led to the evolution of multidisciplinary teams (MDTs), allowing all key professionals to jointly discuss individual patients and to contribute independently to clinical decisions. Data regarding BC MDTs in different regions and countries are scarce. Methods: The investigators of a large global phase III adjuvant BC trial being conducted by the Breast International Group were invited to respond to a questionnaire about the extent, structure, and function of BC MDTs. Results: One hundred and fifty-two responses from 39 countries were received, and remarkable differences were noted in different geographic regions. Sixty-five percent of the respondents from eastern Europe, 63% from western Europe, 35% from Asia, and 25% from South America declared that MDT was a mandatory part of BC care in their country. Ninety percent of the respondents from Europe stated their MDTs met weekly, compared with only half of the respondents from Asia. Conclusion: This survey is perhaps the first large-scale effort to collect information regarding BC MDTs from different parts of the world and provides objective information of frequency, composition, function, and working mechanism of BC MDTs. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), the Breast International Group (BIG), Breast European Adjuvant Study Team (BrEAST) and Frontier Science Foundation (FS) today announced positive results from the Phase III APHINITY study. The study met its primary endpoint and showed that adjuvant (after surgery) treatment with the combination of Perjeta® (pertuzumab), Herceptin® (trastuzumab) and chemotherapy (the Perjeta-based regimen) achieved a statistically significant reduction in the risk of recurrence of invasive disease or death (invasive disease-free survival; iDFS) in people with HER2-positive early breast cancer (EBC) compared to Herceptin and chemotherapy alone. The safety profile of the Perjeta-based regimen was consistent with that seen in previous studies, and no new safety signals were identified. Full results from the APHINITY trial will be presented at an upcoming medical meeting in 2017. “These results from the positive APHINITY study represent an important addition to the body of data for Perjeta in the treatment of people with HER2-positive early breast cancer,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development. “We look forward to discussing these adjuvant results with global regulatory authorities.” Gunter von Minckwitz, M.D., study coordinator from the Breast International Group and academic study partners, added, “APHINITY provides yet another example of the importance of industry-academic collaborations and their value in advancing cancer care for people affected by this challenging disease.” HER2-positive breast cancer is an aggressive form of the disease, which affects approximately one in five people with breast cancer and is associated with a poor prognosis if left untreated. Despite advancements in the treatment of HER2-positive EBC, up to one in three people treated with Herceptin and chemotherapy may eventually see their cancer return. Treatment options are needed to improve the outcomes of people with this aggressive disease. Treating breast cancer early, before it has spread, may improve the chance of preventing the disease from returning and potentially reaching an incurable stage. Adjuvant therapy is given after surgery and is aimed at killing any remaining cancer cells to reduce the risk of the cancer returning. In the U.S., the combination of Perjeta, Herceptin and docetaxel chemotherapy is currently available under accelerated approval for neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node-positive) as part of a complete treatment regimen for early breast cancer. This approval is based primarily on data from a Phase II study showing that nearly 40 percent of people receiving the combination of Perjeta, Herceptin and docetaxel chemotherapy had no evidence of microscopic tumor tissue detectable at the time of surgery (known as a pathological complete response, or pCR) compared to almost 22 percent in the Herceptin and docetaxel chemotherapy arm. The APHINITY trial reflects the commitment to evaluate the Perjeta-based regimen as part of a complete treatment approach for EBC. These data will be discussed with the FDA with the hope to convert the current accelerated approval to a full