Dual-Parallel Artificial Intelligence Framework for Breast Cancer Grading via High-Intensity Ultrasound and Biomarkers.

Purpose: Somatic mutations in the tyrosine kinase domain of human epidermal growth factor receptor2 (HER2) have been reported to lead to resistance to HER2-targeted therapies in HER2-positive breast cancer, while activating mutations of HER2 have been described in HER2-negative breast cancer. The prevalence, clinicopathological characteristics, and phenotypes of HER2 mutations are not well established, thus we sought to describe the HER2 mutation profile of Chinese breast cancer patients. Methods: DNA samples were gathered from breast cancer patients undergoing neoadjuvant (N=102) or adjuvant therapy (N=498) at Fudan University Shanghai Cancer Center between January 1, 2006 and December 31, 2012. Sanger sequencing was performed to analyze all exons of HER2 to identify somatic mutations. To determine the phenotypes of novel HER2 mutations, in vitro kinase assays, protein structure analysis, cell culture, and xenograft experiments were conducted. Results: 10 HER2 somatic mutations were observed in 17 patients (17/600, 2.83%). 7 novel HER2 mutations were uncovered, 4 in the transmembrane domain and 3 in the kinase domain. Kinase domain mutations L768S and V773L were detected in HER2-negative tumors, while K753E was found in HER2-positive disease. In vitro kinase assays found that L768S and V773L exhibited a significant increase of tyrosine kinase-specific activity, while Western blots showed that L768S and V773L strongly increased phosphorylation of all signaling proteins in both MCF10A and MCF7cell lines, indicating that they were activating mutations. In Matrigel cultures, L768S and V773L formed acini when seeded in vehicle, but maintained spherical morphology when seeded in culture containing trastuzumab. The addition of lapatinib in Matrigel culture inhibited the growth of all except K753E, which was successfully inhibited by neratinib. Similarly, L768S, V773L and K753E increased the number of cell colonies formed in soft agar, trastuzumab and lapatinib treatment decreased the number of colonies formed by L768S and V773L, but only neratinib could inhibit the colony growth of K753E. Xenograft showed L768S and V773L displayed a more rapid growth, while K753E showed resistance to lapatinib in vivo. MCF10A cells bearing K753E mutation were found to be resistant to lapatinib (IC50>10,000 nmol/L), but could be inhibited by neratinib, though requiring a relatively higher dosage (IC50 of 32 nmol/L) than HER2 WT (IC50 of 480 nmol/L for lapatinib, <2 nmol/L for neratinib) and other HER2 mutations. Meanwhile, clinical follow-up showed that the 2 patients with K753E mutation who received adjuvant trastuzumab treatment presented with either brain or bone metastasis, in their 3rd and 5th year after initial cancer diagnosis, suggesting K753E mutation may have a role in trastuzumab resistance as well. Conclusions: HER2 somatic mutations were found in 2.83% of patients in this study. HER2-positive tumors harboring certain HER2 kinase domain resistance mutations may not benefit from trastuzumab or lapatinib treatment, and neratinib may offer an alternative treatment option for these patients. HER2-negative disease with activating mutations may benefit from HER2-targeted therapies, and may be of interest in prospective clinical trials. Citation Format: Wen-Jia Zuo, Yi-Zhou Jiang, Ke-Da Yu, Zhi-Ming Shao. Activating HER2 mutations promote oncogenesis and resistance to HER2-targeted therapies in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-04-04.

