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Drugi po redu uzročnik smrti u Hrvatskoj predstavljaju novotvorevine. Karcinom koji se najviše dijagnosticira kod žena je karcinom dojke te gotovo 70% pacijentica koje su oboljele od karcinoma dojke imaju hormonski ovisan tip karcinoma. Terapija hormonski ovisnog karcinoma dojke često obuhvaća AET. Adjuvantna endokrina terapija se sastoji od supresije jajnika, SERM-ova (tamoksifen) i AI (anastrozol, letrozol i eksemestan). Unatoč dokazanim koristima koji se postižu primjenom AET adherencija pacijentica nije zadovoljavajuća. Smatra se kako se uzrok tome može pronaći u dugom trajanju terapije, ali i u nuspojavama koje sama terapija uzrokuje. Cilj ovog diplomskog rada bilo je ustanoviti adherenciju pacijentica s HR+ karcinomom dojke koje se liječe adjuvantnom endokrinom terapijom. Istraživanje je dizajnirano kao presječno, opažajno u kojem su podatci prikupljeni u jednoj točci u vremenu. U istraživanju je sudjelovalo 353 ispitanice srednje dobi 54 (± 11,89) godine. Većina ispitanica bila je udana ili je živjelo u izvanbračnoj zajednici, visoko obrazovano te zaposleno na puno radno vrijeme. Postotak ispitanica koje je bilo na terapiji tamoksifenom je 39,1% dok je na terapiji AI bilo 55,0% ispitanica (23,8% anastrozol, letrozol 26,5%, eksemestan 4,7%). Za procjenu adherencije ispitanice su popunjavale validirani upitnik MARS_5. Ispitanice smo, s obzirom na njihove odgovore, bili podijelili na adherentne i neadherentne pacijentice. Rezultati MARS_5 upitnika su pokazali kako je adherentno bilo 53,0% ispitanica dok je neadherentno bilo 40,2% ispitanica (24,1%, nenamjerno neadherentno, 3,1%, namjerno neadherentno, 13,0% namjerno i nenamjerno neadherentno). Postoji značajna razlika u adherenciji između pacijentica koje su bile na terapiji AI (70,8%) u odnosu na one koje su bile na terapiji tamoksifenom (37,2%). Istraživanje ovakvog tipa na ženama koje su preboljele karcinom dojke te su trenutno na AET, prvi put je provedeno u Hrvatskoj. Ovo istraživanje doprinosi boljem razumijevanju adherencije žena koje su na AET te je važno identificirati razloge neadherencije pri AET te donijeti pravilne odluke o daljnjim intervencijama. Second leading cause of death in Croatia is cancer. The most diagnosed carcinoma in women is breast cancer, almost 70% of patients with breast cancer have a hormon dependant breast cancer. Therapy for hormone-dependent breast cancer frequently include AET. Adjuvant endocrine therapy consists of ovarian suppression, SERMs (tamoxifen) and AI (anastrozole, letrozole and exemestane). Despite the proven benefits achieved by using AET, the adherence of patients is not satisfactory. It is believed that the cause of this can be found in the long duration of the therapy, but also in the side effects caused by the therapy itself. The goal of this thesis was to examine the adherence of patients with HR+ breast cancer treated with adjuvant endocrine therapy. The research was designed as a cross-sectional, observational study in which data were collected at one point in time. Research was conducted on 353 respondents with an average age of 54 (± 11,89). Most of the respondents were married or cohabiting, highly educated and were employed full-time. Percentage of subjects who were on tamoxifen therapy is 39,1%, while 55,0% of subjects were on AI therapy (23,8% anastrozole, 26,5% letrozole, 4,7% exemestane). To assess adherence, the subjects filled out the validated questionnaire MARS_5. Based on their answers, we divided the subjects into adherent and non-adherent patients. The results of the MARS_5 questionnaire showed that 53,0% of respondents were adherent, while 40,2% of respondents were non-adherent (24,1%, unintentionally non-adherent, 3,1%, intentionally non-adherent, 13,0% intentionally and unintentionally non-adherent). There was a significant difference in adherence between patients on AI therapy (70,8%) compared to those on tamoxifen therapy (37,2%). Research of this type on women who have survived breast cancer and are currently on AET was conducted for the first time in Croatia. This research contributes to a better understanding of the adherence of women who are on AET. It is important to identify why adherence to AET is so low and to make proper decisions about further interventions.

Background: Adjuvant endocrine therapy (AET) reduces breast cancer recurrence and mortality of women with hormone-receptor-positive tumors, but poor adherence remains a significant problem. The aim of this study was to analyze AET side effects and their impact on adherence to treatment. Methods: A total of 373 breast cancer patients treated with AET filled out a specific questionnaire during their follow up visits at the Breast Unit of our Centre. Results: Side effects were reported by 81% of patients, 84% of those taking tamoxifen and 80% of those taking aromatase inhibitors (AIs). The most common side effect in the tamoxifen group was hot flashes (55.6%), while in the AI group it was arthralgia (60.6%). The addition of GnRH agonists to both tamoxifen and AI significantly worsened all menopausal symptoms. Overall, 12% of patients definitively discontinued AET due to side effects, 6.4% during the first 5 years and 24% during extended therapy. Patients who had previously received chemotherapy or radiotherapy reported a significantly lower discontinuation rate. Conclusions: AET side effects represent a significant problem in breast cancer survivors leading to irregular assumption and discontinuation of therapy. Adherence to AET may be improved by trustful patient–physician communication and a good-quality care network.

Emilia Montagna,1 Paola Zagami,1,2 Marianna Masiero,3,4 Ketti Mazzocco,3,4 Gabriella Pravettoni,3,4 Elisabetta Munzone1 1Division of Medical Senology, IEO European Institute of Oncology IRCCS, Milan, Italy; 2Division of Early Drug Development for Innovative Therapies, IEO European Institute of Oncology IRCCS, Milan, Italy; 3Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; 4Applied Research Division for Cognitive and Psychological Science, IEO European Institute of Oncology IRCCS, Milan, 20141, ItalyCorrespondence: Emilia MontagnaDivision of Medical Senology, European Institute of Oncology, IRCCS, Via Ripamonti 435, Milan, 20141, ItalyTel +39 02 57489439Fax +39 02 574829212Email emilia.montagna@ieo.itAbstract: Adjuvant endocrine therapy (AET) is generally proposed to all patients with hormone receptor-positive breast cancer to reduce the risk of recurrence and death. Adherence to therapy is crucial. However, non-adherence to AET is common, with estimates of up to 50% of patients not successfully completing a five-year course of treatment, and it is significantly associated with lower survival rates and a higher risk of recurrence. Currently, no gold standard is available to assess adherence. Several studies, most of them retrospective in nature, have used both direct and indirect methods to monitor the adherence to therapy in breast cancer. The indirect method is more widely used, and it is based on pharmacy prescription refills and patient administered questionnaires. On the other hand, direct methods such as a measurement of the level of the drug or its metabolites in blood or urine are much more precise, but more expensive and not routinely implemented. In this review, we analyzed the results of the major studies focused on the adherence to tamoxifen in breast cancer patients. We identified several factors associated with poor adherence, such as the side effects of therapy, the lack of shared decision-making between the physician and patient, the context in which the discussion takes place, and whether the patients are enrolled in a clinical trial. Moreover, we discussed possible methods to improve adherence to adjuvant therapy in breast cancer.Keywords: adherence, adjuvant endocrine therapy, tamoxifen, breast cancer

Kirsti I Toivonen,1 Linda E Carlson,2,3 Joshua A Rash,4 Tavis S Campbell1 1Department of Psychology, University of Calgary, Calgary, AB, Canada; 2Department of Oncology, University of Calgary, Calgary, AB, Canada; 3Department of Psychosocial Resources, Tom Baker Cancer Centre, Calgary, AB, Canada; 4Department of Psychology, Memorial University of Newfoundland, St. John’s, NL, CanadaCorrespondence: Tavis S CampbellDepartment of Psychology, University of Calgary, 2500 University Dr NW, Calgary, T2N 1N4, AB, CanadaTel +1 403-210-8606Email t.s.campbell@ucalgary.caPurpose: Despite the efficacy of adjuvant endocrine therapy (AET) in reducing breast cancer recurrence and mortality, suboptimal AET adherence is common and hence an important clinical issue among breast cancer survivors. Delineating potentially modifiable patient-level factors associated with AET adherence may support the development of successful adherence-enhancing interventions.Patients and Methods: The present study included 133 breast cancer survivors prescribed AET recruited from a cancer pharmacy. Women completed a baseline questionnaire examining psychosocial factors and self-reported adherence and consented to their prescription records being monitored for the proceeding 12 months to ascertain proportion of days covered (PDC), an objective measure of adherence. Regression analyses were used to identify the factors most strongly associated with both self-reported and objective adherence. Exploratory moderation analyses examined whether factors were differentially associated with adherence based on AET type (aromatase inhibitors or tamoxifen).Results: Adherence was high in this sample (PDC over 12 months was 95%). Side effect severity was most strongly associated with self-reported adherence, followed by self-efficacy, and medication/healthcare system-related barriers. Medication/healthcare system-related barriers was the only factor that uniquely predicted objective adherence. Within medication/healthcare system-related barriers, fear of side effects was most strongly associated with both measures of adherence. There were no significant interactions between AET type and potentially modifiable factors in predicting self-reported or objective adherence.Conclusion: Side effects, reactions to side effects, and self-efficacy may represent modifiable targets through which AET adherence can be improved. Associations between potentially modifiable factors and adherence did not vary by AET type, despite distinct side-effect profiles.Keywords: adjuvant endocrine therapy, breast cancer, adherence, patient reported outcomes, side effects, symptom management

Adjuvant endocrine therapy (AET) is generally proposed to all patients with hormone receptor-positive breast cancer to reduce the risk of recurrence and death. Adherence to therapy is crucial. However, non-adherence to AET is common, with estimates of up to 50% of patients not successfully completing a five-year course of treatment, and it is significantly associated with lower survival rates and a higher risk of recurrence. Currently, no gold standard is available to assess adherence. Several studies, most of them retrospective in nature, have used both direct and indirect methods to monitor the adherence to therapy in breast cancer. The indirect method is more widely used, and it is based on pharmacy prescription refills and patient administered questionnaires. On the other hand, direct methods such as a measurement of the level of the drug or its metabolites in blood or urine are much more precise, but more expensive and not routinely implemented. In this review, we analyzed the results of the major studies focused on the adherence to tamoxifen in breast cancer patients. We identified several factors associated with poor adherence, such as the side effects of therapy, the lack of shared decision-making between the physician and patient, the context in which the discussion takes place, and whether the patients are enrolled in a clinical trial. Moreover, we discussed possible methods to improve adherence to adjuvant therapy in breast cancer.

