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1.  Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 
Annals of Oncology  2013;24(9):2206-2223.
The 13th St Gallen International Breast Cancer Conference (2013) Expert Panel reviewed and endorsed substantial new evidence on aspects of the local and regional therapies for early breast cancer, supporting less extensive surgery to the axilla and shorter durations of radiation therapy. It refined its earlier approach to the classification and management of luminal disease in the absence of amplification or overexpression of the Human Epidermal growth factor Receptor 2 (HER2) oncogene, while retaining essentially unchanged recommendations for the systemic adjuvant therapy of HER2-positive and ‘triple-negative’ disease. The Panel again accepted that conventional clinico-pathological factors provided a surrogate subtype classification, while noting that in those areas of the world where multi-gene molecular assays are readily available many clinicians prefer to base chemotherapy decisions for patients with luminal disease on these genomic results rather than the surrogate subtype definitions. Several multi-gene molecular assays were recognized as providing accurate and reproducible prognostic information, and in some cases prediction of response to chemotherapy. Cost and availability preclude their application in many environments at the present time. Broad treatment recommendations are presented. Such recommendations do not imply that each Panel member agrees: indeed, among more than 100 questions, only one (trastuzumab duration) commanded 100% agreement. The various recommendations in fact carried differing degrees of support, as reflected in the nuanced wording of the text below and in the votes recorded in supplementary Appendix S1, available at Annals of Oncology online. Detailed decisions on treatment will as always involve clinical consideration of disease extent, host factors, patient preferences and social and economic constraints.
doi:10.1093/annonc/mdt303
PMCID: PMC3755334  PMID: 23917950
surgery; radiation therapy; systemic adjuvant therapies; early breast cancer; St Gallen Consensus; subtypes
2.  Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer 
The New England journal of medicine  2014;371(2):107-118.
BACKGROUND
Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor–positive breast cancer.
METHODS
In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor–positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials.
RESULTS
After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane–ovarian suppression group and 87.3% in the tamoxifen–ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane–ovarian suppression group, as compared with 88.8% in the tamoxifen–ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane–ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P = 0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane–ovarian suppression group and 29.4% of those in the tamoxifen–ovarian suppression group, with profiles similar to those for postmenopausal women.
CONCLUSIONS
In premenopausal women with hormone-receptor–positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.)
doi:10.1056/NEJMoa1404037
PMCID: PMC4175521  PMID: 24881463
3.  Symptoms of endocrine treatment and outcome in the BIG 1–98 study 
Background
There may be a relationship between the incidence of vasomotor and arthralgia/myalgia symptoms and treatment outcomes for postmenopausal breast cancer patients with endocrine-responsive disease who received adjuvant letrozole or tamoxifen.
Patients and methods
Data on patients randomized into the monotherapy arms of the BIG 1–98 clinical trial who did not have either vasomotor or arthralgia/myalgia/carpal tunnel (AMC) symptoms reported at baseline, started protocol treatment and were alive and disease-free at the 3-month landmark (n=4798) and at the 12-month landmark (n=4682) were used for this report. Cohorts of patients with vasomotor symptoms, AMC symptoms, neither, or both were defined at both 3 and 12 months from randomization. Landmark analyses were performed using Kaplan-Meier method for disease-free survival (DFS) and competing risk methodology for breast cancer free interval (BCFI). Median follow-up was 7.0 years.
Results
Reporting of AMC symptoms was associated with better outcome for both the 3- and 12-month landmark analyses (e.g. 12-month landmark, HR (95% CI) for DFS=0.65 (0.49–0.87), and for BCFI=0.70 (0.49–0.99)). By contrast, reporting of vasomotor symptoms was less clearly associated with DFS (12-month DFS HR (95% CI)=0.82 (0.70–0.96)) and BCFI (12-month DFS HR (95% CI)=0.97 (0.80–1.18). Interaction tests indicated no effect of treatment group on associations between symptoms and outcomes.
Conclusions
While reporting of AMC symptoms was clearly associated with better DFS and BCFI, the association between vasomotor symptoms and outcome was less clear, especially with respect to breast cancer-related events.
doi:10.1007/s10549-013-2792-7
PMCID: PMC3913479  PMID: 24305979
aromatase inhibitor; side effects; breast cancer; endocrine therapy
4.  The AURORA initiative for metastatic breast cancer 
British Journal of Cancer  2014;111(10):1881-1887.