HER2 is overexpressed in 20–25% of breast cancers. Overexpression of HER2 is an adverse prognostic factor and correlates with decreased patient survival. HER2 stimulates breast tumorigenesis via a number of intracellular signaling molecules, including PI3K/AKT and MAPK/ERK.S100A14,one member of the S100 protein family, is significantly associated with outcome of breast cancer patients. Here, for the first time, we show that S100A14 and HER2 are coexpressed in invasive breast cancer specimens,andthere is a significant correlation between the expression levels of the two proteins by immunohistochemistry. S100A14 and HER2 are colocalized in plasma membrane of breast cancer tissue cells and breast cancer cell lines BT474 and SK-BR3. We demonstrate that S100A14 binds directly to HER2 by co-immunoprecipitation and pull-down assays. Further study shows that residues 956–1154 of the HER2 intracellular domain and residue 83 of S100A14 are essential for the two proteins binding.Moreover,we observe a decrease of HER2 phosphorylation, downstream signaling, and HER2-stimulated cell proliferation in S100A14-silenced MCF-7, BT474, and SK-BR3 cells. Our findings suggest that S100A14 functions as a modulator of HER2 signaling and provide mechanistic evidence for its role in breast cancer progression.

AIMS: The aim of the study was to investigate the prognostic value of Ki-67 and histological grade in patients with estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) negative early breast cancer. Although the proliferation activity of different tumors assessed with antigen Ki-67 was extensively studied in the last decade and showed that Ki67 expression was a useful prognostic factor in breast cancer, there is still a controversy about the utility value of Ki-67. METHODS: The retrospective study covered the period from 2016 to 2022. Year included 106 patients from Brcko District, with early estrogen-positive and HER2 receptors-negative breast cancer. The average patients’ age was 62.37 ± 11.65 years. Patients were divided into groups with high/low Ki-67 and high/low histological grade. Multiple linear regression analysis was performed for disease relapse and mortality. RESULTS: Patients with high Ki-67 were more frequent postmenopausal, had higher histological grade, cancer ˂2 cm, more frequent lymph nodes’ metastases, more frequently underwent to axillary surgery, and had a higher mortality rate. Patients with high histological grade were older, more frequent postmenopausal, had more frequent metastases to the lymph nodes, more frequent occurrence of high Ki-67, more frequent relapse of disease, and more frequent of death. CONCLUSION: Combination of high Ki-67 with high histological grade in ER positive and HER2-negative early breast cancer is an important prognostic factor.

The tumor suppressor gene, BRCA1 has been conferred to increase the susceptibility to breast cancer in younger women. This work studied the expression of BRCA1 (mRNA) in women with breast cancer in relation to other prognostic parameters such as histological type and grade of cancer, hormone receptor status, human epidermal growth factor receptor 2 (HER2/neu) and CA15-3. Thirty patients with positive family history of breast cancer and a control group of 20 healthy subjects were also included for the study. Ribonucleic acid (RNA) extraction from breast cancer tissues was done (considered suitable for RNA extraction if 70% or more of the tissue section contained tumor) and was followed by real-time reverse transcription polymerase chain reaction. BRCA1 expression was assessed and correlated with age, histological type and grade of breast cancer, estrogen and progesterone receptor (ER, PR) status, HER2/neu expression and CA15-3 levels. The mean age of patients was 54.8 ± 10.49 years. Of the 30 breast cancer cases studied, the majority (77%) was of high histological grade and the most common histological type was infiltrating ductal carcinoma (20 cases). ER expression was positive in 53.3% of breast cancers, while PR expression was positive in 50% of cancers. BRCA1 mRNA was found in 6 patient samples (20% of the breast cancer patients) while the remaining 24 patients (80%) showed negative BRCA1 mRNA expression as well as the control group. A positive significant relationship was demonstrated between BRCA1 (mRNA) expression and high histological grade, negative estrogen and progesterone receptor status, and high levels of serum CA15-3. A significant negative correlation was found between BRCA1 mRNA expression and age (r = −0.683; p < 0.01). The study demonstrated lack of BRCA1 gene expression (mRNA) in the majority of breast cancer cases and confirmed the relationship between BRCA1 expression and parameters that determine poor prognosis in breast cancer. The results suggested that BRCA1 is seen in high-risk women known with positive family history of breast cancer.

