Background. The omission of sentinel lymph node biopsy in low-risk elderly breast cancer patients has been introduced in several guidelines. Despite evidence to support its safety, this ...recommendation has not been implemented by many clinicians. We have examined two aspects of this recommendation that may explain why sentinel lymph node biopsy continues to be performed in most of these patients. Firstly, we quantified the proportion of patients diagnosed with axillary metastases postoperatively. Secondly, we examined adherence to antihormonal therapy in the same group of patients. Methods. In this single-centre retrospective cohort study, the study population comprised 98 patients with breast cancer. Patients were aged ≥70 years and diagnosed with hormone receptor positive breast cancers less than 20 mm (T1). All patients underwent surgery and were subsequently prescribed five years of adjuvant antihormonal treatment. Results. Axillary lymph node metastases, as confirmed by the postoperative histology report, were seen in 36.3%. Nonadherence was seen in 33.7% of the patients. Primary nonadherence, that is, patients that never collect their first or subsequent prescriptions at the pharmacy, comprised 11.2% of the total study population. Conclusion. The high proportion of axillary metastases demonstrated suggests that clinical examination of the axilla alone is not sufficient in the preoperative assessment of the axilla. The less-than-optimal adherence rates show that adherence in these patients cannot be taken for granted. We suggest that these factors reflect some of the reluctance among clinicians to omit the sentinel lymph node procedure in these patients.
Background Antihormonal treatment for hormone receptor (HR) positive breast cancer has highly beneficial effects on both recurrence rates and survival. We investigate adherence and persistence in ...this group of patients. Methods The study population comprised 1192 patients with HR-positive breast cancer who were prescribed adjuvant antihormonal treatment from 2004 to 2013. Adherence was defined as a medical possession ratio (MPR) of greater than or equal to80. Results Of the 1192 included patients, 903 (75.8%) were adherent and 289 (24.2%) were non-adherent. Primary non-adherence was seen in 101 (8.5%) patients. The extremes of age (< 40 and greater than or equal to 80 years) were associated with poor adherence. Patients with metastasis to axillary lymph nodes and those who received radiotherapy and/or chemotherapy were more likely to be adherent. Better adherence was also shown for those who switched medication at 2 years after diagnosis. Primary non-adherence seems to be associated with cancers with a good prognosis. Conclusion Adherence to antihormonal therapy for breast cancer is suboptimal. Primary non-adherence occurs among patients with a relatively good prognosis. Non-adherent patients tend to terminate their antihormonal therapy in the initial part of the treatment period. Targeted interventions to improve adherence should be focused on the first part of the treatment period. Keywords: Breast cancer, Antihormonal treatment, Tamoxifen, Aromatase inhibitors, Adherence, Primary non-adherence
Adjuvant endocrine treatment is essential for treating luminal subtypes of breast cancer, which constitute 75% of all breast malignancies. However, the detrimental side effects of treatment make it ...difficult for many patients to complete the guideline-required treatment. Such non-adherence may jeopardize the lifesaving ability of anti-estrogen therapy. In this systematic review, we aimed to assess the consequences of non-adherence and non-persistence from available studies meeting strict statistical and clinical criteria.
A systematic literature search was performed using several databases, yielding identification of 2,026 studies. After strict selection, 14 studies were eligible for systematic review. The review included studies that examined endocrine treatment non-adherence (patients not taking treatment as prescribed) or non-persistence (patients stopping treatment prematurely), in terms of the effects on event-free survival or overall survival among women with non-metastatic breast cancer.
We identified 10 studies measuring the effects of endocrine treatment non-adherence and non-persistence on event-free survival. Of these studies, seven showed significantly poorer survival for the non-adherent or non-persistent patient groups, with hazard ratios (HRs) ranging from 1.39 (95% CI, 1.07 to 1.53) to 2.44 (95% CI, 1.89 to 3.14). We identified nine studies measuring the effects of endocrine treatment non-adherence and non-persistence on overall survival. Of these studies, seven demonstrated significantly reduced overall survival in the groups with non-adherence and non-persistence, with HRs ranging from 1.26 (95% CI, 1.11 to 1.43) to 2.18 (95% CI, 1.99 to 2.39).