approval. APHINITY (Adjuvant Pertuzumab and Herceptin IN Initial TherapY in Breast Cancer, NCT01358877/ BO25126/ BIG 4-11) is an international, Phase III, randomized, double-blind, placebo-controlled, two-arm study evaluating the efficacy and safety of Perjeta plus Herceptin and chemotherapy compared to Herceptin and chemotherapy as an adjuvant therapy in 4,805 people with operable HER2-positive EBC. People enrolled in the study underwent surgery and were randomized to one of two arms (1:1) to receive either: Radiotherapy and/or endocrine therapy could be initiated at the end of adjuvant chemotherapy. The APHINITY study allowed for a range of standard chemotherapy regimens to be used and both lymph node-positive and lymph node-negative participants were eligible for enrollment. The primary efficacy endpoint of the APHINITY study is iDFS, which is the time a patient lives without return of invasive breast cancer at any site or death from any cause after adjuvant treatment. Secondary endpoints include cardiac and overall safety, overall survival, disease-free survival and health-related quality of life. Perjeta is a medicine that targets the HER2 receptor, a protein found on the outside of many normal cells and in high quantities on the outside of cancer cells in HER2-positive cancers. Perjeta is designed specifically to prevent the HER2 receptor from pairing (or ‘dimerizing’) with other HER receptors (EGFR/HER1, HER3 and HER4) on the surface of cells, a process that is believed to play a role in tumor growth and survival. Binding of Perjeta to HER2 may also signal the body’s immune system to destroy the cancer cells. The mechanisms of action of Perjeta and Herceptin are believed to complement each other, as both bind to the HER2 receptor, but to different places. The combination of Perjeta and Herceptin is thought to provide a more comprehensive, dual blockade of HER signaling pathways, thus preventing tumor cell growth and survival. Perjeta is approved for use prior to surgery in combination with Herceptin and docetaxel chemotherapy in people with HER2-positive, locally advanced, inflammatory, or early stage (tumor is greater than two centimeters in diameter or node-positive) breast cancer. Perjeta should be used as part of a complete treatment regimen for early stage breast cancer. This use of Perjeta is based on an improvement in the percentage of patients whose cancer shrinks or disappears after treatment. Currently, no data have shown whether or not treatment with Perjeta prior to surgery improves survival. Perjeta may cause heart problems, including those without symptoms (such as reduced heart function) and those with symptoms (such as congestive heart failure). Receiving Perjeta during pregnancy can result in the death of an unborn baby and birth defects. Other possible serious side effects Knowing if Perjeta is right for the patient Perjeta has only been shown to work in people with HER2-positive breast cancer. A patient must have a HER2 test to know if their breast cancer is HER2-positive before receiving an anti-HER2 treatment, such as Perjeta. The most common side effects of Perjeta when given with Herceptin and docetaxel as part of an early breast cancer regimen before surgery are: The most common side effects of Perjeta when given with Herceptin and docetaxel following three cycles of epirubicin, cyclophosphamide and fluorouracil as part of an early breast cancer regimen before surgery are: The most common side effects of Perjeta when given with Herceptin, docetaxel and carboplatin as part of an early breast cancer regimen before surgery are: Patients are encouraged to report side effects to Genentech and the FDA. Report side effects to the FDA at (800) FDA-1088 or Report side effects to Genentech at (888) 835-2555. Please see the full Prescribing Information for additional Important Safety Information, including most serious side effects, at Herceptin is approved for the treatment of early stage breast cancer that is HER2-positive and has spread into the lymph nodes, or is HER2-positive and has not spread into the lymph nodes. If it has not spread into the lymph nodes, the cancer needs to be estrogen receptor/progesterone receptor (ER/PR)-negative or have one high risk feature.