Metastatic breast cancer is one of the leading causes of cancer-related mortality among women in the Western world. To date most research efforts have focused on the molecular analysis of the primary tumour to dissect the genotypes of the disease. However, accumulating evidence supports a molecular evolution of breast cancer during its life cycle, with metastatic lesions acquiring new molecular aberrations. Recognising this critical gap of knowledge, the Breast International Group is launching AURORA, a large, multinational, collaborative metastatic breast cancer molecular screening programme. Approximately 1300 patients with metastatic breast cancer who have received no more than one line of systemic treatment for advanced disease will, after giving informed consent, donate archived primary tumour tissue, as well as will donate tissue collected prospectively from the biopsy of metastatic lesions and blood. Both tumour tissue types, together with a blood sample, will then be subjected to next generation sequencing for a panel of cancer-related genes. The patients will be treated at the discretion of their treating physicians per standard local practice, and they will be followed for clinical outcome for 10 years. Alternatively, depending on the molecular profiles found, patients will be directed to innovative clinical trials assessing molecularly targeted agents. Samples of outlier patients considered as ‘exceptional responders' or as ‘rapid progressors' based on the clinical follow-up will be subjected to deeper molecular characterisation in order to identify new prognostic and predictive biomarkers. AURORA, through its innovative design, will shed light onto some of the unknown areas of metastatic breast cancer, helping to improve the clinical outcome of breast cancer patients.
doi:10.1038/bjc.2014.341
PMCID: PMC4229627  PMID: 25225904
breast cancer; metastatic; molecular profiling; targeted clinical trials; next generation sequencing
6.  Patterns of Recurrence and Outcome According to Breast Cancer Subtypes in Lymph Node–Negative Disease: Results From International Breast Cancer Study Group Trials VIII and IX 
Journal of Clinical Oncology  2013;31(25):3083-3090.
Purpose
To retrospectively evaluate the pattern of recurrence and outcome of node-negative breast cancer (BC) according to major subtypes.
Patients and Methods
In all, 1,951 patients with node-negative, early-stage BC randomly assigned in International Breast Cancer Study Group Trials VIII and IX with centrally reviewed pathology data were included. BC subtypes were defined as triple negative (TN; n = 310), human epidermal growth factor receptor 2 (HER2) positive (n = 369), and hormone receptor positive with high (luminal B–like [LB-like]; n = 763) or low (luminal A–like [LA-like]; n = 509) proliferative activity by Ki-67 labeling index. BC-free interval (BCFI) events were invasive BC recurrence in local, contralateral breast, nodal, bone, or visceral sites. Time to first site–specific recurrence was evaluated by using cumulative incidence and competing risks regression analysis.
Results
Median follow-up was 12.5 years. The 10-year BCFI was higher for patients with LA-like (86%) BC compared with LB-like (76%), HER2 (73%), and TN (71%; P < .001) BC. TN and HER2 cohorts had higher hazard of BCFI event in the first 4 years after diagnosis (pre-trastuzumab). LB-like cohorts had a continuously higher hazard of BCFI event over time compared with LA-like cohorts. Ten-year overall survival was higher for LA-like (89%) compared with LB-like (83%), HER2 (77%), and TN (75%; P < .001) BC. LB-like subtypes had higher rates of bone as first recurrence site than other subtypes (P = .005). Visceral recurrence as first site was lower for the LA-like subgroup, with similar incidence among the other subgroups when treated with chemotherapy (P = .003).
Conclusion
BC subtypes have different distant recurrence patterns over time. Defining different patterns of BC recurrence can improve BC care through surveillance guidelines and can guide the design of clinical studies.
doi:10.1200/JCO.2012.46.1574
PMCID: PMC3753700  PMID: 23897954
7.  Immune approaches to the treatment of breast cancer, around the corner? 
Immunotherapy for the treatment of breast cancer can be categorized as either (a) specific stimulation of the immune system by active immunization, with cancer vaccines, or (b) passive immunization, such as tumor-specific antibodies (including immune modulators) or adoptive cell therapy that inhibit the function of, or directly kill, tumor cells. We will present the current information and the future perspectives of immunotherapy in patients with breast cancer, including the prognostic role of tumor infiltrating lymphocytes, immune signatures, targeted therapies modulating the immune system, and tumor antigen cancer vaccines. Active immunotherapy in breast cancer and its implementation into clinical trials have been largely a frustrating experience in the last decades. The concept that the immune system regulates cancer development is experiencing a new era of interest. It is clear that the cancer immunosurveillance process indeed exists and potentially acts as an extrinsic tumor suppressor. Also, the immune system can facilitate tumor progression by sculpting the immunogenic phenotype of tumors as they develop. Cancer immunoediting represents a refinement of the cancer immunosurveillance hypothesis and resumes the complex interaction between tumor and immune system into three phases: elimination, equilibrium, and escape. Major topics in the field of immunology deserve a response: what do we know about tumor immunogenicity, and how might we therapeutically improve tumor immunogenicity? How can we modulate response of the immune system? Is there any gene signature predictive of response to immune modulators? The success of future immunotherapy strategies will depend on the identification of additional immunogenic antigens that can serve as the best tumor-rejection targets. Therapeutic success will depend on developing the best antigen delivery systems and on the elucidation of the entire network of immune signaling pathways that regulate immune responses in the tumor microenvironment.
