Prognostic and predictive value of the urokinase-type plasminogen activator (uPA) and its inhibitors PAI-1 and PAI-2 in operable breast cancer

The present study on the prognostic and predictive value of serine proteases was conducted in 460 early breast cancer patients mostly treated with some kind of adjuvant systemic therapy: 156 received chemotherapy, 141 hormone therapy and 111 a combination of both. Already in univariate analysis PAI-1 was the only proteolytic factor with a significant impact on DFS, which was retained in multivariate analysis (p = 0.020); PAI-2 showed borderline significance in univariate analysis (p = 0.0503) and uPA did not present as a significant prognostic factor for DFS in our patient series. In a separate univariate analysis of DFS on patient subgroups defined by adjuvant systemic therapy, a higher risk of relapse associated with higher uPA and PAI-1 levels was found in the subgroup of patients who did not receive any treatment; this difference did not reach the level of significance, probably due to the small number (n = 52) of patients in this group (HR 1.37; p = 0.71 and HR 2.14; p = 0.321, respectively). A higher risk of relapse was also found in the subgroup of patients treated with adjuvant chemotherapy (HR 1.44; p = 0.381 and HR 2.48; p = 0.003, respectively). In contrast, the bad prognostic impact of high uPA and PAI-1 levels was lost in the subgroup of patients treated with adjuvant hormone therapy (HR 0.79; p = 0.693 and HR 0.26; p = 0.204, respectively). The same observations were made for the uPA/PAI-1 combination. Our study confirmed the prognostic value of serine proteases in early breast cancer. In addition, it pointed to a possible predictive value of these tumor markers for response to adjuvant hormone therapy with tamoxifen, which should be confirmed in further studies.     

Chronological age or biological age: What drives the choice of adjuvant treatment in elderly breast cancer patients?

Ma and colleagues reported in their study on 12,004 elderly patients published on Breast J. 2020, that adjuvant chemotherapy was not associated with overall survival. Given the toxicities associated with systemic treatments, caution recommendation or omission of chemotherapy may be considered in elderly patient selection especially when comorbidities are present. We agree with authors final conclusions but we want to highlight that to define the adjuvant therapy in BC elderly patients several factors need to be taken into account. One of the main issues is the lack of universal and unique guidelines to define elderly patients. In clinical practice it can be very difficult to estimate the benefit/risk ratio in elderly patients because chemotherapy-induced toxicity is worse than in younger individuals. For these reasons, beyond comorbidities, the choice of adjuvant therapy for elderly patients must also be based both on chronological and biological age. Moreover, the multidisciplinary team for the elderly patient evaluation should include both the geriatrician and the molecular biologist.     

The Promher Study: An Observational Italian Study on Adjuvant Therapy for HER2-Positive,pT1a-b pN0 Breast Cancer

BackgroundThe management of pT1a-b pN0 HER2-positive breast cancer is controversial and no data about the efficacy of trastuzumab in this setting are available from randomized clinical trials. The aims of this retrospective study were to assess how patients are managed in clinical practice in Italy, which clinical or biological characteristics influenced the choice of adjuvant systemic therapy and the outcome of patients.MethodsData of consecutive patients who underwent surgery from January 2007 to December 2012 for HER2-positive, pT1a-b pN0 M0 breast cancer were retrospectively collected from 28 Italian centres. Analysis of contingency tables and multivariate generalized logit models were used to investigate the association between the baseline clinical and biological features and the treatment strategy adopted.ResultsAmong 303 enrolled patients, 204 received adjuvant systemic therapy with trastuzumab, 65 adjuvant systemic therapy without trastuzumab and 34 did not receive adjuvant systemic therapy. At the multivariate analysis age, tumor size, proliferation index and hormone receptor status were significantly associated with the treatment choice. Five-year disease-free survival (DFS) probability was 95%, 94.3% and 69.6% for patients treated with adjuvant systemic therapy and trastuzumab, with adjuvant systemic therapy without trastuzumab and for patients who did not receive adjuvant systemic therapy, respectively (p<0.001).ConclusionsThe majority of patients (66%) with pT1a-b pN0 HER2-positive breast cancer enrolled in this retrospective study received adjuvant systemic therapy with trastuzumab, whereas only 11% patients did not receive any adjuvant systemic therapy. The choice of treatment type seems to be mainly influenced by tumor size, proliferation index, hormone receptor status and age. The 5-year DFS probability was significantly higher for patients receiving adjuvant systemic therapy with trastuzumab compared with patients not receiving adjuvant systemic therapy or receiving adjuvant systemic therapy without trastuzumab.     