* Herceptin can be used in several different ways: *High risk is defined as ER/PR-positive with one of the following features: tumor size greater than 2 cm, age less than 35 years, or tumor Grade 2 or 3. Possible serious side effects with Herceptin Not all people have serious side effects, but side effects with Herceptin therapy are common. Although some people may have a life-threatening side effect, most do not. A patient’s doctor will stop treatment if any serious side effects occur. Herceptin is not for everyone. A patient should be sure to contact their doctor if they are experiencing any of the following: These include heart problems—such as congestive heart failure or reduced heart function—with or without symptoms. The risk for and seriousness of these heart problems were highest in people who received both Herceptin and a certain type of chemotherapy (anthracycline). In a study of adjuvant (early) breast cancer, one patient died of significantly weakened heart muscle. A patient’s doctor will check for signs of heart problems before, during, and after treatment with Herceptin. These signs usually happen within 24 hours after receiving Herceptin. A patient should be sure to contact their doctor if they: Are a woman who could become pregnant, or may be pregnant Herceptin may result in the death of unborn baby and birth defects. Birth control should be used while receiving Herceptin and after a patient's last dose of Herceptin. If a patient is exposed to Herceptin during pregnancy or within seven months of becoming pregnant, the patient is encouraged to enroll in the MotHER Pregnancy Registry by contacting (800) 690-6720 or visiting and to report Herceptin exposure to Genentech at (888) 835-2555. Have any signs of SEVERE LUNG PROBLEMS, including: A patient’s doctor may check for signs of severe lung problems when he or she examines the patient. Low white blood cell counts can be life threatening. Low white blood cell counts were seen more often in patients receiving Herceptin plus chemotherapy than in patients receiving chemotherapy alone. A patient’s doctor may check for signs of low white blood cell counts when he or she examines the patient. Before taking Herceptin, a patient must have a HER2 test to determine if their cancer is HER2-positive. This is because the benefit of treatment with Herceptin has been shown only in patients whose tumors are HER2-positive. Side effects seen most often with Herceptin Some patients receiving Herceptin for breast cancer had the following side effects: A patient should contact their doctor immediately if they have any of the side effects listed above. Patients are encouraged to report side effects to Genentech and the FDA. Report side effects to the FDA at (800) FDA-1088 or Report side effects to Genentech at (888) 835-2555. Please see the full Prescribing Information, including Boxed WARNINGS and additional Important Safety Information, at Breast cancer is the most common cancer among women worldwide. According to the American Cancer Society, approximately 255,180 people in the United States will be diagnosed with breast cancer, and 41,070 will die from the disease in 2017. In HER2-positive breast cancer, increased quantities of the Human Epidermal growth factor Receptor 2 (HER2) are present on the surface of tumor cells. This is known as “HER2 positivity” and affects approximately 15-20 percent of people with breast cancer. HER2-positive cancer is a particularly aggressive form of breast cancer. Genentech has spent more than 30 years studying the role of HER2 in cancer, and Perjeta is a result of this research. A diagnostic test is used to determine if a person’s tumor is HER2-positive and whether treatment with HER2-targeted medicines is appropriate. Access Solutions is part of Genentech’s commitment to helping people access the Genentech medicines they are prescribed, regardless of their ability to pay. The team of in-house specialists at Access Solutions is dedicated to helping people navigate the access and reimbursement process, and to providing assistance to eligible patients in the United States who are uninsured or cannot afford the out-of-pocket costs for their medicine. To date, the team has helped more than 1.5 million patients access the medicines they need. Please contact Access Solutions (866) 4ACCESS/(866) 422-2377 or visit for more information. Founded 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious or life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit

Criscitiello C.,Free University of Colombia | Metzger-Filho O.,Free University of Colombia | Saini K.S.,Free University of Colombia | Saini K.S.,Breast International Group | And 6 more authors.
Breast Cancer Research | Year: 2012

The concept of 'targeted' therapies implies that such drugs only act on cells that specifically express the particular target, therefore giving rise to a low incidence of side effects. However, targeted therapies currently approved for the treatment of breast cancer have demonstrated a relatively high incidence of cardiovascular events. The anti-HER2 agents trastuzumab and lapatinib may cause left ventricular dysfunction or even congestive heart failure. Bevacizumab, an antiangiogenic drug, has been shown to increase the risk of hypertension, cardiovascular dysfunction and thromboembolic events. In addition, several anti-human epidermal growth factor receptor 2 (HER2) and antiangiogenic agents plus their combinations are currently being developed and evaluated for the treatment of breast cancer. In this review, we aim to assess the incidence of cardiac adverse events associated with targeted therapies designed to block HER2 and angiogenic pathways. © 2012 BioMed Central Ltd.

News Article | December 14, 2015

By sifting through the 20,000 protein-encoding genes in the human genome, Yale researchers discovered new complexities behind drug resistance and identified patterns of mutations that could predict which therapies will benefit patients with aggressive breast cancer. The findings will be presented Dec. 11 at the 2015 San Antonio Breast Cancer Symposium. Her2-positive breast cancer is an aggressive form that comprises 20 percent of all cases. Using tissue from the international NeoALTTO study, the Yale team sequenced 203 Her2-positive cancer samples to assess which mutations in which genes predicted response or resistance to Her2-targeted therapies. In the study, patients with early stage breast cancer were treated pre-operatively with either paclitaxel chemotherapy in combination with one of two breast cancer drugs (trastuzumab or lapatinib), or with the drugs alone. “The key finding is that different cancers acquire resistance to trastuzumab through different mutations in different genes,” said presenting and senior author Lajos Pusztai, M.D., professor of medicine and chief of breast medical oncology. “The silver lining is that these genes participate in biological processes that are all connected through the PIK3CA gene.” Mutations in the PIK3CA gene were already known to be markers of lower sensitivity to trastuzumab, but these new results extend this association to a broader network of genes. The investigators also identified a different set of genes whose mutations were associated with greater sensitivity to lapatinib. All of these genes involve the regulation of a biological process called RhoA-activation that controls cell movement. The study concludes that alterations at the level of pathways may be more informative as predictive markers than single gene mutations, Pusztai said. This study was supported by the Breast Cancer Research Foundation. The NeoALTTO trial was conducted by the Breast International Group and SOLTI clinical trial groups with the support of GlaxoSmithKlein, now Novartis Pharma.

Mendola A.,Catholic University of Louvain | Schlogel M.J.,Catholic University of Louvain | Ghalamkarpour A.,Catholic University of Louvain | Irrthum A.,Catholic University of Louvain | And 13 more authors.
Molecular Syndromology | Year: 2013

Lymphedema is caused by dysfunction of lymphatic vessels, leading to disabling swelling that occurs mostly on the extremities. Lymphedema can be either primary (congenital) or secondary (acquired). Familial primary lymphedema commonly segregates in an autosomal dominant or recessive manner. It can also occur in combination with other clinical features. Nine mutated genes have been identified in different isolated or syndromic forms of lymphedema. However, the prevalence of primary lymphedema that can be explained by these genetic alterations is unknown. In this study, we investigated 7 of these putative genes. We screened 78 index patients from families with inherited lymphedema for mutations in FLT4, GJC2, FOXC2, SOX18, GATA2, CCBE1, and PTPN14. Altogether, we discovered 28 mutations explaining 36% of the cases. Additionally, 149 patients with sporadic primary lymphedema were screened for FLT4, FOXC2, SOX18,CCBE1, and PTPN14. Twelve mutations were found that explain 8% of the cases. Still unidentified is the genetic cause of primary lymphedema in 64% of patients with a family history and 92% of sporadic cases. Identification of those genes is important for understanding of etiopathogenesis, stratification of treatments and generation of disease models. Interestingly, most of the proteins that are encoded by the genes mutated in primary lymphedema seem to act in a single functional pathway involving VEGFR3 signaling. This underscores the important role this pathway plays in lymphatic development and function and suggests that the unknown genes also have a role. © 2013 S. Karger AG, Basel.