doi:10.1186/bcr3620
PMCID: PMC3978442
8.  Proposed new clinicopathological surrogate definitions of luminal A and luminal B (HER2-negative) intrinsic breast cancer subtypes 
Introduction
The St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 recognized substantial progress in the pathological characterization of breast cancer subtypes. A useful surrogate definition was developed to distinguish luminal A–like breast cancer from luminal B–like disease based on a combination of estrogen receptor (ER), progesterone receptor (PgR) and Ki-67 status, without a requirement for molecular diagnostics. Differences depend upon the choice of the threshold value for Ki-67 and the requirement for substantial PgR positivity. We aimed to verify the suitability of the new surrogate definitions of luminal subtypes in terms of distant disease control in a large series of patients.
Methods
We studied 9,415 women with a median follow-up of 8.1 years who (1) had ER-positive, human epidermal growth factor receptor 2 (HER2)–negative early breast cancer and (2) had undergone surgery at the European Institute of Oncology between 1994 and 2006. We evaluated distant disease-free survival of patients with “low” (<14%), “intermediate” (14% to 19%) or “high” (≥20%) Ki-67 positivity stratified by PgR expression (negative or low versus high). We calculated the cumulative incidence of distant events, considered competing events and performed multivariable analysis adjusted for pathologic tumor stage, pathologic node stage, tumor grade, peritumoral vascular invasion and menopausal status.
Results
Lack of substantial PgR positivity was associated with poorer outcomes only for patients with an intermediate Ki-67 level (P < 0.001). The 4,890 patients (51.9%) with low Ki-67 level (any PgR expression level) or with intermediate Ki-67 level but substantial PgR positivity had comparably good outcomes and thus may represent a most advantageous grouping of those with luminal A–like disease.
Conclusions
The updated pathological definition of intrinsic molecular subtypes may maximize the number of patients classified as having the luminal A–like intrinsic subtype of breast cancer and for whom the use of cytotoxic drugs could mostly be avoided.
doi:10.1186/bcr3679
PMCID: PMC4095689  PMID: 24951027
9.  Adjuvant pegylated liposomal doxorubicin for older women with endocrine nonresponsive breast cancer who are NOT suitable for a “standard chemotherapy regimen”: the CASA randomized trial 
Breast (Edinburgh, Scotland)  2013;22(2):130-137.
Summary
There is no optimal treatment for breast cancers lacking estrogen (ER) and progesterone (PgR) receptors in elderly women with co-morbidities that prevent use of “standard chemotherapy regimens” such as AC or CMF. The CASA trial studied pegylated liposomal doxorubicin (PLD) and low dose, metronomic cyclophosphamide+ methotrexate (CM) for older (>65), vulnerable women with operable, ER and PgR-negative breast cancer. After two years the trial closed early, due to slow and inadequate accrual, with 77 patients (38:PLD, 36:CM, 3:nil). Sixty-eight percent completed PLD; 83% completed CM (both 16-weeks). Patients on PLD reported worse quality of life, cognitive and physical functioning than non-PLD regimens (primarily CM). At a median follow-up of 42 months, 78% of randomized patients remained free of any breast cancer recurrence. Based on our limited experience, PLD and CM may be reasonable options for further study for elderly vulnerable patients with endocrine non-responsive breast cancer.
doi:10.1016/j.breast.2013.01.015
PMCID: PMC3613787  PMID: 23453899
adjuvant treatment; endocrine non-responsive; chemotherapy; pegylated liposomal doxorubicin; elderly; breast cancer
10.  Biopsy confirmation of metastatic sites in breast cancer patients: clinical impact and future perspectives 
Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome, and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations, the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future, advances in targeted therapy will depend on the availability of metastatic tissue.
doi:10.1186/bcr3630
PMCID: PMC4052940  PMID: 25032257
11.  Immune Checkpoint Blockade in Cancer Treatment: A Double-Edged Sword Cross-Targeting the Host as an “Innocent Bystander” 
Toxins  2014;6(3):914-933.