The tumor suppressor gene, BRCA1 has been conferred to increase the susceptibility to breast cancer in younger women. This work studied the expression of BRCA1 (mRNA) in women with breast cancer in relation to other prognostic parameters such as histological type and grade of cancer, hormone receptor status, human epidermal growth factor receptor 2 (HER2/neu) and CA15-3. Thirty patients with positive family history of breast cancer and a control group of 20 healthy subjects were also included for the study. Ribonucleic acid (RNA) extraction from breast cancer tissues was done (considered suitable for RNA extraction if 70% or more of the tissue section contained tumor) and was followed by real-time reverse transcription polymerase chain reaction. BRCA1 expression was assessed and correlated with age, histological type and grade of breast cancer, estrogen and progesterone receptor (ER, PR) status, HER2/neu expression and CA15-3 levels. The mean age of patients was 54.8 ± 10.49 years. Of the 30 breast cancer cases studied, the majority (77%) was of high histological grade and the most common histological type was infiltrating ductal carcinoma (20 cases). ER expression was positive in 53.3% of breast cancers, while PR expression was positive in 50% of cancers. BRCA1 mRNA was found in 6 patient samples (20% of the breast cancer patients) while the remaining 24 patients (80%) showed negative BRCA1 mRNA expression as well as the control group. A positive significant relationship was demonstrated between BRCA1 (mRNA) expression and high histological grade, negative estrogen and progesterone receptor status, and high levels of serum CA15-3. A significant negative correlation was found between BRCA1 mRNA expression and age (r = −0.683; p &amp;lt; 0.01). The study demonstrated lack of BRCA1 gene expression (mRNA) in the majority of breast cancer cases and confirmed the relationship between BRCA1 expression and parameters that determine poor prognosis in breast cancer. The results suggested that BRCA1 is seen in high-risk women known with positive family history of breast cancer.

The tumor suppressor gene, BRCA1 has been conferred to increase the susceptibility to breast cancer in younger women. This work studied the expression of BRCA1 (mRNA) in women with breast cancer in relation to other prognostic parameters such as histological type and grade of cancer, hormone receptor status, human epidermal growth factor receptor 2 (HER2/neu) and CA15-3. Thirty patients with positive family history of breast cancer and a control group of 20 healthy subjects were also included for the study. Ribonucleic acid (RNA) extraction from breast cancer tissues was done (considered suitable for RNA extraction if 70% or more of the tissue section contained tumor) and was followed by real-time reverse transcription polymerase chain reaction. BRCA1 expression was assessed and correlated with age, histological type and grade of breast cancer, estrogen and progesterone receptor (ER, PR) status, HER2/neu expression and CA15-3 levels. The mean age of patients was 54.8 ± 10.49 years. Of the 30 breast cancer cases studied, the majority (77%) was of high histological grade and the most common histological type was infiltrating ductal carcinoma (20 cases). ER expression was positive in 53.3% of breast cancers, while PR expression was positive in 50% of cancers. BRCA1 mRNA was found in 6 patient samples (20% of the breast cancer patients) while the remaining 24 patients (80%) showed negative BRCA1 mRNA expression as well as the control group. A positive significant relationship was demonstrated between BRCA1 (mRNA) expression and high histological grade, negative estrogen and progesterone receptor status, and high levels of serum CA15-3. A significant negative correlation was found between BRCA1 mRNA expression and age (r = −0.683; p &lt; 0.01). The study demonstrated lack of BRCA1 gene expression (mRNA) in the majority of breast cancer cases and confirmed the relationship between BRCA1 expression and parameters that determine poor prognosis in breast cancer. The results suggested that BRCA1 is seen in high-risk women known with positive family history of breast cancer.