Adjuvant endocrine therapy (AET) is recommended after hormone receptor-positive breast cancer to reduce risk of recurrence, but adherence is sub-optimal in many women. Behavioral interventions have been ineffective in improving adherence rates to AET. This qualitative descriptive study investigates factors that support women in AET use and suggestions for interventions to improve AET use and management. Interviews with women who persisted with AET (n = 23), women who discontinued AET (n = 15), and healthcare providers (HCPs, oncologists, oncology residents, and pharmacists, n = 9) were conducted, transcribed, and described using thematic analysis. Data collection stopped once saturation occurred (i.e., no new codes or themes emerged during interviews). Two researchers created codes and developed themes in an iterative process, a third researcher verified the representativeness of final themes. This study was approved by the Health Research Ethics Board of Alberta (ID: HREBA.CC-17-0513). Women who persisted described being prepared for side effects and having self-management strategies, strong rationale for AET use, supportive HCPs, and available resources as relevant factors. Women who discontinued described feeling overwhelmed by side effects, information needs, drawbacks of AET, helpful/unhelpful experiences with HCPs, and contextual factors as relevant to their discontinuation. HCPs described health system-related and patient-related barriers, side effect management, and patient-provider interactions as relevant to supporting AET use. The considerable overlap in themes among the three groups suggests broad recognition of salient factors relevant to AET use and that associated strategies to improve use may be acceptable to patients and providers alike. Factors supporting AET use could include the following: education (which may be necessary but insufficient), developing a strong personal rationale for use, being prepared for side effects, having side effect management strategies, reciprocal communication between patients and HCPs, and accessible resources.

Background A systematic review and meta-analysis was conducted to assess breast cancer (BC) outcomes among patients with early-stage hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) BC, receiving adjuvant endocrine therapy. Methods Randomized controlled trials (RCTs) and real-world evidence (RWE) studies were identified using Ovid MEDLINE®, Embase, and Evidence-Based Medicine Reviews. Clinical and methodological similarities including alignment of outcome definitions with standardized definitions for efficacy endpoints criteria were assessed to evaluate feasibility of conducting a meta-analysis. Where feasible, 5-year probabilities of BC recurrence or death were estimated using a Bayesian hierarchical arm-based model. Results Of 21 included studies, 8 RCTs and 4 RWE studies reported outcome data of interest. There was heterogeneity in outcome reporting, as well as variation in recurrence risk amongst studies with aligned reporting. Of the 12 studies, 10 were considered for inclusion in a meta-analysis of BC recurrence or death. Only a subgroup analysis of node-positive patients (3 studies; n = 7307) was deemed feasible. The 5-year probability of BC recurrence or death was 17.2% (95% credible interval: 14.6%–20.3%). Conclusion Although studies reporting recurrence outcomes were limited, there remains a high risk of BC recurrence, especially among node-positive patients. Approximately 1 in 6 women with node-positive HR+/HER2- early-stage BC receiving endocrine therapy experience recurrence or death within 5-years of initiating treatment, suggesting a need for novel treatments for this population., Highlights • Recurrence data from RCTs and RWE studies in HR+/HER2- early BC is limited. • Recurrence rates for patients receiving endocrine therapy (ET) were summarized. • Substantial outcome and clinical heterogeneity between studies was identified. • An estimated 1 in 6 patients with node-positive BC may relapse within 5-years. • Unmet need exists for therapies to further reduce recurrence in high-risk early BC.

Background Adjuvant endocrine therapies are known to induce undesirable adverse effects such as vasomotor, vaginal and musculoskeletal symptoms among breast cancer patients. Drugs used in these therapies are often metabolised by cytochrome P450 (CYP) enzymes, in which their metabolising activities can be modified by single nucleotide polymorphisms (SNP) in CYP genes and CYP genotypes. This review aims to explore whether SNPs or genotypes of CYP are associated with the occurrence, frequency and severity of vasomotor, vaginal and musculoskeletal symptoms in breast cancer patients on adjuvant endocrine therapies. Methods A literature review was conducted using five electronic databases, resulting in the inclusion of 14 eligible studies, and their findings were presented narratively. Selected items from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist were used for critical appraisal of the reporting quality of the included studies. Results Most of the included studies showed that SNPs or genotypes of CYP that modify its metabolising activity have no effect on the occurrence, frequency or severity of vasomotor symptoms, including hot flashes. One study showed no correlation of these genetic variations in CYP with musculoskeletal symptoms, and no data were available on the association between such genetic variations and vaginal symptoms. Conclusions Overall, genetic variations in CYP have no effect on the experience of hot flashes among breast cancer patients. We recommend exploration of the link between the active metabolites of chemotherapeutic drugs and the molecules shown to affect the occurrence or severity of hot flashes, and the establishment of the relationship between such genetic variations and patients’ experience of musculoskeletal and vaginal symptoms. Subgroup analyses based on patients’ duration of adjuvant endocrine therapies in such studies are recommended.

Han Bai,1 Jianjun Yu,2 Shidong Jia,2 Xiaoran Liu,1 Xu Liang,1 Huiping Li1 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, People’s Republic of China; 2Huidu Shanghai Medical Sciences, Shanghai, 201499, People’s Republic of ChinaCorrespondence: Xu Liang; Huiping LiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital and Institute, No. 52, Fucheng Road, Haidian District, Beijing, 100142, People’s Republic of ChinaTel/Fax +86-10-88196739Email liangxu15@outlook.com; huipingli2012@hotmail.comPurpose: The status of TP53 mutations was measured in cell-free DNA from patients with metastatic breast cancer (MBC) to investigate disease characteristics and the prognostic role of different locations of the TP53 mutation site.Patients and Methods: Blood samples were taken from a total of 187 patients diagnosed with MBC who were treated at the Department of Breast Oncology, Peking University Cancer Hospital between January 2013 and March 2020. Next-generation sequencing was used to investigate the TP53 mutation spectra of circulating free DNA in these blood samples.Results: Among the 187 MBC patients, TP53-mutated patients had a significantly shorter median disease-free survival (DFS) and overall survival (OS) compared with TP53 wild-type patients (P=0.001 and P=0.006, respectively). Additionally, in hormone receptor positive/HER2 negative (HR+/HER2-) and triple negative (TNBC) cohorts, TP53-mutated patients had a significantly shorter median DFS than TP53 wild-type patients (P=0.038 and P=0.023, respectively). The 79 patients with TP53 mutations carried 87 somatic TP53 mutations, of which most (77.0%) mapped to the DNA-binding domain (DBD) of the protein encoded by TP53 exons 5– 8. In patients with TP53 mutations, those occurring in the non-DBD had a significantly shorter median DFS and OS than TP53 wild type (P< 0.001 and P=0.001, respectively). Additionally, patients with non-missense mutations in the DBD had a significantly shorter median DFS and OS than TP53 wild-type patients (P=0.001 and P< 0.001, respectively). TP53-mutated patients had a significantly shorter DFS than TP53 wild-type patients in the adjuvant endocrine therapy sensitive group (P=0.008), but differences in the endocrine therapy resistant group were not significant.Conclusion: TP53-mutated MBC patients had a significantly worse outcome than TP53 wild-type patients especially those in HR+/HER2– and TNBC cohorts. Of TP53-mutated patients, those with non-missense mutations in the DBD had worse breast cancer-related survival. TP53 mutations were also associated with endocrine resistance.Keywords: advanced breast cancer, TP53 mutation, NGS, adjuvant endocrine therapy, DNA-binding domain

Adherence to adjuvant endocrine therapy (AET) for breast cancer is suboptimal. The purpose of this study was to: (1) explore the experiences and perspectives of healthcare providers (HCPs) in providing care to breast cancer survivors prescribed AET, (2) identify how social and structural factors influence the provision of AET-related care, and (3) ascertain HCP recommendations for optimizing AET adherence and related care. Individual, in-depth interviews were conducted with 14 HCPs using an interpretive descriptive approach to inquiry and the theoretical lens of relational autonomy. Data was analyzed using thematic and constant comparative techniques. Healthcare providers focused on four main components of AET-related care: (1) the importance of having careful conversations about AET, (2) difficulties in navigating transitions in care, (3) symptom management as a big part of their role, and (4) dealing with AET discontinuation. Recommendations to improve AET adherence focused on developing sustainable and efficient models of delivering high-quality care to women on AET. Healthcare providers play a pivotal role educating women about AET and supporting their adherence to therapy. Sustainable healthcare system innovations and new models of care that address current system gaps are needed to enhance survivorship care, AET adherence, and ultimately, reduce cancer recurrence and mortality.

Aromatase inhibitors (AIs) cause symptoms of musculoskeletal pain, and some mechanisms have been proposed to explain them. However, signaling pathways downstream from kinin B2 (B2R) and B1 (B1R) receptor activation and their possible sensitizing of the Transient Receptor Potential Ankyrin 1 (TRPA1) remain unknown. The interaction between the kinin receptor and the TRPA1 channel in male C57BL/6 mice treated with anastrozole (an AI) was evaluated. PLC/PKC and PKA inhibitors were used to evaluate the signaling pathways downstream from B2R and B1R activation and their effect on TRPA1 sensitization. Anastrozole caused mechanical allodynia and muscle strength loss in mice. B2R (Bradykinin), B1R (DABk), or TRPA1 (AITC) agonists induced overt nociceptive behavior and enhanced and prolonged the painful parameters in anastrozole-treated mice. All painful symptoms were reduced by B2R (Icatibant), B1R (DALBk), or TRPA1 (A967079) antagonists. We observed the interaction between B2R, B1R, and the TRPA1 channel in anastrozole-induced musculoskeletal pain, which was dependent on the activation of the PLC/PKC and PKA signaling pathways. TRPA1 seems to be sensitized by mechanisms dependent on the activation of PLC/PKC, and PKA due to kinin receptors stimulation in anastrozole-treated animals. Thus, regulating this signaling pathway could contribute to alleviating AIs-related pain symptoms, patients’ adherence to therapy, and disease control.