Tumor-biological factors uPA and PAI-1 as stratification criteria of a multicenter adjuvant chemotherapy trial in node-negative breast cancer

In axillary node-negative primary breast cancer, 70% of the patients will be cured by locoregional treatment alone. Therefore, adjuvant systemic therapy is only needed for those 30% of node-negative patients who will relapse after primary therapy and eventually die of metastases. Traditional histomorphological and clinical factors do not provide sufficient information to allow accurate risk group assessment in order to identify node-negative patients who might benefit from adjuvant systemic therapy. In the last decade various groups have reported a strong and statistically independent prognostic impact of the serine protease uPA (urokinase-type plasminogen activator) and its inhibitor PAI-1 (plasminogen activator inhibitor type 1) in node-negative breast cancer patients. Based on these data, a prospective multicenter therapy trial in node-negative breast cancer patients was started in Germany in June 1993, supported by the German Research Association (DFG). Axillary node-negative breast cancer patients with high levels of either or both proteolytic factors in the tumor tissue were randomized to adjuvant CMF chemotherapy versus observation only. Recruitment was continued until the end of 1998, by which time 684 patients had been enrolled. Since then, patients have been followed up in order to assess the value of uPA and PAI-1 determination as an adequate selection criterion for adjuvant chemotherapy in node-negative breast cancer patients. This paper reports on the rationale and design of this prospective multicenter clinical trial, which may have an impact on future policies in prognosis-oriented treatment strategies.     

Systemic adjuvant therapy for node-negative breast cancer.

In response to recent advice from the US National Cancer Institute concerning the use of systemic adjuvant therapy for node-negative breast cancer we reviewed the literature and found that several studies have shown evidence of a disease-free, but not an overall, survival advantage for treated patients. The benefits have been modest and may not outweight the cost and toxic effects of such therapy. Routine use does not seem to be justified. Factors must be identified to differentiate between patients at low risk and those at high risk. It should then be determined if adjuvant therapy is truly beneficial in those who are at high risk.     

Survival among clinical stage I–III rectal cancer patients treated with different preoperative treatments: A population-based comparison

BackgroundRadical resection is regarded as the cornerstone of rectal cancer treatment. Preoperative (chemo)radiotherapy and adjuvant chemotherapy are often administered. This population-based study compares the survival in clinical stage I–III rectal cancer patients who received either preoperative radiotherapy, preoperative chemoradiotherapy or no preoperative therapy. As secondary research questions, the association of type of radical resection and adjuvant chemotherapy on survival is also investigated.MethodsPatients diagnosed between January 2006 and December 2011 with stage I–III rectal adenocarcinoma were retrieved from the Belgian Cancer Registry database. Multivariable Cox proportional hazards regression models were applied to evaluate the association of preoperative treatment, type of radical resection and use of adjuvant chemotherapy with survival, adjusting for the baseline characteristics age, gender, WHO performance status and clinical stage.ResultsA total of 5173 rectal cancer patients were identified. Preoperative treatment was as follows: none in 1354 (26.2%), radiotherapy in 797 (15.4%) and chemoradiotherapy in 3022 (58.4%) patients. The patient group who did not receive preoperative therapy or radiotherapy followed by radical resection had a lower observed survival compared to the patient group receiving preoperative chemoradiotherapy. The patient groups who underwent abdominoperineal excision and those receiving adjuvant chemotherapy had a worse observed survival compared to the patient group treated with sphincter-sparing surgery and no adjuvant therapy respectively. These effects were age-dependent. Multivariable analysis demonstrated similar findings for the observed survival conditional on surviving the first year since surgery.ConclusionIn this population-based study among clinical stage I–III rectal cancer patients treated with radical resection, a superior observed survival was noticed in the patient group receiving preoperative chemoradiotherapy compared to the patients groups receiving no or preoperative radiotherapy only, adjusting for case mix, type of radical resection and adjuvant chemotherapy. Additionally, higher adjusted observed survival was also detected for the patient groups with sphincter-sparing surgery or no adjuvant chemotherapy.     