Background: A rising trend in the incidence of estrogen receptor (ER)-positive subtype over time is observed in several high-income countries, while the incidence of ER-negative subtype is decreasing in some areas. It has been found that decreased parity and late age at 1st full-term pregnancy (FTP1) can increase the risk of breast cancer (BC). This study aims at investigating the association between two reproductive factors, parity and FTP1, and the odds of BC subtypes in premenopausal and postmenopausal patients. Patients and method: This study included patients diagnosed with early-stage BC after the age of 34, who were treated in UZ Leuven between January 2000 and November 2020. The patients were classified into four subtypes defined by ER and human epidermal growth factor receptor-2 (HER2). ER positivity was defined as &amp;gt;1% of cells staining positive while HER2 positivity was based on fluorescence in situ hybridization (FISH) testing of samples with immunohistochemistry score of 2+ or 3+. Baseline-category logit models with subtype as the response (ER+/HER2- as the baseline) and adjusted for age at diagnosis and BMI, were performed for premenopausal and postmenopausal patients separately. First, we exclude nulliparous patients. Parity (1-2 or ≥3) and FTP1 (continuous) were included in the models as the covariates of interest in the first model. To evaluate the effects of reproductive patterns compared to nulliparity, a new variable reproductive pattern was created by taking intersection of parity groups and FTP1 groups (&amp;lt; 27, ≥27). Reproductive pattern was set as the covariate of interest in the second model. Result: After imputing the missing values, we included 9606 patients in the study. 8125 of them were parous. In parous patients, high FTP1 was associated with low odds of ER-/HER2- BC relative to ER+/HER2- BC for both premenopausal and postmenopausal patients (table 1). In postmenopausal patients, low parity was associated with low odds of ER-/HER2- BC and high odds of ER+/HER2+ BC relative to ER+/HER2- BC. There was no evidence that parity affects the odds of subtypes in premenopausal patients. When investigating the effect of different reproductive patterns compared to nulliparity on the odds of subtypes, there was no evidence that reproductive patterns will affect the odds of subtypes in premenopausal patients. Postmenopausal patients who had FTP1 before 27 years old and had at least three children tended to have higher odds of ER-/HER2- BC relative to ER+/HER2- BC compared to nulliparous patients. Conclusion: In parous patients, increased FTP1 was associated with reduced odds of ER-/HER2- relative to ER+/HER2- BC. In postmenopausal patients, patients with at least three children tended to have low odds of ER-/HER2- BC and high odds of ER+/HER2+ BC relative to ER+/HER2- BC. When compared to nulliparity, the combination of having at least three children and having the first child before 27 years old increased the odds of ER-/HER2- BC relative to ER+/HER2- BC in postmenopausal patients. Table 1 Effect of FTP1, parity on subtype odds Menopause Subtype Effect Odds ratio (95%CI) p-value pre ER-/HER2- FTP1 (continuous) 0.960 (0.935, 0.985) 0.0021 post 0.969 (0.948, 0.990) 0.0047 pre ER-/HER2+ 0.992 (0.952, 1.034) 0.7166 post 1.005 (0.977, 1.034) 0.7081 pre ER+/HER2+ 0.976 (0.949, 1.004) 0.0962 post 1.015 (0.992, 1.039) 0.1969 pre ER-/HER2- Parity 1-2 vs ≥3 1.194 (0.899, 1.585) 0.2200 post 0.784 (0.648, 0.949) 0.0124 pre ER-/HER2+ 1.152 (0.723, 1.834) 0.5521 post 0.896 (0.684, 1.173) 0.4228 pre ER+/HER2+ 1.080 (0.795, 1.469) 0.6220 post 1.300 (1.022, 1.654) 0.0329 The baseline category is ER+/HER2- subtype Effect of age at first full-term pregnancy and parity on subtype odds Citation Format: Zhao Liu, Jiumeng Zhang, Karen Van Baelen, Maja Vangoitsenhoven, Hans Wildiers, Adelheid Soubry, Patrick Neven. Parity and age first full term pregnancy affects the odds of different breast cancer subtypes defined by estrogen receptor and human epidermal growth factor receptor-2 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-02-14.