Athirah Saiful Bahri, Tuan Mazlelaa Tuan Mahmood, Siti Azdiah Abdul-Aziz, Mohd Makmor-Bakry, Noraida Mohamed Shah Centre of Quality Management of Medicines, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, MalaysiaCorrespondence: Noraida Mohamed ShahCentre of Quality Management of Medicines, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, 50300, MalaysiaTel +60 3 9289 8038Email noraida_mshah@ukm.edu.myContext: Globally, breast cancer is the most common cancer affecting women, and adjuvant endocrine therapy (AET) is part of its treatment modality, which improves patients’ outcome. However, there are concerns on side effects related to its use, which may affect treatment adherence.Purpose: This study was conducted to explore attitude and practice on using AET among breast cancer patients in Malaysia.Patients and Methods: Postmenopausal breast cancer patients on at least 3 months of AET attending the outpatient oncology clinic at a tertiary care hospital were interviewed. Patients underwent in-depth interviews exploring their attitude and practices while on AET using a semi-structured interview guide. The interviews were transcribed verbatim and analyzed using thematic analysis.Results: There were four main themes for attitude toward the use of AET: 1) benefits of using AET, 2) concerns on taking AET, 3) beliefs on alternative treatment, and 4) beliefs toward the doctor. For practice, six themes were obtained: 1) correct use of AET, 2) appointment adherence, 3) information-seeking behavior, 4) counseling services obtained, 5) experienced side effects of AET, and 6) usage of complementary and alternative medicines.Conclusion: Several themes concerning attitude and practice of breast cancer patients receiving AET were identified, which may be addressed during treatment consultations in clinical practice.Keywords: adjuvant endocrine therapy, breast cancer, interview, attitude, practice

Athirah Saiful Bahri, Tuan Mazlelaa Tuan Mahmood, Siti Azdiah Abdul-Aziz, Mohd Makmor-Bakry, Noraida Mohamed Shah Centre of Quality Management of Medicines, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, MalaysiaCorrespondence: Noraida Mohamed ShahCentre of Quality Management of Medicines, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, 50300, MalaysiaTel +60 3 9289 8038Email noraida_mshah@ukm.edu.myContext: Globally, breast cancer is the most common cancer affecting women, and adjuvant endocrine therapy (AET) is part of its treatment modality, which improves patients’ outcome. However, there are concerns on side effects related to its use, which may affect treatment adherence.Purpose: This study was conducted to explore attitude and practice on using AET among breast cancer patients in Malaysia.Patients and Methods: Postmenopausal breast cancer patients on at least 3 months of AET attending the outpatient oncology clinic at a tertiary care hospital were interviewed. Patients underwent in-depth interviews exploring their attitude and practices while on AET using a semi-structured interview guide. The interviews were transcribed verbatim and analyzed using thematic analysis.Results: There were four main themes for attitude toward the use of AET: 1) benefits of using AET, 2) concerns on taking AET, 3) beliefs on alternative treatment, and 4) beliefs toward the doctor. For practice, six themes were obtained: 1) correct use of AET, 2) appointment adherence, 3) information-seeking behavior, 4) counseling services obtained, 5) experienced side effects of AET, and 6) usage of complementary and alternative medicines.Conclusion: Several themes concerning attitude and practice of breast cancer patients receiving AET were identified, which may be addressed during treatment consultations in clinical practice.Keywords: adjuvant endocrine therapy, breast cancer, interview, attitude, practice

Introduction: Endocrine therapy for breast cancer (BC) patients is highly underutilized in rural Ethiopia and other African countries. Objective: This study aims to assess the feasibility of and adherence to tamoxifen therapy in rural Ethiopia. Methods: We ascertained the hormone receptor (HR) status in 101 women diagnosed with BC from January 2010 to December 2015 and who had surgery in Aira Hospital, in rural Ethiopia. From 2013, tamoxifen was offered to patients with HR-positive (HR+) tumors. Prescription refill records and a structured questionnaire were used to assess receipt of and adherence to tamoxifen. Results: Of the 101 BC patients tested for HR status during the study period, 66 (65%) patients were HR+ and were eligible for tamoxifen treatment. However, 15 of the HR+ patients died before tamoxifen became available in 2013. Of the remaining 51 HR+ patients, 26 (51%) initiated tamoxifen but only 9 of them (35%) adhered to therapy (medication possession rate ≥80%, median observation 16.2 months). After 1 year, 52% of the patients were still adherent, and 9 patients had discontinued therapy. The reasons for non-initiation of tamoxifen included patient factors (n = 5), including financial hardship or lack of transportation, and health care provider factors (n = 12). Conclusions: Endocrine therapy for BC patients seems feasible in rural Western Ethiopia, although non-adherence due to financial hardship and a less developed health care infrastructure remains a major challenge. We postulate that the implementation of breast nurses could reduce patient and health system barriers and improve initiation of and adherence to endocrine treatment.

There is an increasing trend towards using oral antitumoral agents in oncological patients. Compared to parenteral therapy, oral treatment offers convenience for both the patient and the healthcare system, with similar efficacy. However, the benefit deriving from oral drugs will be obtained only if patients adhere strictly to the treatment. Medical oncologists must therefore seek to optimize patient adherence. Breast cancer patients, particularly, are often treated with oral hormonal anticancer agents. In this review, we summarized evidence about adherence of breast cancer patients to oral hormonal anticancer agents and the consequences of poor compliance, the barriers to oral treatment and strategies to overcome them.

Endocrine therapy represents the gold standard for the adjuvant treatment of luminal-like early breast cancer, but its personalization is still a major point of debate. To define the most appropriate therapeutic strategy, both the patient's menopausal status at the moment of diagnosis and the individual risk of disease recurrence should be taken into account. Five years of therapy with tamoxifen represent the standard of care for low-risk pre/perimenopausal patients, whilst the combination of ovarian suppression with tamoxifen or an aromatase inhibitor should be considered for high-risk patients. Also, to high-risk patients, an extended strategy can be proposed. Postmenopausal patients, instead, should receive an upfront aromatase inhibitor and an extended strategy can be considered for a high risk of disease recurrence. Aim of this review is to set a focus on the major studies investigating the optimal type and duration of adjuvant endocrine therapy and evaluate emerging options.

Background Long-term use of adjuvant endocrine therapy (AET) among women with early-stage, hormone receptor-positive breast cancer significantly reduces the risk of hospitalizations, cancer recurrence, and mortality. AET is associated with adverse symptoms that often result in poor adherence. A web-enabled app offers a novel way to communicate and manage symptoms for women on AET. In a region with significant racial disparities in breast cancer outcomes, our study tests the impact of a web-enabled app that collects and transmits patient-reported symptoms to healthcare teams to facilitate timely and responsive symptom management on medication adherence. Methods In this randomized controlled trial, we randomize 300 patients initiating AET to one of three arms: 1) an “App” group (n = 100) that receives weekly reminders to use the THRIVE study app; 2) an “App+Feedback” group (n = 100) that receives weekly reminders and tailored feedback based on their use of the app; or 3) a “Usual Care” group (n = 100) that receives usual care only. Participants are stratified by race: 50% White and 50% Black. The duration of the intervention is six months following enrollment, and outcomes are assessed at 12-months. The primary outcome is adherence, which is captured using an electronic monitoring pillbox. Secondary outcomes include symptom burden, quality of life, self-efficacy for managing symptoms, and healthcare costs. We also evaluate the impact of the intervention on racial disparities in adherence. Data are derived from three sources: electronic health record data to capture treatment changes, healthcare utilization, and health outcomes; self-report survey data related to adherence, symptom burden, and quality of life; and an electronic medication monitoring device that captures adherence. Discussion A successful web-enabled intervention could be disseminated across systems, conditions, and populations. By evaluating the impact of this intervention on a comprehensive set of measures, including AET adherence, patient outcomes, and costs, our study will provide valuable and actionable results for providers, policy makers, and insurers who strive to achieve the “Triple Aim” – reduce costs while improving health outcomes and the patient care experience. Trial registration NCT03592771. Prospectively registered on July 19, 2018.

Purpose Side-effects of adjuvant endocrine therapy (AET) are common in breast cancer survivors, and can affect adherence to treatment. We synthesised the evidence for strategies to self-manage these side-effects. Methods We searched for systematic reviews and clinical guidelines on self-management strategies for AET side-effects (arthralgia, fatigue, hot flashes, gastrointestinal discomfort, nausea, vulvovaginal symptoms, and sleep disturbance). We searched oncology organisation’s websites and eight databases (Inception-November 2020). Screening, data extraction and quality assessment were completed independently in duplicate. PROSPERO: 2019CRD4201914001. Results We identified 33 systematic reviews and 18 clinical guidelines. 21% of reviews were high quality, and the average quality score for guidelines was 44%. Evidence for most strategies was absent or weak. There was consensus from a low-quality review and multiple guidelines to recommend moisturisers, gels and lubricants for vulvovaginal symptoms. Evidence was weak for physical activity for self-managing most symptoms, although two high-quality reviews indicated yoga and aerobic exercise could reduce fatigue. Primary research was often biased by weak and underpowered study designs. Eleven reviews did not report information on adverse events. Conclusions Most self-management strategies for breast cancer survivors experiencing side-effects from AET lack evidence. Primary research is needed using high-quality well-powered designs focusing on implementable strategies. Implications for Cancer Survivors Patients and clinicians should be aware that although the risk of harm is low for these self-management strategies, the likelihood of benefit is often unclear. Women should consider moisturisers, gels or lubricants for self-managing vulvovaginal symptoms, and yoga or aerobic exercise for alleviating fatigue.