The present systematic review demonstrates that non-adherence and non-persistence to endocrine treatment negatively affect event-free and overall survival. Improved follow-up, with focus on adherence and persistence, is vital for improving health outcomes among patients with non-metastatic breast cancer.
Endocrine therapy is a key treatment strategy to control or eradicate hormone-responsive breast cancer. However, resistance to endocrine therapy leads to breast cancer relapse. The recent extension ...of adjuvant tamoxifen treatment up to 10 years actualizes the need for identifying biological markers that may be used to monitor predictors of treatment response. MicroRNAs are promising biomarkers that may fill the gap between preclinical knowledge and clinical observations regarding endocrine resistance. MicroRNAs regulate gene expression by posttranscriptional repression or degradation of mRNA, most often leading to gene silencing. MicroRNAs have been identified directly in the primary tumor, but also in the circulation of breast cancer patients. The few available studies investigating microRNA in patients suggest that seven microRNAs (miR-10a, miR-26, miR-30c, miR-126a, miR-210, miR-342 and miR-519a) play a role in tamoxifen resistance. Ingenuity Pathway Analysis (IPA) reveals that these seven microRNAs interact more readily with estrogen receptor (ER)-independent pathways than ER-related signaling pathways. Some of these pathways are targetable (e.g., PIK3CA), suggesting that microRNAs as biomarkers of endocrine resistance may have clinical value. Validation of the role of these candidate microRNAs in large prospective studies is warranted.
Conflicting results have been reported on the influence of carbohydrates in breast cancer.
To determine the influence of pre-operative per-oral carbohydrate load on proliferation in breast tumors.
...Randomized controlled trial.
University hospital with primary and secondary care functions in South-West Norway.
Sixty-one patients with operable breast cancer from a population-based cohort.
Per-oral carbohydrate load (preOp™) 18 and 2-4 h before surgery (n = 26) or standard pre-operative fasting with free consumption of tap water (n = 35).
The primary outcome was post-operative tumor proliferation measured by the mitotic activity index (MAI). The secondary outcomes were changes in the levels of serum insulin, insulin-c-peptide, glucose, IGF-1, and IGFBP3; patients' well-being, and clinical outcome over a median follow-up of 88 months (range 33-97 months).
In the estrogen receptor (ER) positive subgroup (n = 50), high proliferation (MAI ≥ 10) occurred more often in the carbohydrate group (CH) than in the fasting group (p = 0.038). The CH group was more frequently progesterone receptor (PR) negative (p = 0.014). The CH group had a significant increase in insulin (+ 24.31 mIE/L, 95% CI 15.34 mIE/L to 33.27 mIE/L) and insulin c-peptide (+ 1.39 nM, 95% CI 1.03 nM to 1.77 nM), but reduced IGFBP3 levels (- 0.26 nM; 95% CI - 0.46 nM to - 0.051 nM) compared to the fasting group. CH-intervention ER-positive patients had poorer relapse-free survival (73%) than the fasting group (100%; p = 0.012; HR = 9.3, 95% CI, 1.1 to 77.7). In the ER-positive patients, only tumor size (p = 0.021; HR = 6.07, 95% CI 1.31 to 28.03) and the CH/fasting subgrouping (p = 0.040; HR = 9.30, 95% CI 1.11 to 77.82) had independent prognostic value. The adverse clinical outcome of carbohydrate loading occurred only in T2 patients with relapse-free survival of 100% in the fasting group vs. 33% in the CH group (p = 0.015; HR = inf). The CH group reported less pain on days 5 and 6 than the control group (p < 0.001) but otherwise exhibited no factors related to well-being.
Only applicable to T2 tumors in patients with ER-positive breast cancer.
Pre-operative carbohydrate load increases proliferation and PR-negativity in ER-positive patients and worsens clinical outcome in ER-positive T2 patients.
CliniTrials.gov; NCT03886389. Retrospectively registered March 22, 2019.