Overexpression of fatty acid binding protein-7 correlates with basal-like subtype of breast cancer

In the article that accompanies this editorial, Mackey et al present the results of ROSE/TRIO-12, a randomized phase III trial comparing single agent docetaxel to the combination of docetaxel and ramucirumab in front-line metastatic breast cancer. This large, wellpowered, placebo-controlled international trial replaced bevacizumab (a vascular endothelial growth factor [VEGF] –A ligand blocking antibody used in numerous phase III trials) with ramucirumab (a human immunoglobulin G1 VEGF receptor [VEGFR] –2–binding monoclonal antibody recently approved for gastric cancer) as the anti-VEGF agent to be studied. The results are disappointing but familiar to those who have followed the story of anti-VEGF therapy in breast cancer—yet another failure. Bevacizumab, the first anti-VEGF therapy to enter the breast cancer arena, electrified the field in 2005 with the E2100 trial, which showed a doubling in progression-free survival (PFS) when combined with weekly paclitaxel. Two subsequent trials (AVADO [Phase III Trial of Avastin and Docetaxel] and RIBBON-1 [Regimens in Bevacizumab for Breast Oncology]) combined bevacizumab with docetaxel, and while neither demonstrated the same degree of PFS benefit as the initial trial, all three demonstrated statistically significant improvements in PFS. These trials were based on a substantial body of preclinical and clinical evidence suggesting the centrality of angiogenesis in general, and VEGF in particular, to breast cancer growth, invasion, and metastasis. Increased tumor VEGF was associated with impaired outcome in numerous clinical studies, and inhibition of VEGF in preclinical models (alone or in combination with other chemotherapeutics and biologics) was associated with improved outcome. Taxanes are imbued with their own antiangiogenic activity, and the combination of taxanes with bevacizumab in particular appeared to provide synergistic antitumor activity in preclinical models of breast cancer. Things went downhill from the initial presentation of the first three randomized trials. After the approval of bevacizumab for metastatic breast cancer by the US Food and Drug Administration (following a contentious ODAC meeting), mature survival results demonstrated that the three trials (individually and collectively) failed to demonstrate an overall survival advantage. Bevacizumab, the beneficiary of an accelerated approval based on initial results, lost its breast cancer label in the United States. Other failures followed. An ambitious adjuvant program was launched, based on the original disease-free survival results. The main results of these large adjuvant trials are now in, and like the metastatic trials, they disappoint. Whether the anti-VEGF hypothesis was tested in a general population (E5103), a human epidermal growth factor receptor 2 (HER2) –positive population (BETH [Treatment of HER2 Positive Breast Cancer With Chemotherapy Plus Trastuzumab vs Chemotherapy Plus Trastuzumab Plus Bevacizumab]) or in triplenegative breast cancer (BEATRICE [A Study of Avastin (Bevacizumab) Adjuvant Therapy in Triple Negative Breast Cancer]) the results were the same: no statistically significant improvement in disease-free survival was seen. Was this failure a failure of bevacizumab, or of the underlying anti-VEGF hypothesis for breast cancer? This is a reasonable question to ask: we do not always get it right with the first drug to target a malignant process. Sunitinib, a small molecule receptor tyrosine kinase inhibitor of VEGFR2 (and many, many other kinases) struck out in multiple phase III trials in metastatic breast cancer, despite interesting phase II monotherapy results. And now ramucirumab joins the list of failed attempts to use anti-VEGF therapy in metastatic breast cancer. Ramucirumab is a human immunoglobulin G1 monoclonal antibody that binds the extracellular domain of VEGFR-2, as opposed to bevacizumab’s ligand-binding qualities. While there was a numerically increased PFS resulting from the addition of ramucirumab to docetaxel (from 8.2 to 9.5 months), this did not reach statistical significance (P .077), and failed to prolong overall survival (27.3 v 27.3 months). The drug, in addition, added significantly more toxicity, in the form of increased rates of fatigue, hypertension, febrile neutropenia, hand-foot syndrome, and stomatitis. The US Food and Drug Administration approved ramucirumab for use in gastric cancer, where it (albeit modestly) improves both PFS and overall survival. So once again (as with bevacizumab and sunitunib) this seems a breast cancer failure rather than a general failure for the anti-VEGF hypothesis. Since ramucirumab, like bevacizumab and sunitunib, target essentially the same process (VEGF-driven angiogenesis) in the same disease, its failure is perhaps unsurprising. But why has VEGF-based therapy for breast cancer, which began with such promise, failed so completely? In particular, why has the improvement seen in PFS seen with bevacizumab (and at least hinted at with ramucirumab) not translated to an improvement in overall survival in the metastatic setting, or in disease-free survival in the adjuvant setting? JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 2 JANUARY 1