Kirsti I Toivonen,1 Linda E Carlson,2,3 Joshua A Rash,4 Tavis S Campbell1 1Department of Psychology, University of Calgary, Calgary, AB, Canada; 2Department of Oncology, University of Calgary, Calgary, AB, Canada; 3Department of Psychosocial Resources, Tom Baker Cancer Centre, Calgary, AB, Canada; 4Department of Psychology, Memorial University of Newfoundland, St. John’s, NL, CanadaCorrespondence: Tavis S CampbellDepartment of Psychology, University of Calgary, 2500 University Dr NW, Calgary, T2N 1N4, AB, CanadaTel +1 403-210-8606Email t.s.campbell@ucalgary.caPurpose: Despite the efficacy of adjuvant endocrine therapy (AET) in reducing breast cancer recurrence and mortality, suboptimal AET adherence is common and hence an important clinical issue among breast cancer survivors. Delineating potentially modifiable patient-level factors associated with AET adherence may support the development of successful adherence-enhancing interventions.Patients and Methods: The present study included 133 breast cancer survivors prescribed AET recruited from a cancer pharmacy. Women completed a baseline questionnaire examining psychosocial factors and self-reported adherence and consented to their prescription records being monitored for the proceeding 12 months to ascertain proportion of days covered (PDC), an objective measure of adherence. Regression analyses were used to identify the factors most strongly associated with both self-reported and objective adherence. Exploratory moderation analyses examined whether factors were differentially associated with adherence based on AET type (aromatase inhibitors or tamoxifen).Results: Adherence was high in this sample (PDC over 12 months was 95%). Side effect severity was most strongly associated with self-reported adherence, followed by self-efficacy, and medication/healthcare system-related barriers. Medication/healthcare system-related barriers was the only factor that uniquely predicted objective adherence. Within medication/healthcare system-related barriers, fear of side effects was most strongly associated with both measures of adherence. There were no significant interactions between AET type and potentially modifiable factors in predicting self-reported or objective adherence.Conclusion: Side effects, reactions to side effects, and self-efficacy may represent modifiable targets through which AET adherence can be improved. Associations between potentially modifiable factors and adherence did not vary by AET type, despite distinct side-effect profiles.Keywords: adjuvant endocrine therapy, breast cancer, adherence, patient reported outcomes, side effects, symptom management

ispartof: EUROPEAN JOURNAL OF GYNAECOLOGICAL ONCOLOGY vol:42 issue:4 pages:621-633 status: published

Background: Ovarian function suppressor (OFS) plus either tamoxifen (TAM) or aromatase inhibitor (AI) could improve the survival outcome for premenopausal hormone receptor-positive (HR+) breast cancer. However, the optimal OFS-based regimen and medication duration remain uncertain. This article aims to systematically evaluate the OFS-based adjuvant endocrine therapy for premenopausal breast cancer. Methods: We searched several public databases from January 1980 to November 2020. A random model was adopted in this meta-analysis. We used the hazard ratio (HR) with a 95% confidence interval (CI) for the statistical analysis of efficacy. The primary outcome measures included overall survival and disease-free survival. Results: A total of 32 articles with 37,224 cases were included in this network meta-analysis. OFS+TAM improved 5-year disease-free survival (HR –0.09, 95% CI –0.16 to –0.01) and 5-year overall survival (HR –0.18, 95% CI –0.33 to –0.03) compared with TAM monotherapy. For OFS+AI, although the 5-year disease-free survival was improved (HR –0.18, 95% CI –0.29 to –0.08), the 5-year overall survival was not improved (HR –0.13, 95% CI –0.43 to 0.18). In subgroup analysis, both OFS+AI and OFS+TAM showed a protective effect in stage I–III patients compared with stage I–II patients. For the course of therapy, OFS+TAM for 2-years could achieve clinical benefit and the best course of therapy of OFS+AI still waits for further study. Conclusions: OFS+TAM might be a better option than OFS+AI for premenopausal intensive adjuvant endocrine therapy. Stage III patients are more suitable for the OFS-based therapy. For the medication duration, the 2-years course of OFS+TAM could be effective. This analysis provides helpful information for selecting therapeutic regimen in intensive adjuvant endocrine therapy and identifying the target population.

Lei Xu1, Aiping Wang2 1Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 2Department of Nursing, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of ChinaCorrespondence: Aiping WangDepartment of Nursing, The First Affiliated Hospital of China Medical University, No. 155, Nanjing St. Heping District, Shenyang 110001, People’s Republic of ChinaTel +86 248 328 2827Fax +86 248 328 2830Email jianghaoran88@hotmail.comObjective: The aim of this study is to describe the connotations of health beliefs about adjuvant endocrine therapy (AET) in premenopausal breast cancer survivors in Northeast China and to explore the reasons underlying bad behaviours and influential factors of AET adherence and persistence.Methods: Semi-structured interviews were conducted using a qualitative description research method with 30 premenopausal breast cancer survivors who had undergone surgery and AET for more than half a year. The researcher collected and coded the interview transcripts and extracted the concepts and themes.Results: Two main categories of themes regarding the health beliefs of survivors who were undergoing AET were formed in the conceptual framework: connotations and modifiable factors. Subcategories of the first category included perceptions of the survivors regarding the risks and effects of recurrence or metastasis of breast cancer; the methods, benefits and barriers of AET; behavioural clues; and self-efficacy. Subcategories of the second category included religious belief, disposition, matrimony and other demographic factors as well as traditional Chinese female characteristics, gender role and other socio-cultural factors.Conclusion: Demographic, socio-cultural and other factors play an important role in the health beliefs of breast cancer survivors. Health beliefs such as related knowledge of AET, related cognition of recurrence or metastasis of breast cancer directly affect adherence to and persistence with AET. Therefore, implementing interventions with respect to health beliefs may enhance adherence to AET.Keywords: adherence, adjuvant endocrine therapy, breast neoplasm, health belief

ObjectiveTo assess adherence to endocrine therapy and its relation to recurrence and mortality in women with early breast cancer.MethodsThis is a retrospective cohort study in population-based cancer registries in two Catalonian provinces of Spain. We included all cases of invasive stage I-III breast cancer diagnosed from 2007 to 2011 and with follow-up to 2017. Adherence to endocrine therapy was measured by means of prescription refills. Patients were considered non-adherent if they filled less than 80% of their prescriptions. After collecting data from patients' medical records, we analysed clinical variables and their relation with adherence by means of logistic and Cox regression models.ResultsThe study included 2413 women. Five-year adherence was 84.5%; the greatest risk for non-adherence was in women under 50years of age, diagnosed with stage III cancer, treated with neoadjuvant therapy, or receiving tamoxifen or sequential treatment. Adverse effects were associated with greater adherence. Non-adherence was significantly and independently associated with recurrence (hazard ratio [HR] 1.71, 95% confidence interval [CI] 1.16-2.51) and all-cause mortality (HR 2.11, 95% CI 1.62-2.74), after adjusting for age and tumour stage.ConclusionsAlthough non-adherence was relatively infrequent in this population-based study, its impact on the risk of recurrence and mortality was considerable. Clinicians should make efforts to ensure therapeutic adherence during clinical follow-up of women with breast cancer.

Jo Brett, Mary Boulton, Eila Watson Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0FL, UK Background: Adjuvant endocrine therapy (AET) is prescribed to women for 5–10 years after treatment for estrogen receptor positive (ER+ve), early-stage breast cancer. AET has proven effectiveness in reducing the risk of recurrence of breast cancer and mortality. However, adherence is known to be suboptimal with around 20% discontinuing by 2 years and up to 50% discontinuing by 5 years. Interventions are needed to support women taking AET after breast cancer. The aim of this study was to develop and pilot test an e-health app for this population. Methods: Two focus groups (n=15) and five interviews were conducted with women following treatment for early-stage breast cancer to assess the likely acceptability of an e-health app and to inform the content (Phase I). Following development of a prototype e-health app, a simple heuristic usability test was completed by five women in order to identify any design usability problems (Phase II). A further 18 women used the app for 1 month between July and August 2016, after which they were interviewed by telephone to collect their experiences and views of the app (Phase III). Results: The prototype e-health app included evidence-based information on effectiveness of AET, an electronic side-effects diary, a peer support forum, a repeat prescription reminder, suggested strategies for facilitating adherence and managing any side effects that occur, and a link to further evidence and useful organizations for further information and support. The app was received positively by women. Women found the app useful as it emphasized the importance of taking AET, helped them manage their side effects and provided details of support organizations, while offering empathy and exchange of suggestions for self-management strategies through the peer support forum. Conclusion: Overall, findings suggest that this novel e-health app has potential as a feasible medium for promoting adherence to AET. Future research should evaluate the efficacy of the app in supporting women and promoting adherence. Keywords: adjuvant endocrine therapy, breast cancer, e-health app, support

Jessica Keim-Malpass,1 Aubrey Doede,1 Shayna L Showalter2 1Department of Acute and Specialty Care, University of Virginia School of Nursing, Charlottesville, VA 22908, USA; 2Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, USA Purpose: Functional health literacy is critical for patients’ functional understanding and management of disease including adherence to medications and treatment recommendations. The purpose of this study was to determine if there is a relationship between self-reported health literacy and 1) decision to take adjuvant endocrine therapy and 2) adherence to adjuvant endocrine therapy at 2 years among women with breast cancer.Methods: We initiated a prospective health literacy assessment to determine the relationship between health literacy and breast health outcomes. Among our overall cohort, we determined women who had estrogen receptor positive (ER+) disease and were recommended to take adjuvant endocrine therapy, those who initiated treatment, and those adherent at 2 years following diagnosis. Descriptive statistics and logistic regression were calculated to determine the relationship between health literacy and both initiation and adherence.Results: Among the 340 patients in the sample who were recommended to take adjuvant endocrine therapy, 296 (87.1%) initiated the therapy. Two-year follow-up data are available in 136 patients with ER+ tumors. Among the patients with 2-year longitudinal data available, 108 (79.4%) were adherent and still taking the endocrine therapy at 2years following diagnosis. In univariate logistic regression analysis, there was no statistical significance between health literacy and initiation of adjuvant endocrine therapy or adherence to adjuvant endocrine therapy at 2 years.Conclusion: Despite the underpinnings regarding health literacy and medication adherence supporting our hypothesis, we did not find an association between health literacy and the decision to initiate therapy or continued adherence at 2 years following diagnosis. Further study is needed to determine the nuances in adherence to adjuvant endocrine therapy for women with breast cancer. Keywords: health literacy, adjuvant endocrine therapy, breast cancer, adherence