Tamoxifen is an endocrine treatment for hormone receptor positive breast cancer. The effectiveness of tamoxifen may be compromised in patients with metabolic resistance, who have insufficient ...metabolic generation of the active metabolites endoxifen and 4-hydroxy-tamoxifen. This has been challenging to validate due to the lack of measured metabolite concentrations in tamoxifen clinical trials.
activity is the primary determinant of endoxifen concentration. Inconclusive results from studies investigating whether
genotype is associated with tamoxifen efficacy may be due to the imprecision in using
genotype as a surrogate of endoxifen concentration without incorporating the influence of other genetic and clinical variables. This review summarizes the evidence that active metabolite concentrations determine tamoxifen efficacy. We then introduce a novel approach to validate this relationship by generating a precision endoxifen prediction algorithm and comprehensively review the factors that must be incorporated into the algorithm, including genetics of
and other pharmacogenes. A precision endoxifen algorithm could be used to validate metabolic resistance in existing tamoxifen clinical trial cohorts and could then be used to select personalized tamoxifen doses to ensure all patients achieve adequate endoxifen concentrations and maximum benefit from tamoxifen treatment.
The metabolic consequences of preoperative carbohydrate load in breast cancer patients are not known. The present explorative study investigated the systemic and tumor metabolic changes after ...preoperative per-oral carbohydrate load and their influence on tumor characteristics and survival.
The study setting was on university hospital level with primary and secondary care functions in south-west Norway. Serum and tumor tissue were sampled from a population-based cohort of 60 patients with operable breast cancer who were randomized to either per-oral carbohydrate load (preOp™; n = 25) or standard pre-operative fasting (n = 35) before surgery. Magnetic resonance (MR) metabolomics was performed on serum samples from all patients and high-resolution magic angle spinning (HR-MAS) MR analysis on 13 tumor samples available from the fasting group and 16 tumor samples from the carbohydrate group.
Fourteen of 28 metabolites were differently expressed between fasting and carbohydrate groups. Partial least squares discriminant analysis showed a significant difference in the metabolic profile between the fasting and carbohydrate groups, compatible with the endocrine effects of insulin (i.e., increased serum-lactate and pyruvate and decreased ketone bodies and amino acids in the carbohydrate group). Among ER-positive tumors (n = 18), glutathione was significantly elevated in the carbohydrate group compared to the fasting group (p = 0.002), with a positive correlation between preoperative S-insulin levels and the glutathione content in tumors (r = 0.680; p = 0.002). In all tumors (n = 29), glutamate was increased in tumors with high proliferation (t-test; p = 0.009), independent of intervention group. Moreover, there was a positive correlation between tumor size and proliferation markers in the carbohydrate group only. Patients with ER-positive / T2 tumors and high tumor glutathione (≥1.09), high S-lactate (≥56.9), and high S-pyruvate (≥12.5) had inferior clinical outcomes regarding relapse-free survival, breast cancer-specific survival, and overall survival. Moreover, Integrated Pathway Analysis (IPA) in serum revealed activation of five major anabolic metabolic networks contributing to proliferation and growth.
Preoperative carbohydrate load increases systemic levels of lactate and pyruvate and tumor levels of glutathione and glutamate in ER-positive patients. These biological changes may contribute to the inferior clinical outcomes observed in luminal T2 breast cancer patients.
ClinicalTrials.gov; NCT03886389. Retrospectively registered March 22, 2019.
Background. Despite adequate hormone substitution in Hashimoto disease, some patients may have persistent symptoms with a possible autoimmune pathophysiology. A recent randomized trial (RCT) using ...patient-reported outcome measures as the primary endpoint showed benefit in total thyroidectomy, but at a cost of high complication rates. Objective. To verify results from the RCT in an observational study including a wider range of patients and explore means of predicting who may benefit from such surgery. Design. A total of 154 patients with Hashimoto disease, euthyroid with or without thyroid hormone substitution, and persistent Hashimoto-related symptoms were subjected to total thyroidectomy and followed for 18 months after surgery. The primary outcome was the General Health (GH) dimensional score in the Short Form-36 Health Survey (SF-36). Results. Eighteen months after surgery, a clinically significant improvement in GH was seen, similar to the findings in the previous RCT. Anti-TPO antibody titers were markedly reduced after surgery, but preoperative titers or other preoperative parameters could not predict the outcome of surgery. Three (1.9%) of 154 patients experienced permanent unilateral recurrent nerve palsy and six (3.9%) experienced hypoparathyroidism after surgery. Conclusions. Thyroidectomy had a beneficial symptom-reducing effect in euthyroid patients with Hashimoto disease and persistent symptoms. The pathophysiology of residual symptoms remains unclear, and surgical complication rates are high. If thyroidectomy is considered as a treatment option, it should be performed in dedicated centers with experienced endocrine surgeons and as part of further studies on persistent symptoms. This trial is registered with NCT-02319538.