To investigate if breast cancer stage and grade affect fertility preservation outcomes. We performed a retrospective cohort study that included premenopausal women with breast cancer undergoing fertility preservation diagnosed between January 2011 and January 2019. The primary outcome measure was the number of mature oocytes (MII) per antral follicle count (AFC). Secondary outcome measures included total oocytes retrieved, total mature oocytes retrieved, and greater than 10 mature oocytes preserved. Univariate and multivariate models were used to assess the association of low vs. high stage (low stage I-II and high stage III-IV) and grade I vs. grade II/III with each outcome, with adjustment for confounders. A total of 267 premenopausal breast cancer patients undergoing fertility preservation were included in our study, with the majority presenting with low stage (N = 215, 80.5%), grade II/III (N = 235, 88.1%) disease. Baseline AFC, total gonadotropin dose, days of stimulation, and follicles [Formula: see text] 13mm on the day of trigger did not differ by stage or grade. After adjusting for age, BMI, and baseline AFC, we found that the mean MII per AFC did not differ by stage (1.0 vs. 1.1, P = 0.3) or grade (1.0 vs. 1.0, P = 0.92). Similarly, total oocytes retrieved, total MII retrieved, and percentage of patients who were able to preserve greater than 10 MII did not differ by breast cancer stage or grade (all P > 0.2). Breast cancer grade and stage do not impact ovarian stimulation or fertility preservation outcome.

Body mass is inversely related to breast cancer risk among premenopausal women. Leptin, an essential cytokine regulating food intake, energy expenditure, glucose, and fat metabolism may be part of the mechanistic pathway. We investigated 50 tagging and candidate SNPs in the leptin (LEP) and leptin receptor (LEPR) genes for associations with premenopausal breast cancer incidence using 405 cases and 810 controls nested within the Nurses' Health Study II. We also examined associations between these SNPs and circulating leptin (among 910 women) and breast cancer grade (among 267 patients). Permutation tests were performed to adjust for multiple testing. We did not detect a significant association between SNPs in the LEP or LEPR gene and either breast cancer incidence or plasma leptin levels. Among cases, 14 SNPs of the LEPR gene were significantly associated with cancer grade, and rs1137101 (Q223R) survived multiple testing adjustment (adjusted P=0.04). The G carriers of rs1137101 were more likely to have poorly differentiated than well-differentiated cancers. Our data suggest that common genetic variation in the LEP or LEPR gene has no strong association with premenopausal breast cancer risk. The LEPR gene might be associated with breast cancer grade.

Background: Body mass is inversely related to breast cancer risk among premenopausal women. Leptin, an essential cytokine regulating food intake, energy expenditure, glucose and fat metabolism may be part of the mechanistic pathway. Methods: We investigated 50 tagging and candidate SNPs in the leptin (LEP) and leptin receptor (LEPR) genes, for associations with premenopausal breast cancer incidence using 405 cases and 810 controls nested within the Nurses' Health Study II. We also examined associations between these SNPs and circulating leptin (among 910 women) and breast cancer grade (among 267 patients). Permutation tests were performed to adjust for multiple testing. Results: We did not detect a significant association between SNPs in the LEP or LEPR gene and either breast cancer incidence or plasma leptin levels. However, among cases, 14 SNPs of the LEPR gene were significantly associated with cancer grade, and rs1137101 (Q223R) survived multiple testing adjustment (adjusted p=0.04). The G carriers of rs1137101 were more likely to have poorly differentiated than well differentiated cancers. Conclusions: Our data suggest that common genetic variation in the LEP or LEPR gene has no strong association with premenopausal breast cancer risk. The LEPR gene might be associated with breast cancer grade. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A104.