Biomarkers as prognostic factors in endometrial cancer

Endometrial cancer is the most common gynecologic malignancy in more developed countries. Approximately 75% of cases are diagnosed at an early stage with a tumor confined to the uterine corpus. Although most patients are cured by surgery alone, about 15-20% with no signs of locally advanced or metastatic disease at primary treatment recurs, with limited responsiveness to systemic therapy. The most common basis for determining the risk of recurrent disease has been classification of endometrial cancers into two subtypes. Type I, associated with a good prognosis and endometrioid histology and type II, associated with a poor prognosis and non-endometrioid histology. This review will focus primarily on the molecular biomarkers that have supported the dualistic model of endometrial carcinoma and help determine which patients would benefit from either adjuvant therapy or more aggressive primary treatment.     

A ten-microRNA expression signature predicts survival in glioblastoma

Glioblastoma (GBM) is the most common and aggressive primary brain tumor with very poor patient median survival. To identify a microRNA (miRNA) expression signature that can predict GBM patient survival, we analyzed the miRNA expression data of GBM patients (n=222) derived from The Cancer Genome Atlas (TCGA) dataset. We divided the patients randomly into training and testing sets with equal number in each group. We identified 10 significant miRNAs using Cox regression analysis on the training set and formulated a risk score based on the expression signature of these miRNAs that segregated the patients into high and low risk groups with significantly different survival times (hazard ratio [HR]=2.4; 95% CI=1.4-3.8; p<0.0001). Of these 10 miRNAs, 7 were found to be risky miRNAs and 3 were found to be protective. This signature was independently validated in the testing set (HR=1.7; 95% CI=1.1-2.8; p=0.002). GBM patients with high risk scores had overall poor survival compared to the patients with low risk scores. Overall survival among the entire patient set was 35.0% at 2 years, 21.5% at 3 years, 18.5% at 4 years and 11.8% at 5 years in the low risk group, versus 11.0%, 5.5%, 0.0 and 0.0% respectively in the high risk group (HR=2.0; 95% CI=1.4-2.8; p<0.0001). Cox multivariate analysis with patient age as a covariate on the entire patient set identified risk score based on the 10 miRNA expression signature to be an independent predictor of patient survival (HR=1.120; 95% CI=1.04-1.20; p=0.003). Thus we have identified a miRNA expression signature that can predict GBM patient survival. These findings may have implications in the understanding of gliomagenesis, development of targeted therapy and selection of high risk cancer patients for adjuvant therapy.     

A phase-II trial of Corynebacterium parvum as adjuvant to surgery in the treatment of operable lung cancer

A phase-II randomized trial has been undertaken in 49 patients with operable lung cancer, to determine the effect of a single IV infusion of killed C. parvum vaccine as an adjuvant to surgery. The number of patients was insufficient to provide a decisive result, but analysis 6 years after the last patient was admitted shows that the adjuvant therapy certainly did not shorten, and may well have prolonged, survival. Of the patients with squamous cell carcinoma who were alive 1 year after operation all except one in the C. parvum-treated group were alive 4 years later, whereas five in the control group died during this interval. Judgement concerning the value of IV administration of CP as adjuvant therapy in patients with operable lung cancer should be deferred until further evidence is available.     

Immunotherapy for superficial bladder cancer

The treatment of superficial bladder cancer requires adjuvant therapies besides transurethral resection because of a high recurrence rate after this standard treatment alone. Current adjuvant therapies involve intravesical chemotherapy for patients at low and intermediate risk for recurrence and progression, and intravesical bacillus Calmette-Guérin for patients at intermediate and high risk. However, these adjuvant therapies fail in a significant number of patients, dictating the need for new and improved adjuvant treatment modalities for superficial bladder cancer. Immunotherapy aiming at the modulation of the immune system of the patient is a promising alternative adjuvant. This review discusses the current status of the clinical development of various immunotherapy approaches for superficial bladder cancer, including passive immunotherapy, immune stimulants, immunogene therapy and cancer vaccination.     

A phase-II trial of Corynebacterium parvum as adjuvant to surgery in the treatment of operable lung cancer

Summary A phase-II randomized trial has been undertaken in 49 patients with operable lung cancer, to determine the effect of a single IV infusion of killed C. parvum vaccine as an adjuvant to surgery. The number of patients was insufficient to provide a decisive result, but analysis 6 years after the last patient was admitted shows that the adjuvant therapy certainly did not shorten, and may well have prolonged, survival. Of the patients with squamous cell carcinoma who were alive 1 year after operation all except one in the C. parvum-treated group were alive 4 years later, whereas five in the control group died during this interval.Judgement concerning the value of IV administration of CP as adjuvant therapy in patients with operable lung cancer should be deferred until further evidence is available.Emeritus Professor of Surgery, University of EdinburghConsultant Cardio-Thoracic Surgeon     