Targeted immune checkpoint blockade augments anti-tumor immunity and induces durable responses in patients with melanoma and other solid tumors. It also induces specific “immune-related adverse events” (irAEs). IrAEs mainly include gastrointestinal, dermatological, hepatic and endocrinological toxicities. Off-target effects that arise appear to account for much of the toxicity of the immune checkpoint blockade. These unique “innocent bystander” effects are likely a direct result of breaking immune tolerance upon immune check point blockade and require specific treatment guidelines that include symptomatic therapies or systemic corticosteroids. What do we need going forward to limit immune checkpoint blockade-induced toxicity? Most importantly, we need a better understanding of the roles played by these agents in normal tissues, so that we can begin to predict potentially problematic side effects on the basis of their selectivity profile. Second, we need to focus on the predictive factors of the response and toxicity of the host rather than serially focusing on individual agents. Third, rigorous biomarker-driven clinical trials are needed to further elucidate the mechanisms of both the benefit and toxicity. We will summarize the double-edged sword effect of immunotherapeutics in cancer treatment.
doi:10.3390/toxins6030914
PMCID: PMC3968368  PMID: 24594636
checkpoint-blocking antibodies; immune response; toxicity; immune therapies; ipilimumab
12.  IBCSG 23-01 randomised controlled trial comparing axillary dissection versus no axillary dissection in patients with sentinel node micrometastases 
The lancet oncology  2013;14(4):297-305.
Background
For breast cancer patients with a metastatic sentinel node (SN), axillary dissection (AD) has been standard treatment. However, for patients with minimal SN involvement, AD may be overtreatment. IBCSG Trial 23-01 was designed to determine whether no AD is non-inferior to AD in patients with one or more micrometastatic (≤2 mm) SNs and tumour ≤5 cm.
Methods
In this multicentre trial patients were randomised to AD or no AD. Eligibility was limited to patients with clinically-palpable axillary lymph node(s) and a primary tumour ≤ 5 cm who, after sentinel node biopsy, had one or more micrometastatic (≤ 2 mm) sentinel lymphs nodes with no extracapsular extension. The primary endpoint was disease-free survival (DFS). Non-inferiority was defined as a hazard ratio of <1·25 for no AD vs. AD. The analysis was intention to treat. Patients were randomly allocated in a 1:1 ratio to AD or no AD with stratification by centre and menopausal status. There was no attempt to blind the treatment assignment. The trial is registered with ClinicalTrials.gov, NCT00072293. Per protocol, disease and survival information continues to be collected yearly.
Findings
From 2001 to 2010, 934 patients were randomised; 931 were evaluable (464 in the AD group and 467 in the no AD group). After a median follow-up of 5·0 (IQR 3.6–7.3) years, there were 124 DFS events, including breast-cancer-related events in 95 patients (local, 18; contralateral breast, 12; regional, 6; and distant, 59), and other events in 29 (second malignancy, 26; death without prior cancer event, 3). Five-year DFS was 87·8% (95% CI 84·4%–91·2%) in the no AD group and 84·4% (95% CI 80·7%–88·1%) in the AD group (log-rank p=0·16) (HR no AD vs. AD=0·78, 95% CI 0·55–1·11, non-inferiority p=0·0042). Patients with reported long-term surgical events (grade 3–4) included 1 sensory neuropathy (grade 3), 3 lymphedema (2 grade 3 and 1 grade 4), and 3 motor neuropathy (grade 3), all in the AD group, and 1 grade 3 motor neuropathy in the no AD group. One serious adverse event was reported, a post-operative infection in the axilla in the AD group.
Interpretation
AD in patients with early breast cancer represented in this study (most had tumours < 3 cm (92%; 856/931), received breast conserving surgery (91%; 845/931) and adjuvant systemic therapy (96%; 892/931)) should be avoided when the SN is minimally involved, thus eliminating complications of axillary surgery with no adverse effect on survival.
Funding
Supported in part: local participating centres, IBCSG central funds, CA075362 from the U.S. National Cancer Institute, and Swiss Cancer League/Cancer Research- Switzerland/Oncosuisse (ICPOCS 01688-03-2005). No pharmaceutical company funds were used.
doi:10.1016/S1470-2045(13)70035-4
PMCID: PMC3935346  PMID: 23491275
breast cancer; sentinel node; axillary node; micrometastasis; sentinel node biopsy; axillary dissection; lymph node
13.  Prognostic Impact of Pregnancy After Breast Cancer According to Estrogen Receptor Status: A Multicenter Retrospective Study 
Journal of Clinical Oncology  2012;31(1):73-79.
Purpose
We questioned the impact of pregnancy on disease-free survival (DFS) in women with history of breast cancer (BC) according to estrogen receptor (ER) status.
Patients and Methods
A multicenter, retrospective cohort study in which patients who became pregnant any time after BC were matched (1:3) to patients with BC with similar ER, nodal status, adjuvant therapy, age, and year of diagnosis. To adjust for guaranteed time bias, each nonpregnant patient had to have a disease-free interval at least equal to the time elapsing between BC diagnosis and date of conception of the matched pregnant one. The primary objective was DFS in patients with ER-positive BC. DFS in the ER-negative cohort, whole population, and overall survival (OS) were secondary objectives. Subgroup analyses included DFS according to pregnancy outcome and BC–pregnancy interval. With a two-sided α = 5% and β = 20%, 645 ER-positive patients were required to detect a hazard ratio (HR) = 0.65.