Tumor markers are playing an increasingly important role in cancer detection and management. These laboratory-based tests are potentially useful in screening for early malignancy, aiding cancer diagnosis, determining prognosis, surveillance following curative surgery for cancer, up front predicting drug response or resistance, and monitoring therapy in advanced disease. Clinically useful markers include fecal occult blood testing in screening for early colorectal cancer, carcinoembryonic antigen in the management of patients with colorectal cancer, both α-fetoprotein and human chorionic gonadotrophin in the management of patients with non-seminomatous germ cell tumors, CA 125 for monitoring therapy in patients with ovarian cancer, estrogen receptors for predicting response to hormone therapy in breast cancer, human epidermal growth factor receptor 2 for the identification of women with breast cancer likely to respond to trastuzumab (Herceptin) and KRAS mutational status for identifying patients with advanced colorectal cancer likely to benefit from treatment with the anti-epidermal growth factor receptor antibodies, cetuximab and panitumumab. Although widely used, the value of prostate-specific antigen screening in reducing mortality from prostate cancer is unclear.

Does adjuvant therapy reduce postmetastatic survival?

The past decade has brought enormous advances in the way we manage breast cancer patients with systemic therapies. An explosion in our understanding of the molecular pathogenesis of breast cancer, a harnessing of powerful new diagnostic technologies, and the culmination of a series of pivotal randomized trials of cytotoxic and novel targeted therapies have yielded significant improvements in outcomes for patients with both early and advanced disease. A series of review articles published in Breast Cancer Research written by leading clinical researchers explores these advances in different areas of breast cancer management. Miles [1] discusses new advances in the management of metastatic breast cancer focusing particularly on human epidermal growth factor receptor (HER)-negative disease. His review addresses pivotal trials of cytotoxic therapy and highlights optimal management in 2009. In addition, it focuses on the role played by targeted agents, and particularly anti-angiogenic agents, highlighting new data with agents such as bevacizumab. New approaches to the management of 'triple negative' breast cancer are also discussed. Advances in the management of patients with HER2-positive metastatic breast cancer are reviewed by Esteva and colleagues [2]. Optimal use of currently available targeted agents such as trastuzumab and lapatanib are discussed, including the use of both in clinical scenarios such as relapse after adjuvant trastuzumab or progression following first-line use of trastuzumab in the metastatic setting. The potential role of newer agents targeting the HER family are also highlighted, as is the case for the use of combined targeted agents. Key issues in the use of adjuvant systemic therapy for early breast cancer are reviewed by Martin and Lopez-Tarruella [3]. Current 'gold standard' options for the use of adjuvant chemotherapy are discussed within the setting of node-positive and node-negative disease. Issues such as which patients should receive taxane-based chemotherapy and the optimal schedule for such regimens are covered. Clinical trials of novel targeted therapies are also discussed. The increasing use of neoadjuvant systemic therapy is highlighted by Untch and von Minckwitz [4]. Pivotal trials in this area are reviewed, and the use of clinical and biological surrogate markers of long-term outcome is discussed. Finally, Di Leo and colleagues [5] discuss the evidence base behind some of the new molecular prognostic and predictive profile technologies. They review the concept of using biomarkers to predict outcome and the place of tests such as Oncotype DX (Genomic Health, Redwood, CA, USA) and MammaPrint (Agendia, Huntington Beach, CA, USA). What do they add over existing expertise and in which areas should they be used in everyday practice, if at all? They also discuss ongoing clinical trials using these technologies, such as the TAILORx (Trial for Assigning IndividuaLized Options for Treatment) and MINDACT (Microarray In Node-negative Disease may Avoid ChemoTherapy) trials. In summary these reviews provide a snapshot of current state-of-the-art medical practice in the use of systemic cytotoxic and targeted therapy for breast cancer management. If the past decade has helped to crystallize incremental gains in outcome for patients with early and metastatic disease, this decade promises further advance by using the molecular advances described above to help identify which groups of patients may gain from particular types of therapy.