Ades F.,University of Waterloo | Zardavas D.,Breast International Group | Bozovic-Spasojevic I.,Serbian Institute for Oncology and Radiology of Serbia | Pugliano L.,University of Waterloo | And 5 more authors.
Journal of Clinical Oncology | Year: 2014

Gene expression profiling has reshaped our understanding of breast cancer by defining and characterizing four main intrinsic molecular subtypes: human epidermal growth factor receptor 2-enriched, basal-like, luminal A, and luminal B subtypes. Luminal B breast cancer has been reported to have lower expression of hormone receptors, higher expression of proliferation markers, and higher histologic grade than luminal A. It also exhibits worse prognosis and has a distinct profile of response to hormone therapy and chemotherapy. Although luminal cancers share similarities, the studies conducted in recent years using next-generation sequencing technology show that luminal A and B breast cancers should be perceived as distinct entities, with specific oncogenic drivers, rather than more proliferative varieties of luminal tumors. This review discusses the definition and molecular characterization of luminal B breast cancer and presents the available clinical evidence for chemotherapy and endocrine therapy patterns of response. It also provides an overview of ongoing research on molecularly targeted agents for this disease. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.

Saini K.S.,Breast International Group | Saini K.S.,Free University of Colombia | Loi S.,Peter MacCallum Cancer Center | de Azambuja E.,Free University of Colombia | And 6 more authors.
Cancer Treatment Reviews | Year: 2013

Alterations of signal transduction pathways leading to uncontrolled cellular proliferation, survival, invasion, and metastases are hallmarks of the carcinogenic process. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and the Raf/mitogen-activated and extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways are critical for normal human physiology, and also commonly dysregulated in several human cancers, including breast cancer (BC). In vitro and in vivo data suggest that the PI3K/AKT/mTOR and Raf/MEK/ERK cascades are interconnected with multiple points of convergence, cross-talk, and feedback loops. Raf/MEK/ERK and PI3K/AKT/mTOR pathway mutations may co-exist. Inhibition of one pathway can still result in the maintenance of signaling via the other (reciprocal) pathway. The existence of such "escape" mechanisms implies that dual targeting of these pathways may lead to superior efficacy and better clinical outcome in selected patients. Several clinical trials targeting one or both pathways are already underway in BC patients. The toxicity profile of this novel approach of dual pathway inhibition needs to be closely monitored, given the important physiological role of PI3K/AKT/mTOR and Raf/MEK/ERK signaling. In this article, we present a review of the current relevant pre-clinical and clinical data and discuss the rationale for dual inhibition of these pathways in the treatment of BC patients. © 2013 Elsevier Ltd.

News Article | August 25, 2016

A test that identifies genetic markers in early stage breast cancer tumors is helping clinicians determine if a patient needs to get chemotherapy treatment or not. Researchers conducted a study, published today in the New England Journal of Medicine, to see how effective a test called MammaPrint was at predicting the risk of cancer recurrence in 6,693 women with a common type of early stage breast cancer. The study involved patients from 112 hospitals in nine European countries. The test looked at the activity of 70 genes to determine a specific patient’s genomic risk of recurrence. Doctors then evaluated patients’ clinical risk based on conventional methods like tumor size, the presence of hormone receptors and metastasis to lymph nodes. “Early stage” in the study referred to Stage 1 or 2, which in the U.S. is classified as tumors that are generally less than 5 centimeters and haven’t spread to more than three lymph nodes. More than half of breast cancer cases in the U.S. are diagnosed in the early stages. Twenty-three percent of the total patients showed high clinical risk, but low genomic risk according to the MammaPrint results. The patients that fell into this group were randomly assigned to either receive chemo or to not. Both groups still had usual initial treatments such as surgery, hormonal therapy and radiation. A five year follow-up found that 94.4 percent were still alive and not showing any distant spread of the cancer. The survival rate was only 1.5 percent lower than the group who did receive chemo, at 95.9 percent. The results indicate that 46 percent of women with early stage breast cancer who are thought to be at high clinical risk may actually be able to skip chemo and avoid its significant side effects. This correlates to 35,000 to 40,000 women in the U.S. per year. The MammaPrint testing device was developed in part by Laura van ‘t Veer, director of Applied Genomics at the UCSF Helen Diller Family Comprehensive Cancer Center. The results of the study came from an international research collaboration, MINDACT ("Microarray In Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy"), which involves 112 academic cancer centers, van 't Veer's company, Agendia NV, the European Organization for Research and Treatment of Cancer and the Breast International Group.

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