Results
A total of 333 pregnant patients and 874 matched nonpregnant patients were analyzed, of whom 686 patients had an ER-positive disease. No difference in DFS was observed between pregnant and nonpregnant patients in the ER-positive (HR = 0.91; 95% CI, 0.67 to 1.24, P = .55) or the ER-negative (HR = 0.75; 95% CI, 0.51 to 1.08, P = .12) cohorts. However, the pregnant group had better OS (HR = 0.72; 95% CI, 0.54 to 0.97, P = .03), with no interaction according to ER status (P = .11). Pregnancy outcome and BC–pregnancy interval did not seem to impact the risk of relapse.
Conclusion
Pregnancy after ER-positive BC does not seem to reduce the risk of BC recurrence.
doi:10.1200/JCO.2012.44.2285
PMCID: PMC3530692  PMID: 23169515
14.  Obesity and Risk of Recurrence or Death After Adjuvant Endocrine Therapy With Letrozole or Tamoxifen in the Breast International Group 1-98 Trial 
Journal of Clinical Oncology  2012;30(32):3967-3975.
Purpose
To examine the association of baseline body mass index (BMI) with the risk of recurrence or death in postmenopausal women with early-stage breast cancer receiving adjuvant tamoxifen or letrozole in the Breast International Group (BIG) 1-98 trial at 8.7 years of median follow-up.
Patients and Methods
This report analyzes 4,760 patients with breast cancer randomly assigned to 5 years of monotherapy with letrozole or tamoxifen in the BIG 1-98 trial with available information on BMI at randomization. Multivariable Cox modeling assessed the association of BMI with disease-free survival, overall survival (OS), breast cancer–free interval, and distant recurrence-free interval and tested for treatment-by-BMI interaction. Median follow-up was 8.7 years.
Results
Seventeen percent of patients have died. Obese patients (BMI ≥ 30 kg/m2) had slightly poorer OS (hazard ratio [HR] = 1.19; 95% CI, 0.99 to 1.44) than patients with normal BMI (< 25 kg/m2), whereas no trend in OS was observed in overweight (BMI 25 to < 30 kg/m2) versus normal-weight patients (HR = 1.02; 95% CI, 0.86 to 1.20). Treatment-by-BMI interactions were not statistically significant. The HRs for OS comparing obese versus normal BMI were HR = 1.22 (95% CI, 0.93 to 1.60) and HR = 1.18 (95% CI, 0.91 to 1.52) in the letrozole and tamoxifen groups, respectively.
Conclusion
There was no evidence that the benefit of letrozole over tamoxifen differed according to patients' BMI.
doi:10.1200/JCO.2011.40.8666
PMCID: PMC3488270  PMID: 23045588
15.  Prognosis of medullary breast cancer: analysis of 13 International Breast Cancer Study Group (IBCSG) trials 
Annals of Oncology  2012;23(11):2843-2851.
Background
To evaluate whether medullary breast cancer has a better prognosis compared with invasive ductal tumors.
Methods
Among 12 409 patients, 127 were recorded as invasive medullary tumors and 8096 invasive ductal tumors. Medullary and ductal invasive tumors were compared with regard to stage, age at diagnosis, grade, hormone receptor status, peritumoral vascular invasion, and local and systemic treatment. Pattern of relapse, distant recurrence-free interval (DRFI), and overall survival (OS) were determined for both histological groups. Two cohorts were investigated: a full cohort including the pathologist-determined medullary histology without regard to any other tumor features and a cohort restricted to patients with ER-negative grade 3 tumors.
Results
Fourteen-year DRFI and OS percents for medullary tumors (n = 127) and invasive ductal tumors (n = 8096) of the full cohort were 76% and 64% [hazard ratio (HR) 0.52, P = 0.0005] and 66% and 57% (HR = 0.75, P = 0.03), respectively. For the restricted cohort, 14-year DRFI and OS percents for the medullary (n = 47) and invasive ductal tumors (n = 1407) were 89% and 63% (HR 0.24, P = 0.002) and 74% and 54% (HR = 0.55, P = 0.01), respectively. Competing risk analysis for DRFI favored medullary tumors (HR medullary/ductal = 0.32; 95% confidence interval = 0.13–0.78, P = 0.01).
Conclusion
Medullary tumors have a favorable prognosis compared with invasive ductal tumors.
doi:10.1093/annonc/mds105
PMCID: PMC3477879  PMID: 22707751
breast cancer; histology; invasive ductal; medullary; prognosis
16.  Patterns and risk factors for locoregional failures after mastectomy for breast cancer: an International Breast Cancer Study Group report 
Annals of Oncology  2012;23(11):2852-2858.