Generation of “Virtual” Control Groups for Single Arm Prostate Cancer Adjuvant Trials

It is difficult to construct a control group for trials of adjuvant therapy (Rx) of prostate cancer after radical prostatectomy (RP) due to ethical issues and patient acceptance. We utilized 8 curve-fitting models to estimate the time to 60%, 65%, … 95% chance of progression free survival (PFS) based on the data derived from Kattan post-RP nomogram. The 8 models were systematically applied to a training set of 153 post-RP cases without adjuvant Rx to develop 8 subsets of cases (reference case sets) whose observed PFS times were most accurately predicted by each model. To prepare a virtual control group for a single-arm adjuvant Rx trial, we first select the optimal model for the trial cases based on the minimum weighted Euclidean distance between the trial case set and the reference case set in terms of clinical features, and then compare the virtual PFS times calculated by the optimum model with the observed PFSs of the trial cases by the logrank test. The method was validated using an independent dataset of 155 post-RP patients without adjuvant Rx. We then applied the method to patients on a Phase II trial of adjuvant chemo-hormonal Rx post RP, which indicated that the adjuvant Rx is highly effective in prolonging PFS after RP in patients at high risk for prostate cancer recurrence. The method can accurately generate control groups for single-arm, post-RP adjuvant Rx trials for prostate cancer, facilitating development of new therapeutic strategies.     

Aromatase inhibitors--socioeconomical issues

With costs of health care in general and for cancer therapy in particular escalating due to implementation of novel compounds, there is an increasing focus on therapy costs in most countries. A common way of assessing therapeutic utility versus cost is by assessing cost per additional life year gained or cost per additional quality-adjusted life year (QALY) gained with a novel therapy. While endocrine therapy in general is associated with low costs, the fact that aromatase inhibitors are administered over several years to each patient in the adjuvant setting, together with the substantial number of postmenopausal breast cancer patients that are candidates for adjuvant treatment with aromatase inhibitors, advocates critical examination of cost–utilities related to implementation of such therapy in the adjuvant setting. While cost–utility estimates for treatment with aromatase inhibitors in the adjuvant setting look favorable, the estimates are sensitive to variations with respect to long-term benefits but also side effects. For patient groups with a low-risk of relapse but also patients with a limited life expectancy due to high age, cost–utility estimates may exceed the upper limits generally proposed for costs per quality-adjusted life year gained.     

Present status of BCG immunotherapy of malignant melanoma

Summary BCG systemic adjuvant immunotherapy may be effective for improving both the recurrence and survival rates in patients with regional metastases from malignant melanoma. Clinical trials show that many of the principles derived from the study of animal tumor systems are applicable to human cancer in that immunotherapy is most effective for a small residual number of tumor cells. BCG treatment fulfills many of the ideal criteria for adjuvant treatment following surgery when disease burden is lowest. It is relatively nontoxic; it is effective for disseminated melanoma; it has systemic activity in the adjuvant treatment of subclinical metastases. However, until clinical trials are complete, BCG adjuvant therapy must be considered investigational.Supported by USPHS grants CA05252, CA12582, and NIH 0732001 CB43852.     

Intraarterial chemotherapy: the effects on free-tissue transfer

Multimodal therapy including intraarterial chemotherapy is recognized as state-of-the art therapy for soft-tissue cancer. Multimodal therapy often involves regional limb perfusion followed by sarcoma surgery with reconstruction of the resulting defect. This study was performed in an effort to evaluate the potential of free flap reconstruction after intraarterial therapy. A retrospective chart review of 52 patients who had undergone limb perfusion between 1988 and 1998 at the University of Texas M. D. Anderson Cancer Center and the Division of Plastic Surgery, University of Bochum, Germany, identified 16 patients who had undergone intraarterial limb perfusion that was then followed by surgical resection and free flap reconstruction. There were seven women and nine men, with an average age of 37.9 years. All sixteen patients had received preoperative adjuvant systemic chemotherapy. Reconstruction of the lower extremity was performed most commonly with rectus abdominis and latissimus dorsi free flaps. All vessels used for donor recipient anastomosis had been previously perfused. A vein graft was used in one case. Split-thickness skin grafting over the free flaps was used in four cases. The average length of hospitalization was 21.75 days, with an average follow-up of 20 months. No flap loss or infection was observed. Two flaps demonstrated partial edge necrosis. Three patients developed partial split-thickness skin graft loss and one developed a seroma that required no treatment. A draining sinus tract required resection in one patient. The overall flap success rate was 100 percent, with no flap failures. The overall surgical outcome was considered to be good in 12 patients on the basis of improved function and ambulation, and fair in four who had limitations in function and/or ambulation on the basis of both the patient self-evaluation and the physical therapy evaluation. Seven patients had recurrence of their disease. The overall mean survival time after surgery was 20.6 months. Currently, 10 patients are alive and six have died from their disease. The results of this study indicate that preoperative intraarterial chemotherapy does not significantly increase the risk of immediate free flap complications. Although our numbers are small, we believe that there is no clinical evidence justifying hesitation or refusal of free flap reconstruction after limb perfusion and intraarterial chemotherapy. Routine care in vessel selection and microsurgical technique should be performed to maximize favorable outcomes. Vessels should be inspected for their suitability before undertaking any free flap reconstruction.     