Jessica Keim-Malpass,1 Aubrey Doede,1 Shayna L Showalter2 1Department of Acute and Specialty Care, University of Virginia School of Nursing, Charlottesville, VA 22908, USA; 2Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, USA Purpose: Functional health literacy is critical for patients’ functional understanding and management of disease including adherence to medications and treatment recommendations. The purpose of this study was to determine if there is a relationship between self-reported health literacy and 1) decision to take adjuvant endocrine therapy and 2) adherence to adjuvant endocrine therapy at 2 years among women with breast cancer.Methods: We initiated a prospective health literacy assessment to determine the relationship between health literacy and breast health outcomes. Among our overall cohort, we determined women who had estrogen receptor positive (ER+) disease and were recommended to take adjuvant endocrine therapy, those who initiated treatment, and those adherent at 2 years following diagnosis. Descriptive statistics and logistic regression were calculated to determine the relationship between health literacy and both initiation and adherence.Results: Among the 340 patients in the sample who were recommended to take adjuvant endocrine therapy, 296 (87.1%) initiated the therapy. Two-year follow-up data are available in 136 patients with ER+ tumors. Among the patients with 2-year longitudinal data available, 108 (79.4%) were adherent and still taking the endocrine therapy at 2years following diagnosis. In univariate logistic regression analysis, there was no statistical significance between health literacy and initiation of adjuvant endocrine therapy or adherence to adjuvant endocrine therapy at 2 years.Conclusion: Despite the underpinnings regarding health literacy and medication adherence supporting our hypothesis, we did not find an association between health literacy and the decision to initiate therapy or continued adherence at 2 years following diagnosis. Further study is needed to determine the nuances in adherence to adjuvant endocrine therapy for women with breast cancer. Keywords: health literacy, adjuvant endocrine therapy, breast cancer, adherence

Background Socioeconomic differences in receipt of adjuvant treatment contribute to persistent disparities in breast cancer (BCA) outcomes, including survival. Adjuvant endocrine therapy (AET) substantially reduces recurrence risk and is recommended by clinical guidelines for nearly all women with hormone receptor-positive non-metastatic BCA. However, AET use among uninsured or underinsured populations has been understudied. The health reform implemented by the US state of Massachusetts in 2006 expanded health insurance coverage and increased the scope of benefits for many with coverage. This study examines changes in the initiation of AET among BCA patients in Massachusetts after the health reform. Methods We used Massachusetts Cancer Registry data from 2004 to 2013 for a sample of estrogen receptor (ER)-positive BCA surgical patients aged 20–64 years. We estimated multivariable regression models to assess differential changes in the likelihood initiating AET after Massachusetts health reform by area-level income, comparing women from lower- and higher-income ZIP codes in Massachusetts. Results There was a 5-percentage point (p-value Conclusions The expansion of health insurance in Massachusetts was associated with a significant relative increase in the likelihood of AET initiation among women in low-income areas compared with those in high-income areas. Our results suggest that expansions of health insurance coverage and improved access to care can increase the number of eligible patients initiating AET and may ameliorate socioeconomic disparities in BCA outcomes.

Background Age-related breast cancer treatment variance is widespread with many older women having primary endocrine therapy (PET), which may contribute to inferior survival and local control. This propensity-matched study determined if a subgroup of older women may safely be offered PET. Methods Multicentre, prospective, UK, observational cohort study with propensity-matched analysis to determine optimal allocation of surgery plus ET (S+ET) or PET in women aged ≥70 with breast cancer. Data on fitness, frailty, cancer stage, grade, biotype, treatment and quality of life were collected. Propensity-matching (based on age, health status and cancer stage) adjusted for allocation bias when comparing S+ET with PET. Findings A total of 3416 women (median age 77, range 69–102) were recruited from 56 breast units—2854 (88%) had ER+ breast cancer: 2354 had S+ET and 500 PET. Median follow-up was 52 months. Patients treated with PET were older and frailer than patients treated with S+ET. Unmatched overall survival was inferior in the PET group (hazard ratio, (HR) 0.27, 95% confidence interval (CI) 0.23–0.33, P 90 years or >85 with comorbidities or frailty) individualised decision making regarding PET versus S+ET may be appropriate and safe to offer. The Age Gap online decision tool may support this decision-making process (https://agegap.shef.ac.uk/). Trial registration number ISRCTN: 46099296., Highlights • Propensity matched study of women >70 with breast cancer comparing surgery or PET • Unmatched analysis found surgery improves overall & disease-specific survival. • Matched analysis (stage, age, health, frailty) found similar disease-specific survival • Surgery led to adverse events in 19% & negative impacts on QoL and physical function • Less fit women >85 may be offered PET to reduce morbidity, without survival detriment

Purpose The status of TP53 mutations was measured in cell-free DNA from patients with metastatic breast cancer (MBC) to investigate disease characteristics and the prognostic role of different locations of the TP53 mutation site. Patients and Methods Blood samples were taken from a total of 187 patients diagnosed with MBC who were treated at the Department of Breast Oncology, Peking University Cancer Hospital between January 2013 and March 2020. Next-generation sequencing was used to investigate the TP53 mutation spectra of circulating free DNA in these blood samples. Results Among the 187 MBC patients, TP53-mutated patients had a significantly shorter median disease-free survival (DFS) and overall survival (OS) compared with TP53 wild-type patients (P=0.001 and P=0.006, respectively). Additionally, in hormone receptor positive/HER2 negative (HR+/HER2-) and triple negative (TNBC) cohorts, TP53-mutated patients had a significantly shorter median DFS than TP53 wild-type patients (P=0.038 and P=0.023, respectively). The 79 patients with TP53 mutations carried 87 somatic TP53 mutations, of which most (77.0%) mapped to the DNA-binding domain (DBD) of the protein encoded by TP53 exons 5–8. In patients with TP53 mutations, those occurring in the non-DBD had a significantly shorter median DFS and OS than TP53 wild type (P

Simple Summary Endocrine therapy taken after primary breast cancer treatment helps prevent breast cancer recurrence. However, many women are unable to adhere to endocrine therapy. This review examines potentially modifiable factors that are associated with endocrine therapy adherence, which might help future efforts to improve endocrine therapy use. Six categories of factors were identified: side effects, attitudes toward endocrine therapy, psychological factors, healthcare provider-related factors, sociocultural factors, and general or quality of life factors. Overall, self-efficacy (i.e., one’s belief in their ability to do something) and positive decisional balance (i.e., one’s belief that the benefits of endocrine therapy outweigh the risks) were the most consistently associated with adherence. They might represent factors worth investigating in future studies seeking to support the adherence of breast cancer survivors. Abstract Adjuvant endocrine therapy (AET) reduces risk of breast cancer recurrence. However, suboptimal adherence and persistence to AET remain important clinical issues. Understanding factors associated with adherence may help inform efforts to improve use of AET as prescribed. The present systematic review examined potentially modifiable factors associated with adherence to AET in accordance with PRISMA guidelines (PROSPERO registration ID: CRD42019124200). All studies were included, whether factors were significantly associated with adherence or results were null. This review also accounted for the frequency with which a potentially modifiable factor was examined and whether univariate or multivariate models were used. This review also examined whether methodological or sample characteristics were associated with the likelihood of a factor being associated with AET adherence. A total of 68 articles were included. Potentially modifiable factors were grouped into six categories: side effects, attitudes toward AET, psychological factors, healthcare provider-related factors, sociocultural factors, and general/quality of life factors. Side effects were less likely to be associated with adherence in studies with retrospective or cross-sectional than prospective designs. Self-efficacy (psychological factor) and positive decisional balance (attitude toward AET) were the only potentially modifiable factors examined ≥10 times and associated with adherence or persistence ≥75% of the time in both univariate and multivariate models. Self-efficacy and decisional balance (i.e., weight of pros vs. cons) were the potentially modifiable factors most consistently associated with adherence, and hence may be worth focusing on as targets for interventions to improve AET adherence among breast cancer survivors.

In response to Choosing Wisely recommendations that sentinel lymph node biopsy (slnb) should not be routinely performed in elderly patients with node-negative (cN0), estrogen receptor&ndash, positive (er+) breast cancer, we sought to evaluate how nodal staging affects adjuvant treatment in this population. From a prospective database, we identified patients 70 or more years of age with cN0 breast cancer treated with surgery for er+ her2-negative invasive disease during 2012&ndash, 2016. We determined rates of, and factors associated with, nodal positivity (pN+), and compared the use of adjuvant radiation (rt) and systemic therapy by nodal status. Of 364 patients who met the inclusion criteria, 331 (91%) underwent slnb, with 75 (23%) being pN+. Axillary node dissection was performed in 11 patients (3%). On multivariate analysis, tumour size was the only factor associated with pN+ (p = 0.007). Nodal positivity rates were 0%, 13%, 23%, 33%, and 27% for lesions preoperatively sized at 0&ndash, 0.5 cm, 0.5&ndash, 1 cm, 1.1&ndash, 2.0 cm, 2.1&ndash, 5.0 cm, and more than 5.0 cm. Compared with patients assessed as node-negative, those who were pN+ were more likely to receive axillary rt (lumpectomy: 53% vs. 1%, p < 0.001, mastectomy: 43% vs. 2%, p < 0.001), and adjuvant systemic therapy (endocrine: 82% vs. 69%, chemotherapy plus endocrine: 7% vs. 2%, p = 0.002). Of elderly patients with cN0 er+ breast cancer, 23% were pN+ on slnb. Size was the primary predictor of nodal status, and yet significant rates of nodal positivity were observed even in tumours preoperatively sized at 1 cm or less. The use of rt and systemic adjuvant therapies differed by nodal status, although the long-term oncologic implications require further investigation. Multidisciplinary input on a case-by-case basis should be considered before omission of slnb.