Background
Rates and risk factors of local, axillary and supraclavicular recurrences can guide patient selection and target for postmastectomy radiotherapy (PMRT).
Patients and methods
Local, axillary and supraclavicular recurrences were evaluated in 8106 patients enrolled in 13 randomized trials. Patients received chemotherapy and/or endocrine therapy and mastectomy without radiotherapy. Median follow-up was 15.2 years.
Results
Ten-year cumulative incidence for chest wall recurrence of >15% was seen in patients aged <40 years (16.1%), with ≥4 positive nodes (16.5%) or 0–7 uninvolved nodes (15.1%); for supraclavicular failures >10%: ≥4 positive nodes (10.2%); for axillary failures of >5%: aged <40 years (5.1%), unknown primary tumor size (5.2%), 0–7 uninvolved nodes (5.2%). In patients with 1–3 positive nodes, 10-year cumulative incidence for chest wall recurrence of >15% were age <40, peritumoral vessel invasion or 0–7 uninvolved nodes. Age, number of positive nodes and number of uninvolved nodes were significant parameters for each locoregional relapse site.
Conclusion
PMRT to the chest wall and supraclavicular fossa is supported in patients with ≥4 positive nodes. With 1–3 positive nodes, chest wall PMRT may be considered in patients aged <40 years, with 0–7 uninvolved nodes or with vascular invasion. The findings do not support PMRT to the dissected axilla.
doi:10.1093/annonc/mds118
PMCID: PMC3477880  PMID: 22776708
adjuvant treatment; breast cancer; locoregional recurrence; postmastectomy radiotherapy
18.  A Risk Score based on histopathological features predicts higher risk of distant recurrence in premenopausal patients with lymph node-negative endocrine-responsive breast cancer 
Breast (Edinburgh, Scotland)  2012;21(5):621-628.
SUMMARY
Purpose
To develop a Risk Score (RS) to predict distant recurrence among premenopausal women with node-negative endocrine-responsive early breast cancer.
Methods
The Cox model was used to develop the RS using clinical and histopathological features from 378 women participating in the IBCSG Trial VIII who received endocrine therapy alone or following chemotherapy. The performance of the resulting model was validated on a cohort of 1005 patients from a single institution who received endocrine therapy alone.
Results
In a multivariable analysis, the risk of distant recurrence was associated with tumor size, ER, Ki-67 and peritumoral vascular invasion. In the validation cohort, patients with high RS were at greater risk of distant recurrence compared to patients with low RS (HR, 17.41 ; 95% CI, 5.72 to 52.95).
Conclusion
In premenopausal women with node-negative endocrine-responsive early breast cancer, the RS identifies patients at higher risk of distant recurrence.
doi:10.1016/j.breast.2012.06.003
PMCID: PMC3566763  PMID: 22749924
breast cancer; histopathological features; risk score; endocrine therapy; chemotherapy
19.  Tumour dormancy and clinical implications in breast cancer 
ecancermedicalscience  2013;7:320.
The aim of adjuvant therapy in breast cancer is to reduce the risk of recurrence. Some patients develop metastases many years after apparently successful treatment of their primary cancer. Tumour dormancy may explain the long time between initial diagnosis and treatment of cancer, and occurrence of relapse. The regulation of the switch from clinical dormancy to cancer regrowth in locoregional and distant sites is poorly understood. In this review, we report some data supporting the existence of various factors that may explain cancer dormancy including genetic and epigenetic changes, angiogenic switch, microenvironment, and immunosurveillance. A better definition and understanding of these factors should allow the identification of patients at high risk of relapse and to develop new therapeutic strategies in order to improve prognosis.
doi:10.3332/ecancer.2013.320
PMCID: PMC3660156  PMID: 23717341
tumor dormancy; breast cancers; angiogenesis; microenvironment; immune surveillance
20.  CYP2D6 Genotype and Tamoxifen Response in Postmenopausal Women with Endocrine-Responsive Breast Cancer: The Breast International Group 1-98 Trial 
Background
Adjuvant tamoxifen therapy is effective for postmenopausal women with endocrine-responsive breast cancer. Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes tamoxifen to clinically active metabolites, and CYP2D6 polymorphisms may adversely affect tamoxifen efficacy. In this study, we investigated the clinical relevance of CYP2D6 polymorphisms.
Methods
We obtained tumor tissues and isolated DNA from 4861 of 8010 postmenopausal women with hormone receptor–positive breast cancer who enrolled in the randomized, phase III double-blind Breast International Group (BIG) 1-98 trial between March 1998 and May 2003 and received tamoxifen and/or letrozole treatment. Extracted DNA was used for genotyping nine CYP2D6 single-nucleotide polymorphisms using polymerase chain reaction–based methods. Genotype combinations were used to categorize CYP2D6 metabolism phenotypes as poor, intermediate, and extensive metabolizers (PM, IM, and EM, respectively; n = 4393 patients). Associations of CYP2D6 metabolism phenotypes with breast cancer-free interval (referred to as recurrence) and treatment-induced hot flushes according to randomized endocrine treatment and previous chemotherapy were assessed. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.