Concentrations of active tamoxifen metabolites may be predictive of tamoxifen efficacy, and several therapeutic thresholds have been reported. This study of 406 ER+ breast cancer patients replicated ...an association between a previously reported active tamoxifen threshold (Z‐4OHtam ≤ 3.26 nm) and adverse BC outcome. The association was identified in early‐stage premenopausal patients using tamoxifen alone without sequential aromatase inhibitor use.
Low steady‐state levels of active tamoxifen metabolites have been associated with inferior treatment outcomes. In this retrospective analysis of 406 estrogen receptor‐positive breast cancer (BC) patients receiving adjuvant tamoxifen as initial treatment, we have associated our previously reported thresholds for the two active metabolites, Z‐endoxifen and Z‐4‐hydroxy‐tamoxifen (Z‐4OHtam), with treatment outcomes in an independent cohort of BC patients. Among all patients, metabolite levels did not affect survival. However, in the premenopausal subgroup receiving tamoxifen alone (n = 191) we confirmed an inferior BC ‐specific survival in patients with the previously described serum concentration threshold of Z‐4OHtam ≤ 3.26 nm (HR = 2.37, 95% CI = 1.02–5.48, P = 0.039). The ‘dose–response’ survival trend in patients categorized to ordinal concentration cut‐points of Z‐4OHtamoxifen (≤ 3.26, 3.27–8.13, > 8.13 nm) was also replicated (P‐trend log‐rank = 0.048). Z‐endoxifen was not associated with outcome. This is the first study to confirm the association between a published active tamoxifen metabolite threshold and BC outcome in an independent patient cohort. Premenopausal patients receiving 5‐year of tamoxifen alone may benefit from therapeutic drug monitoring to ensure tamoxifen effectiveness.
Currently there are no assays that can simultaneously quantify serum levels of the third-generation aromatase inhibitors (AIs): letrozole, anastrozole, and exemestane, and the ultra-low levels of ...estrogens in postmenopausal breast cancer patients on AI treatment. Such measurements may be pivotal for the determination of optimal and individualized treatment regimens. We aimed at developing a liquid chromatography-tandem mass spectrometry (MS/MS) method for simultaneous assessment of letrozole, anastrozole, exemestane, and 17-hydroxyexemestane as well as subpicomolar levels of estradiol and estrone.
Internal standards, calibrators, serum samples, and quality controls were in fully automated steps transferred to a deep-well plate for a 2-step liquid-liquid extraction. The extracts were reconstituted and analytes were separated chromatographically using 2 serially coupled columns, then subject to MS/MS in electrospray ionization mode. The method was thoroughly validated and is traceable to 2 accredited estrogen methods.
The measurement range for estrone and estradiol was 0.2 to 12 000 pmol/L and 0.8 to 13 000 pmol/L, and covered the expected therapeutic range for the AIs. All analytes had a precision of less than or equal to 13%, and accuracies within 100 ± 8%. As proof of concept, AI and estrogen levels were determined in serum samples from postmenopausal breast cancer patients under treatment.
We present here an assay suitable for the simultaneous measurement of serum levels of all third-generation AIs and ultra-low levels of estrogens, providing a powerful new tool to study drug efficacy and compliance. The method is highly valuable for postmenopausal patients whose pretreatment estradiol levels are below the threshold of detection for most routine assays, but still require suppression.
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