BACKGROUND Compared to tamoxifen, adjuvant treatment with aromatase inhibitors improves disease outcomes of postmenopausal women with hormone receptor-positive early breast cancer. In the international, randomized, double-blind BIG 1-98 trial, 8010 women were randomized to receive tamoxifen, letrozole, or sequential use of the agents for 5 years. With a focus on switching between agents, we investigated cardiovascular events over the entire 5-year treatment period. METHODS Of the 6182 patients enrolled, 6144 started trial treatment and were included in this analysis. Adverse events occurring during study treatment until 30 days after cessation were considered. Eight cardiovascular event types were defined. Cumulative incidence of events were estimated using the Kaplan-Meier method, without consideration for competing events. Multivariable Cox models estimated hazard ratios (HR) with 95% confidence intervals (CI) for pairwise comparisons of treatment arms. RESULTS While on study treatment, 6.5% of patients (n = 397) had any cardiac events reported; for 2.4%, the event was grades 3-5, of which 11 (0.2%) were grade 5. Letrozole monotherapy was associated with higher risk of grade 1-5 ischemic heart disease (HR = 1.81; 95% CI, 1.06-3.08) compared with tamoxifen monotherapy. Patients assigned sequential tamoxifen →letrozole (HR = 1.59; 95% CI, 0.92-2.74) or sequential letrozole → tamoxifen (HR = 1.20; 95% CI, 0.68-2.14) showed a lesser degree of risk elevation. Patients assigned to tamoxifen-containing regimens had significantly higher risk of grade 1-5 thromboembolic events (tamoxifen monotherapy HR = 2.10; 95% CI, 1.42-3.12; tamoxifen → letrozole HR = 1.96; 95% CI, 1.32-2.92; letrozole → tamoxifen HR = 1.56; 95% CI 1.03-2.35) as compared with patients assigned letrozole alone. CONCLUSION When initiating or switching between adjuvant endocrine treatments in postmenopausal patients, age and medical history, with special attention to prior cardiovascular events, should be balanced with expected benefit of the treatment.

Background Previously, we conducted the 5-year open-label, randomized controlled trial (RCT) of leuprorelin adjuvant therapy in post-operative premenopausal patients with endocrine-responsive breast cancer, which was a pilot study to investigate the optimal duration of leuprorelin treatment. Since, however, long-term outcomes became required for the adjuvant endocrine therapy, we performed this follow-up observation study. Methods Follow-up observation study was performed up to 10th year after randomization, continuing RCT to evaluate the efficacy and safety of leuprorelin every 3 months for ≥ 3 versus 2 years, with daily tamoxifen for 5 years. Primary endpoints were disease-free survival (DFS) and 2-year landmark DFS. Results Eligible patients (N = 222) were randomly assigned to receive leuprorelin for either 2 years (N = 112) or ≥ 3 years (N = 110) with tamoxifen. Leuprorelin treatment for ≥ 3 years versus 2 years provided no significant difference in DFS (HR 0.944, 95% CI 0.486–1.8392) or 2-year landmark DFS (N = 99 and 102 in 2-year and ≥ 3-year groups, HR 0.834, 0.397–1.753). In small, higher-risk subgroup (n = 17); however, 2-year landmark DFS in ≥ 3-year group was significantly longer (HR 0.095, 0.011–0.850) than that in 2-year group. The incidence of bone-related adverse events was around 5% in both groups. Conclusions Adjuvant leuprorelin treatment for ≥ 3 years with tamoxifen only showed similar efficacy and safety profiles to those for 2 years in analyses among all patients but suggested greater benefit in higher-risk patients. No new safety signal was identified for long-term leuprorelin treatment. Trial registration number Not applicable. This was an observational study.

International audience; Purpose: Despite the benefits of adjuvant endocrine therapy (AET) for reducing recurrence and mortality risks after hormone-sensitive breast cancer, AET adherence is sub-optimal for a high proportion of women. However, little is known about long-term patterns of AET adherence over the minimally recommended 5 years. Our objectives were to: (1) identify 5-year AET adherence trajectory groups; (2) describe trajectory groups according to adherence measures traditionally used (i.e., Proportion of Days Covered); and (3) explore factors associated with trajectories.Methods: We conducted a 5-year cohort study using data from a French national study that included AET dispensing data. Women diagnosed with first non-metastatic breast cancer and having at least 1 AET dispensing in the 12 months after diagnosis were included. Group-based trajectory modeling was used to identify adherence trajectory groups by clustering similar patterns of monthly AET dispensing. Multinomial logistic regressions were used to identify factors associated with trajectories.Results: Among 674 women, five AET adherence trajectory groups were identified: (1) quick decline and stop (5.2% of women); (2) moderate decline and stop (6.4%); (3) slow decline (17.2%); (4) high adherence (30.0%); and (5) maintenance of very high adherence (41.2%). Mean 5-year Proportion of Days Covered varied from 10 to 97% according to trajectories. Women who did not receive chemotherapy or a personalized care plan were more likely to belong to trajectories where AET adherence declined and stopped.Conclusion: Our results provide information on the diversity of longitudinal AET adherence patterns, the timing of decline and discontinuation and associated factors that could inform healthcare professionals.

Adjuvant endocrine therapy (AET) for ≥ 5 years is generally recommended for women with hormone receptor-positive breast cancer to reduce cancer recurrence/mortality; however, adherence can be suboptimal. We tested determinants of AET adherence using patient characteristics, treatment pathways, AET initiation timing, and multiple healthcare facility use. An underlying objective was to explore how oncological pathways mirror chronic disease management to monitor adherence and target improvement interventions using administrative datasets. Using patient-linked administrative health data from the Italian Lombardy Region, we identified 33.291 surviving patients starting AET in 2010–2016, with two (22.939 patients) or five years (8400 patients) follow-up, using a ≥ 80% prescription refill approach to measure adherence and logistic regression to test determinants of adherence. AET crude adherence falls significantly during follow-up, from 94% at 1 Year to 58% at 5 Years. At 5 Years, patients who were older (>70), prescribed tamoxifen-only (OR 0.69; 95% CI 0.57–0.83; p = 0.0001) vs. aromatase inhibitors-only or therapy switches, treated for depression (OR 0.68; 95% CI 0.60–0.78; p

Interest in adjuvant endocrine therapy in the treatment of women with breast cancer does not fade for many years. In recent decades, more and more attention has been paid to the role of ovarian suppression. Recent publications and data from international congresses confirm the necessity of prescribing predominantly medicamentous ovarian suppression to women with breast cancer and preserved menstrual function not only as a therapy but also for fertility preservation.

// Ingeborg J.H. Vriens 1 , Ashley J.R. De Bie 1 , Maureen J.B. Aarts 1 , Maaike de Boer 1 , Irene E.G. van Hellemond 1 , Joyce H.E. Roijen 1 , Ron J.T. van Golde 2 , Adri C. Voogd 1 , Vivianne C.G. Tjan-Heijnen 1 1 Department of Medical Oncology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands 2 Department of Obstetrics and Gynaecology, Maastricht University Medical Center, Maastricht, The Netherlands Correspondence to: Vivianne C.G. Tjan-Heijnen, email: vcg.tjan.heijnen@mumc.nl Keywords: chemotherapy induced ovarian function failure, breast cancer, chemotherapy, ovarian insufficiency, premenopausal patients Received: July 20, 2016 Accepted: December 26, 2016 Published: January 05, 2017 ABSTRACT Purpose: To assess the incidence of chemotherapy-induced ovarian function failure (COFF) based on estradiol and follicle stimulating hormone (FSH) monitoring in premenopausal women with hormone-receptor positive breast cancer treated with second and third generation (neo-)adjuvant chemotherapy. Results: We identified 115 eligible women. Two years after start of chemotherapy, COFF was significantly more often present in women ≥ 40 years (85.6%) as compared to women < 40 years (8.7%). Only age was significantly associated with COFF two years after start of chemotherapy (HR 12.26; 95% CI 5.21–28.86). In 50% of the patients, premenopausal hormone levels were the first or only evidence of ovarian function recovery (OFR). Materials and Methods: We included all premenopausal women with hormone-receptor positive breast cancer treated with anthracycline-based chemotherapy, with or without taxanes, in our university hospital in the Netherlands in the years 2005-2013. Patients were 3-monthly monitored for ovarian function. Cox proportional hazards model was used to determine the predictive impact of various parameters on the occurrence of COFF. Conclusions: After second- or third generation (neo-)adjuvant chemotherapy, COFF was still present in 8.7% of patients < 40 years after two years. FSH and estradiol monitoring may be relevant for those in whom ovarian function suppression is considered an additional effective endocrine treatment.

Objective The aim of this study is to describe the connotations of health beliefs about adjuvant endocrine therapy (AET) in premenopausal breast cancer survivors in Northeast China and to explore the reasons underlying bad behaviours and influential factors of AET adherence and persistence. Methods Semi-structured interviews were conducted using a qualitative description research method with 30 premenopausal breast cancer survivors who had undergone surgery and AET for more than half a year. The researcher collected and coded the interview transcripts and extracted the concepts and themes. Results Two main categories of themes regarding the health beliefs of survivors who were undergoing AET were formed in the conceptual framework: connotations and modifiable factors. Subcategories of the first category included perceptions of the survivors regarding the risks and effects of recurrence or metastasis of breast cancer; the methods, benefits and barriers of AET; behavioural clues; and self-efficacy. Subcategories of the second category included religious belief, disposition, matrimony and other demographic factors as well as traditional Chinese female characteristics, gender role and other socio-cultural factors. Conclusion Demographic, socio-cultural and other factors play an important role in the health beliefs of breast cancer survivors. Health beliefs such as related knowledge of AET, related cognition of recurrence or metastasis of breast cancer directly affect adherence to and persistence with AET. Therefore, implementing interventions with respect to health beliefs may enhance adherence to AET.