Results
No association between CYP2D6 metabolism phenotypes and breast cancer-free interval was observed among patients who received tamoxifen monotherapy without previous chemotherapy (P = .35). PM or IM phenotype had a non-statistically significantly reduced risk of breast cancer recurrence compared with EM phenotype (PM or IM vs EM, HR of recurrence = 0.86, 95% CI = 0.60 to 1.24). CYP2D6 metabolism phenotype was associated with tamoxifen-induced hot flushes (P = .020). Both PM and IM phenotypes had an increased risk of tamoxifen-induced hot flushes compared with EM phenotype (PM vs EM, HR of hot flushes = 1.24, 95% CI = 0.96 to 1.59; IM vs EM, HR of hot flushes = 1.23, 95% CI = 1.05 to 1.43).
Conclusions
CYP2D6 phenotypes of reduced enzyme activity were not associated with worse disease control but were associated with increased hot flushes, contrary to the hypothesis. The results of this study do not support using the presence or absence of hot flushes or the pharmacogenetic testing of CYP2D6 to determine whether to treat postmenopausal breast cancer patients with tamoxifen.
doi:10.1093/jnci/djs125
PMCID: PMC3309132  PMID: 22395644
21.  Bone Quality Test (BQT) scores of fingernails in postmenopausal patients treated with adjuvant letrozole or tamoxifen for early breast cancer 
Breast (Edinburgh, Scotland)  2009;18(2):84-88.
SUMMARY
Background
The relationship between nail and bone may be measurable, thus making the fingernail a potentially valuable tool for assessing bone health for women receiving treatment for breast cancer. In the BIG 1-98 Fingernail Pilot Substudy, Bone Quality Test (BQT) scores of fingernails were measured at two assessment timepoints.
Methods
Thirteen eligible patients were enrolled into the substudy during their treatment with tamoxifen (4 patients) or letrozole (9 patients). Two fingernails were tested and BQT scores averaged for two assessments six months apart.
Results
BQT scores collected six months later (second assessment) significantly decreased compared with those at first collection (p =0.007) regardless of treatment and prior fracture.
Conclusion
The reduction of BQT scores observed in the patients of our small exploratory study during exposure to bone-altering breast cancer treatments is an incentive for larger studies using this technique.
doi:10.1016/j.breast.2009.01.003
PMCID: PMC3588857  PMID: 19243946
fingernail; bone quality test; breast cancer; hormonal therapy; letrozole
22.  Adjuvant!© Online estimation of chemotherapy effectiveness when added to ovarian function suppression plus tamoxifen for premenopausal women with estrogen-receptor-positive breast cancer 
Purpose
Adjuvant! © Online (Adjuvant!) is a user-friendly, web-based tool that provides estimates of adjuvant therapy outcomes for individual patients. While reliable evidence underpins estimates for most patient cohorts, there is a paucity of data on the effect of adding chemotherapy to complete estrogen blockade for premenopausal women with estrogen-receptor positive breast cancer.
Methods
International Breast Cancer Study Group (IBCSG) Trial 11-93 enrolled 174 premenopausal women with estrogen-receptor positive, node-positive breast cancer. Fifty-five percent of patients had 1 positive axillary lymph node and 97% had 3 or fewer positive nodes. Patients were randomized to receive ovarian function suppression plus five years of tamoxifen with or without anthracycline-based chemotherapy. Estimated hazard rates and corresponding 10-year relapse-free survival percents obtained from Trial 11-93 data were compared with those predicted using Adjuvant!.
Results
The 10-year relapse-free survival percents predicted from Adjuvant! were 64.4% (95% CI, 61.9% to 67.2%) for endocrine therapy alone and 74.9% (95% CI, 73.1% to 76.8%) for chemoendocrine therapy. By contrast, these estimates in Trial 11-93 were 76.4% (95% CI, 65.8% to 84.0%) for endocrine therapy alone and 74.9% (95% CI, 64.5% to 82.7%) for chemoendocrine therapy. The Adjuvant! estimate for the endocrine alone control group is lower than that observed in Trial 11-93 (p=0.03), while the estimates for the two chemoendocrine therapy groups are similar.