Staged breast reconstruction with saline-filled implants in the irradiated breast: recent trends and therapeutic implications

A retrospective review was performed of one surgeon's experience with 40 consecutive patients who had undergone two-stage saline-filled implant breast reconstruction and radiation during the period from 1990 through 1997. A randomly selected group of 40 other two-stage saline-filled implant breast reconstructions from the same surgeon and time period served as controls. This review was undertaken because of the absence of specific information on the outcome of staged saline implant reconstructions in the radiated breast. Previously published reports on silicone gel implants and radiation have been contradictory. At the same time, the criteria for the use of radiation in the treatment of breast cancer have been expanded and the numbers of reconstruction patients who have been radiated are increasing dramatically. For example, in a 1985 report on immediate breast reconstruction, only 1 of 185 patients over a 6-year period underwent adjuvant radiation therapy, whereas in this review, there were 40 radiated breasts with saline-filled implants, 19 of which received adjuvant radiation therapy during their expansion. The study parameters included patient age, breast cup size, implant size, length of follow-up, number of procedures, coincident flap operations, Baker classification, complications, opposite breast procedures, pathologic stage, indications for and details about the radiation, and outcomes. The use of radiation in this review of reconstructed breasts can logically be divided into four groups: previous lumpectomy and radiation (n = 7), mastectomy and radiation before reconstruction (n = 9), mastectomy and adjuvant radiation during reconstruction/expansion (n = 19), and radiation after reconstruction (n = 5). The largest and most rapidly growing group of patients is of those receiving postmastectomy adjuvant radiation therapy. A total of 47.5 percent (19 of 40) of radiated breasts with saline implants ultimately needed the addition of, or replacement by, a flap. Ten percent of a control group with nonradiated saline implant reconstructions also had flaps, none as replacements. Fifty percent or more of both the radiated and control groups had contralateral surgery. Complications were far more common in the radiated group; for example, there were 32.5 percent capsular contractures compared with none in the control group. The control nonradiated implant-only group and the flap plus implant radiated group did well cosmetically. The radiated implant-only group was judged the worst. The increasing use of radiation after mastectomy has important implications for breast reconstruction. The possibility for radiation should be thoroughly investigated and anticipated preoperatively before immediate breast reconstruction. Patients with invasive disease, particularly with large tumors or palpable axillary lymph nodes, are especially likely to be encouraged to undergo postmastectomy radiation therapy. The indications for adjuvant radiation therapy have included four or more positive axillary lymph nodes, tumors 4 cm (or more) in diameter, and tumors at or near the margin of resection. More recently, some centers are recommending adjuvant radiation therapy for patients with as few as one positive lymph node or even in situ carcinoma close to the resection margin. The use of latissimus dorsi flaps after radiation has proven to be an excellent solution to postradiation tissue contracture, which can occur during breast expander reconstruction. The use of the latissimus flap electively with skin-sparing mastectomy preradiation is probably unwise, unless postmastectomy radiation is unlikely. Skin-sparing mastectomy with a latissimus flap thus should be preserved for patients unlikely to undergo adjuvant radiation therapy. Purely autologous reconstruction such as a TRAM flap is another option for these patients, either before or after radiation therapy.     