Background. The aim of this study was to evaluate the prognostic potential of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) tumor tissue levels and examine the association between these biomarkers and classical prognostic factors in early node-negative luminal breast cancer patients. The clinical value of 4G/5G variants of PAI-1 gene was evaluated. Patients and methods. This study involved 81 node-negative, estrogen receptor-positive and/or progesterone receptor-positive and human epidermal growth factor receptor 2-negative operable breast cancer patients who underwent radical surgical resection and received adjuvant endocrine therapy. Determination of uPA and PAI-1 concentrations in the breast cancer tissue extracts was performed using FEMTELLE® uPA/PAI-1 ELISA. An insertion (5G)/deletion (4G) polymorphism at position − 675 of the PAI-1 gene was detected by PCR-RFLP analysis. Results. Our research showed that patients with uPA tumor tissue levels higher than 3 ng/mg of protein had significantly reduced disease-free survival (DFS) and overall survival (OS) when compared to patients with uPA tumor tissue levels lower or equal to 3 ng/mg of protein. Patients with PAI-1 tumor tissue levels higher than 14 ng/mg of protein had significantly decreased OS in comparison with patients with PAI-1 tumor tissue levels lower or equal to 14 ng/mg of protein. ROC analysis confirmed the uPA and PAI-1 discriminative potential for the presence/absence of relevant events in these patients and resulted in higher cut-off values (5.65 ng/mg of protein for uPA and 27.10 ng/mg of protein for PAI-1) than standard reference cut-off values for both biomarkers. The prognostic importance of uPA and PAI-1 ROC cut-off values was confirmed by the impact of uPA higher than 5.65 ng/mg of protein and PAI-1 higher than 27.10 ng/mg of protein on poorer DFS, OS and event-free survival (EFS). We observed that patients with dominant allele in PAI-1 genotype (heterozygote and dominant homozygote, − 675 4G/5G and − 675 5G/5G) had significantly increased DFS, OS and EFS when compared with patients with recessive homozygote genotype (− 675 4G/4G). Conclusion. Our study indicates that uPA and PAI-1 tumor tissue levels and 4G/5G variants of PAI-1 gene might be of prognostic significance in early node-negative luminal HER2-negative breast cancer patients treated with adjuvant endocrine therapy.

The DATA study (NCT00301457) compared 6 and 3 years of anastrozole in postmenopausal women with hormone receptor‐positive early breast cancer after 2–3 years of tamoxifen. Patients with chemotherapy‐induced ovarian function failure (CIOFF) were also eligible, but could be at risk of ovarian function recovery (OFR). The current analysis compared the survival of women with CIOFF with definitely postmenopausal women and examined the influence of OFR on survival. Therefore, we selected patients from the DATA study aged 45–57 years at randomization who had received (neo)adjuvant chemotherapy. They were classified by reversibility of postmenopausal status: possibly reversible in case of CIOFF (n = 395) versus definitely postmenopausal (n = 261). The former were monitored by E2 measurements for OFR. The occurrence of OFR was incorporated as a time‐dependent covariate in a Cox‐regression model for calculating the hazard ratio (HR). We used the landmark method to calculate residual 5‐year survival rates. When comparing CIOFF women with definitely postmenopausal women, the survival was not different. Among CIOFF women with available E2 follow‐up values (n = 329), experiencing OFR (n = 39) had an unfavorable impact on distant recurrence‐free survival (HR 2.27 [95% confidence interval [CI] 0.98–5.25; p = 0.05] and overall survival (HR 2.61 [95% CI 1.11–6.13; p = 0.03]). After adjusting for tumor features, the HRs became 2.11 (95% CI 0.89–5.02; p = 0.09) and 2.24 (95% CI 0.92–5.45; p = 0.07), respectively. The residual 5‐year rate for distant recurrence‐free survival was 76.9% for women with OFR and 92.1% for women without OFR, and for 5‐year overall survival 80.8% and 94.4%, respectively. Women with CIOFF receiving anastrozole may be at increased risk of disease recurrence if experiencing OFR., What's new? In postmenopausal women with hormone receptor‐positive breast cancer, aromatase inhibitors (AIs) can prevent disease recurrence and improve survival better than tamoxifen. However, AI‐monotherapy should not be used in premenopausal women, as it can stimulate the estradiol production. Here, the authors investigated the effect of the AI anastrozole after prior tamoxifen in women with chemotherapy‐induced ovarian function failure (CIOFF) versus postmenopausal women. The Survival was comparable for definitely postmenopausal women and those with CIOFF. However, women with CIOFF whose ovarian function returned had a poorer survival, despite regular monitoring of the estradiol levels.

Background Endocrine treatment with Tamoxifen and aromatase inhibitors (AIs) is a staple in the management of hormone receptor positive breast cancer (HR + BC). It has become clear that HR + BC carries a consistent risk of relapse up to 15 years post-diagnosis. While increasing evidence supports the use of extended adjuvant Tamoxifen over 5 years, controversial data are available on the optimal duration of extended AIs adjuvant treatment. We performed a meta-analysis to assess the real impact of extended adjuvant therapy with AIs on disease-free survival (DFS). Methods A literature-based meta-analysis of randomized controlled trials (RCTs) was undertaken. Relevant publications from PubMed, the Cochrane Library, and abstracts from American Society of Clinical Oncology (ASCO) and San Antonio Breast Cancer (SABCS) symposia were searched. Primary and secondary endpoints were Disease Free Survival (DFS) and overall survival (OS) respectively. A subgroup analysis was also performed to elucidate the impact of nodal involvement. Results The pooled analysis revealed a significant increase in DFS in the extended AIs group (hazard ratio (HR): 0.78, 95% CI: 0.68–0.90; P = 0.0006). The subgroup analysis according to nodal status showed a greater DFS benefit with extended AIs in patients with positive nodes (HR = 0.67 versus 0.80). Our analysis also demonstrated no improvement in OS with extended AIs (HR = 0.99, 95%CI: 0.87–1.12; P = 0.84). Conclusion This work confirmed the efficacy of extended adjuvant treatment with AIs for HR + early breast cancer, with a 22% increase in DFS, but no impact on OS. Greater efficacy was observed in women with positive nodal status.

Chemotherapy-induced premature ovarian insufficiency (POI) is one of the potential drawbacks of chemotherapy use of particular concern for newly diagnosed premenopausal breast cancer patients. Temporary ovarian suppression obtained pharmacologically with the administration of a gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy has been specifically developed as a method to counteract chemotherapy-induced gonadotoxicity with the main goal of diminishing the risk of POI. In recent years, important clinical evidence has become available on the efficacy and safety of this strategy that should now be considered a standard option for ovarian function preservation in premenopausal breast cancer patients, including women who are not interested in conceiving after treatment or that would not be candidates for fertility preservation strategies because of their age. Nevertheless, in women interested in fertility preservation, this is not an alternative to gamete cryopreservation, which remains as the first option to be offered. In this setting, temporary ovarian suppression with GnRHa during chemotherapy should be also proposed following gamete cryopreservation or to women who have no access, refuse, or have contraindications to surgical fertility preservation techniques. In this article, we present an overview about the role of temporary ovarian suppression with GnRHa during chemotherapy in breast cancer patients by addressing the available clinical evidence with the aim of identifying both the best candidates for the use of this strategy and the still existing gray zones requiring further investigation. ispartof: CLINICAL MEDICINE INSIGHTS-REPRODUCTIVE HEALTH vol:13 ispartof: location:United States status: published

Background Several trials evaluated the role of ovarian function suppression for the adjuvant treatment of premenopausal patients with hormone receptor-positive early breast cancer. Based on the results of the SOFT and TEXT trials, international guidelines recommend the addition of ovarian function suppression to standard adjuvant endocrine therapy for patients at higher risk of relapse. Methods The ERA project (Evaluation of Risk factors in the Adjuvant treatment of breast cancer in premenopausal patients) was devised with the objective of obtaining a consensus on the identification of risk factors and the use of ovarian function suppression in the adjuvant treatment of these women. To this aim, a panel of 31 Italian oncologists with expertise in breast cancer participated in a Delphi consensus study in June 2017. Results A total of 29 statements related to prognostic factors, therapeutic strategies and ovarian function suppression were defined and voted to gain final consensus. For each topic we report data supporting the acquired consensus and the relevant issues discussed. Conclusions The SOFT and TEXT trials have changed the standard adjuvant treatment of premenopausal patients with hormone receptor-positive early breast cancer, but the available treatment options require a careful risk assessment and toxicities evaluation to ensure the greatest clinical benefit for each patient.

Background Adjuvant endocrine therapy (AET) significantly decreases the risk of breast cancer recurrence and mortality. Notwithstanding the demonstrated efficacy of AET, 31–73% of breast cancer survivors do not persist with AET. The purpose of this study was to explore breast cancer survivors’ experiences and perspectives of persisting with AET and to identify the psychosocial and healthcare system factors that influence AET persistence. Methods Informed by interpretive descriptive methodology and relational autonomy theory, individual interviews were conducted with 22 women diagnosed with early-stage breast cancer who had been prescribed AET. These participants also completed a demographic form and a survey that assessed their perceived risk of recurrence. Interviews were analysed using inductive thematic and constant comparative analysis to iteratively compare data and develop conceptualizations of the relationships among data. Descriptive statistics were used to summarize the quantitative data. Results The personal, social, and structural factors found to influence AET persistence included AET side effects, perception of breast cancer recurrence risk, medication and necessity beliefs, social support, the patient-provider relationship, and the continuity and frequency of follow-up care. For most women, over time, the decision-making process around AET persistence became a balancing act between quality of life and quantity of life. The interplay between the personal, social, and structural factors was complex and the weight women placed on some factors over others influenced their AET persistence or non-persistence. Conclusion Expanding our understanding of the factors affecting breast cancer survivors’ AET persistence from their perspective is the first step in developing efficacious, patient-centered interventions aimed at improving AET persistence. In order to improve AET persistence, enhanced symptom management is required, as well as the development of supportive care strategies that acknowledge the values and beliefs held by breast cancer survivors while reinforcing the benefits of AET, and addressing women’s reasons for non-persistence. Improved continuity of health care and patient-healthcare provider communication across oncology and primary care settings is also required. The development and evaluation of supportive care strategies that address the challenges associated with AET experienced by breast cancer survivors hold the potential to increase both women’s quality and quantity of life. Electronic supplementary material The online version of this article (10.1186/s12885-018-4644-7) contains supplementary material, which is available to authorized users.