Conclusions
Adjuvant! appears to underestimate the effectiveness of adjuvant endocrine therapy alone for premenopausal women with endocrine responsive breast cancer, thus overestimating the added benefit, if any, from chemotherapy for this patient population.
doi:10.1007/s10549-010-0794-2
PMCID: PMC3588884  PMID: 20195744
Adjuvant! © Online; Estrogen Receptor; Premenopausal; Chemotherapy; Endocrine Therapy; International Breast Cancer Study Group
23.  Prognostic and predictive impact of central necrosis and fibrosis in early breast cancer. Results from two International Breast Cancer Study Group randomized trials of chemoendocrine adjuvant therapy 
Purpose
A minority of early invasive breast cancers show a pattern of central necrosis and fibrosis (CNF). Previous studies have documented an adverse prognostic impact and association with other adverse pathological features, but its predictive importance for therapy selection is unknown.
Methods
We examined the prognostic and predictive value of CNF in two randomized clinical trials comparing chemoendocrine therapy with endocrine therapy alone in patients with node-negative breast cancer. A total of 1850 patients randomly assigned to treatment groups comparing endocrine with chemoendocrine therapy, and with centrally-assessed CNF, ER, PgR and HER2 were included in the analytic cohort. The median follow up was 10 years.
Results
CNF was present in 84 of 1850 trial patients (4.5%). It was associated with tumor characteristics suggesting poor outcome, but was an independent adverse factor for disease-free survival. In the presence of CNF outcome was worse regardless of tumor grade, whereas in the absence of CNF, patients with grade 3 tumors had poorer outcome than those with grade 1-2 tumors. Among patients with estrogen receptor-absent tumors chemoendocrine therapy was superior to endocrine therapy alone only in the absence of CNF [HR (chemoendocrine:endocrine)=0.46 in CNF-absent, 0.90 in CNF-present], while among those with receptor-positive disease chemoendocrine therapy was beneficial only in the presence of CNF [HR=0.34 CNF-present, 0.96 CNF-absent].
Conclusion
The results suggest that the presence of CNF reflects a biological difference in early breast cancer that is important in modulating the efficacy of standard therapies. Accordingly we believe that its presence should be routinely reported.
doi:10.1007/s10549-009-0360-y
PMCID: PMC3588888  PMID: 19280340
central necrosis; fibrosis; chemotherapy; endocrine therapy; breast cancer
24.  Patterns of recurrence of early breast cancer according to estrogen receptor status: a therapeutic target for a quarter of a century 
Background
The current therapeutic strategy in breast cancer is to identify a target, such as estrogen receptor (ER) status, for tailoring treatments.
Methods
We investigated the patterns of recurrence with respect to ER status for patients treated in two randomized trials with 25 years' median follow-up.
Results
In the ER-negative subpopulations most breast cancer events occurred within the first 5–7 years after randomization, while in the ER-positive subpopulations breast cancer events were spread through 10 years. In the ER-positive subpopulation, 1 year endocrine treatment alone significantly prolonged disease-free survival (DFS) with no additional benefit observed by adding one year of chemotherapy. In the small ER-negative subpopulation chemo-endocrine therapy had a significantly better DFS than endocrine alone or no treatment.
Conclusions
Despite small numbers of patients, “old-fashioned” treatments, and competing causes of treatment failure, the value of ER status as a target for response to adjuvant treatment is evident through prolonged follow-up.
doi:10.1007/s10549-008-0282-0
PMCID: PMC3589101  PMID: 19137426
breast cancer; chemotherapy; estrogen receptor; hormonal therapy
25.  Is adjuvant chemotherapy of benefit for postmenopausal women who receive endocrine treatment for highly endocrine-responsive, node-positive breast cancer? International Breast Cancer Study Group Trials VII and 12-93 
Purpose
To compare the efficacy of chemoendocrine treatment with that of endocrine treatment (ET) alone for postmenopausal women with highly endocrine responsive breast cancer.
Patients and methods
In the International Breast Cancer Study Group (IBCSG) Trials VII and 12-93, postmenopausal women with node-positive, estrogen receptor (ER)-positive or ER-negative, operable breast cancer were randomized to receive either chemotherapy or endocrine therapy or combined chemoendocrine treatment. Results were analyzed overall in the cohort of 893 patients with endocrine-responsive disease, and according to prospectively-defined categories of ER, age and nodal status. STEPP analyses assessed chemotherapy effect. The median follow-up was 13 years.
Results
Adding chemotherapy reduced the relative risk of a disease-free survival event by 19% (p=0.02) compared with ET alone. STEPP analyses showed little effect of chemotherapy for tumors with high levels of ER expression (p = 0.07), or for the cohort with one positive node (p = 0.03).
Conclusions
Chemotherapy significantly improves disease-free survival for postmenopausal women with endocrine-responsive breast cancer, but the magnitude of the effect is substantially attenuated if ER levels are high.
doi:10.1007/s10549-008-0225-9
PMCID: PMC3589110  PMID: 18953651
breast cancer; chemoendocrine therapy; estrogen receptors; postmenopausal

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