An estrogen receptor (ER)‐related signature in predicting prognosis of ER‐positive breast cancer following endocrine treatment

Quite a few estrogen receptor (ER)‐positive breast cancer patients receiving endocrine therapy are at risk of disease recurrence and death. ER‐related genes are involved in the progression and chemoresistance of breast cancer. In this study, we identified an ER‐related gene signature that can predict the prognosis of ER‐positive breast cancer patient receiving endocrine therapy. We collected RNA expression profiling from Gene Expression Omnibus database. An ER‐related signature was developed to separate patients into high‐risk and low‐risk groups. Patients in the low‐risk group had significantly better survival than those in the high‐risk group. ROC analysis indicated that this signature exhibited good diagnostic efficiency for the 1‐, 3‐ and 5‐year disease‐relapse events. Moreover, multivariate Cox regression analysis demonstrated that the ER‐related signature was an independent risk factor when adjusting for several clinical signatures. The prognostic value of this signature was validated in the validation sets. In addition, a nomogram was built and the calibration plots analysis indicated the good performance of this nomogram. In conclusion, combining with ER status, our results demonstrated that the ER‐related prognostic signature is a promising method for predicting the prognosis of ER‐positive breast cancer patients receiving endocrine therapy.     

Diagnostic phase antibody response to the human papillomavirus type 16 E2 protein is associated with succesful treatment of genital HPV lesions with systemic interferon α-2b

Background and objective: Systemic interferon α-2b treatment reduces relapses of genital human papillomavirus (HPV) lesions in some but not all females. The aim of the present study was to investigate possible predictive pretreatment factors for the outcome of therapy.Material and methods: HPV DNA status and HPV antibody response were evaluated in 100 randomized patients treated with laser ablation and systemic interferon α-2b or placebo, and followed up to 6 months.Results: Overall, adjuvant therapy with systemic interferon-α did not differ from placebo. However, detectable diagnostic phase levels of serum antibodies to e.g. HPV16 open reading frame (ORF) E2 derived peptide ¹⁴¹EEASVTVVEGQVDYY¹⁵⁵ predicted 10-fold difference in the risk of recurrence of HPV infection following adjuvant interferon α-2b therapy as compared with placebo (odds ratio, OR, 0.5, 95% confidence interval (CI), 0.1–2.3; OR, 4.6, 95% CI 0.5–41, respectively). This trend was statistically significant in the whole study population (2P < 0.05), and in patients with high viral load (2P < 0.01).Conclusions: Evaluation of the E2 antibody responses may help to identify women with genital HPV lesions who respond to systemic interferon α-2b treatment.     

Interferons and osteosarcoma

In 1970, we initiated studies at the Karolinska hospital to find out whether biologically meaningful doses of interferon (IFN) alpha preparations could be administered systemically to patients with viral and tumour diseases without causing unacceptable side effects. Antiviral and antitumour efficiency was demonstrated. Only a limited number of patients were injected due to shortage of high dose IFN preparations. Osteosarcoma patients participated in these early attempts. Due to clinical observations on one patient and due to lack of meaningful systemic standard treatment for osteosarcoma at the time, we decided to continue to give adjuvant IFN treatment to a consecutive series of osteosarcoma patients attending our hospital .We were encouraged by the preliminary follow up results of the series and continued to use this therapeutic principle up to 1990. The clinical results achieved are briefly summarized in this mini-review as are the results obtained in simultaneously ongoing model experiments in vitro and in vivo. A randomized large scale ongoing trial, involving the use of adjuvant IFN treatment of osteosarcoma patients, has been initiated by the European and American osteosarcoma study group 35 years after the first osteosarcoma patient received IFN. The trial is briefly outlined in this article.     

Adjuvant endocrine therapy for postmenopausal breast cancer in the era of aromatase inhibitors: an update

There is overwhelming evidence that optimal adjuvant endocrine therapy for hormone sensitive breast cancer in postmenopausal women should include a third generation aromatase inhibitor (AI). On current evidence, adjuvant anstrozole or letrozole should be used upfront in such patients especially in those with high risk disease (node positive and/or tumours > 2 cm). The sequential approach of tamoxifen for 2–3 years followed by exemestane or anastrozole for 2–3 years is a reasonable alternative to 5 years of AI monotherapy in patients with low risk disease (node negative and tumour smaller than 2 cm) especially if the tumour is positive for estrogen and progesterone receptors.Node-positive patients completing 5 years of adjuvant tamoxifen should be offered letrozole for up 48 months. Further research is required to establish the long-term cardiovascular safety of AIs especially that of letrozole and exmestane, the optimal AI to use, duration of AI therapy and whether monotherapy with an AI for 5 years is superior to sequencing an AI after 2–3 years of tamoxifen.The bone mineral density (BMD) should be measured at baseline and monitored during therapy in women being treated with AIs. Anti-osteoporosis agents should such as bisphosphonates should be considered in patients at high risk of bone fractures.