Background: Hormone-receptor positive breast cancer survivors traditionally were prescribed adjuvant endocrine therapy (AET) for five years at the completion of definitive therapies. The duration of treatment continues to be explored with recommendations indicating that eight to ten years may be more effective in the prevention of breast cancer recurrence. Non-adherence rates are as high as 50% disruption or discontinuation before the recommendation of the provider. With extended durations of treatment, non-adherence rates will continue to be a challenge, impacting the incidence of breast cancer recurrence in these women. Aims: 1). Describe the experience of post-menopausal breast cancer survivors as they transition from acute to chronic management of breast cancer. 2). Identify conditions that support or are barriers to adherence to AET in post-menopausal breast cancer survivors. 3). Generate a grounded theory about post-menopausal breast cancer survivors’ decision-making and other conditions that impact adherence. Methods: Grounded Theory utilizing dimensional analysis was employed. Twenty-one post-menopausal hormone-receptor positive breast cancer survivors, more than three years out from definitive treatment, were recruited. Three Virginia oncology clinics and Facebook support groups were utilized for recruitment. Data collection and data analysis occurred simultaneously. Data-analysis occurred in four phases: initial coding, focused coding, axial coding, and selective coding. Memo-writing was used to support emerging conceptualizations. Findings: Through this constructivist grounded theory study the central perspective of ritualization of adherence was discovered. Women built a foundation that included arming themselves with accurate information, viewing their breast cancer as a chronic condition, utilizing the support of spouses and healthcare providers, and building a healthy lifestyle as a survivor that led them to divergent paths towards adherence or non-adherence. Non-adherence was facilitated by disruptions to routines and side effects, where-as adherence included a continual recommitment process. They lastly built a means of self-protection that included their belief in the power of the medication, their personal values and belief system, and a consequential message that they were strong enough, which overarched their decision to adhere and fueled the ritualization process. Conclusion: Throughout this study, participants described the perspective of ritualization of adherence as a way of explaining what conditions and contexts led to adherence and non-adherence in the extended duration of AET use. Based on the findings in this study, nurses and other healthcare providers are able to target specific areas of education and practice in order to improve the experiences and quality of life of post-menopausal breast cancer survivors. Additionally, this study informs researchers and policy-makers in order to target and improve breast cancer survivorship care.

Background: Several trials evaluated the role of ovarian function suppression for the adjuvant treatment of premenopausal patients with hormone receptor-positive early breast cancer. Based on the results of the SOFT and TEXT trials, international guidelines recommend the addition of ovarian function suppression to standard adjuvant endocrine therapy for patients at higher risk of relapse. Methods: The ERA project (Evaluation of Risk factors in the Adjuvant treatment of breast cancer in premenopausal patients) was devised with the objective of obtaining a consensus on the identification of risk factors and the use of ovarian function suppression in the adjuvant treatment of these women. To this aim, a panel of 31 Italian oncologists with expertise in breast cancer participated in a Delphi consensus study in June 2017. Results: A total of 29 statements related to prognostic factors, therapeutic strategies and ovarian function suppression were defined and voted to gain final consensus. For each topic we report data supporting the acquired consensus and the relevant issues discussed. Conclusions: The SOFT and TEXT trials have changed the standard adjuvant treatment of premenopausal patients with hormone receptor-positive early breast cancer, but the available treatment options require a careful risk assessment and toxicities evaluation to ensure the greatest clinical benefit for each patient.

Background The optimal ways of using aromatase inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain.Methods We undertook meta-analyses of individual data on 31 920 postmenopausal women with oestrogen-receptor-positive early breast cancer in the randomised trials of 5 years of aromatase inhibitor versus 5 years of tamoxifen; of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5; and of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen. Primary outcomes were any recurrence of breast cancer, breast cancer mortality, death without recurrence, and all-cause mortality. Intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded aromatase inhibitor versus tamoxifen first-event rate ratios (RRs).Findings In the comparison of 5 years of aromatase inhibitor versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0.64, 95% CI 0.52-0.78) and 2-4 (RR 0.80, 0.68-0.93), and non-significantly thereafter. 10-year breast cancer mortality was lower with aromatase inhibitors than tamoxifen (12.1% vs 14.2%; RR 0.85, 0.75-0.96; 2p=0.009). In the comparison of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0.74, 0.62-0.89) but not while both groups received aromatase inhibitors during years 2-4, or thereafter; overall in these trials, there were fewer recurrences with 5 years of aromatase inhibitors than with tamoxifen then aromatase inhibitors (RR 0.90, 0.81-0.99; 2p=0.045), though the breast cancer mortality reduction was not significant (RR 0.89, 0.78-1.03; 2p=0.11). In the comparison of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 2-4 (RR 0.56, 0.46-0.67) but not subsequently, and 10-year breast cancer mortality was lower with switching to aromatase inhibitors than with remaining on tamoxifen (8.7% vs 10.1%; 2p=0.015). Aggregating all three types of comparison, recurrence RRs favoured aromatase inhibitors during periods when treatments differed (RR 0.70, 0.64-0.77), but not significantly thereafter (RR 0.93, 0.86-1.01; 2p=0.08). Breast cancer mortality was reduced both while treatments differed (RR 0.79, 0.67-0.92), and subsequently (RR 0.89, 0.81-0.99), and for all periods combined (RR 0.86, 0.80-0.94; 2p=0.0005). All-cause mortality was also reduced (RR 0.88, 0.82-0.94; 2p=0.0003). RRs differed little by age, body-mass index, stage, grade, progesterone receptor status, or HER2 status. There were fewer endometrial cancers with aromatase inhibitors than tamoxifen (10-year incidence 0.4% vs 1.2%; RR 0.33, 0.21-0.51) but more bone fractures (5-year risk 8.2% vs 5.5%; RR 1.42, 1.28-1.57); non-breast-cancer mortality was similar.Interpretation Aromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments diff er, but not thereafter. 5 years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment. Copyright (C) Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Open Access article distributed under the terms of CC BY.

Background Adherence to adjuvant endocrine therapy (HT) is suboptimal among breast cancer patients. A high rate of nonadherence might explain differences in survival between clinical trial and clinical practice. Tailored interventions aimed at improving adherence can only be implemented if subgroups of patients at higher risk of poor adherence are identified. Because no data are available for Italy, we undertook a large survey on adherence among women taking adjuvant HT for breast cancer. Patients and Methods Patients were recruited from 10 cancer clinics in central Italy. All patients taking HT for at least 1 year were invited, during one of their follow-up visit, to fill a confidential questionnaire. The association of sociodemographic and clinical characteristics of participants with adherence was assessed using logistic regression. The RECPAM method was used to evaluate interactions among variables and to identify subgroups of patients at different risk of nonadherence. Results A total of 939 patients joined the study and 18.6% of them were classified as nonadherers. Among possible predictors, only age, working status, and switching from tamoxifen to an aromatase inhibitor were predictive of nonadherence in multivariate analysis. RECPAM analysis led to the identification of 4 classes of patients with a different likelihood of nonadherence to therapy, the lowest being observed in retired women with a low level of education, the highest in the group of unmarried, employed women, or housewives. Conclusion The identification of these subgroups of “real life” patients with a high prevalence of nonadherers might be functional in designing intervention studies aimed at improving adherence.

It is increasingly evident that not only breast cancer cells, but also the tissue embedding these cells: the tumor microenvironment, plays an important role in tumor progression, metastasis formation and treatment sensitivity. This review focuses on the current knowledge of processes by which the microenvironment affects breast cancer, including formation of the metastatic niche, metabolic stimulation, stimulation of tumor cell migration, immune modulation, angiogenesis and matrix remodeling. The number of drugs targeting key factors in these processes is expanding, and the available clinical data is increasing. Therefore current strategies for intervention and prediction of treatment response are outlined. At present, targeting the formation of the metastatic niche and metabolic stimulation by the breast cancer microenvironment, are already showing clinical efficacy. Intervening in the stimulation of tumor cell migration and immune modulation by the microenvironment upcoming fields of great research interest. In contrast, targeting microenvironmental angiogenesis or matrix remodeling appears to be of limited clinical relevance in breast cancer treatment so far. Further research is warranted to optimize intervention strategies and develop predictive tests for the relevance of targeting involved factors within the microenvironment in order to optimally personalize breast cancer treatment. (C) 2014 Elsevier Inc. All rights reserved.

Background Luteinizing hormone-releasing hormone (LH-RH) agonists provide effective adjuvant treatment for premenopausal women with endocrine-responsive breast cancer. Here, we investigated appropriate treatment durations of an LH-RH agonist, leuprorelin. Methods We conducted an open-label, randomized controlled pilot study to evaluate the safety and efficacy of leuprorelin subcutaneously administered every-3-months for 2 versus 3 or more, up to 5 years, together with daily tamoxifen for 5 years in premenopausal endocrine-responsive breast cancer patients. Primary endpoints were disease-free survival (DFS) and safety. Results Eligible patients (N = 222) were randomly assigned to receive leuprorelin for either 2 years (N = 112) or 3 or more years (N = 110) with tamoxifen for 5 years after surgery. Leuprorelin treatment for 3 or more years provided no significant difference in DFS rate over 2 years: 94.1 versus 91.8 % at 144 weeks (3 years) after the second year (week 96) and 90.8 versus 90.4 % at the fifth year (week 240). The overall survival rate was 100 % for both groups during the third through fifth year study period. There were no significant differences in the incidence of adverse events (AEs) between the 2 groups: most AEs were rated grade 1 or 2. Conclusions Adjuvant leuprorelin treatment for 3 or more years with tamoxifen showed a survival benefit and safety profile similar to that for 2 years in premenopausal endocrine-responsive breast cancer patients. No new safety signal was identified for long-term leuprorelin treatment. Longer follow-up observation is needed to determine the optimal duration of leuprorelin treatment.