Symptoms of Anxiety and Depression Among Slovenian Breast Cancer Survivors Post-Treatment During the COVID-19 Pandemic: A Cross-Sectional Study.

Background: Although anxiety and depression are important determinants of mental health, the literature in this area is sparse as most studies focus on the period during treatment. Mental health problems can affect cancer recovery as well as quality of life and survival. In this cross-sectional study, we investigated the prevalence of anxiety and depression in Slovenian cancer survivors after treatment and assessed the associated correlates during the COVID-19 pandemic. Methods: From September 2021 to January 2022, we collected data from 430 breast cancer survivors one to five years after receiving post-local treatment and (neo)adjuvant chemotherapy. We used the Hospital Anxiety and Depression Scale (HADS) to measure anxiety and depression levels. Multivariate linear regression was used to identify factors associated with higher levels of anxiety and depression. Results: Key findings from this study are increased levels of psychological distress and identification of relevant factors associated with those elevated levels. Approximately one-third of breast cancer survivors exhibited symptoms of elevated anxiety and depression, with one in eight meeting clinical thresholds. Multivariate linear regression revealed that age, lower quality of life, heightened fear of cancer recurrence (FCR), reduced resilience, limited social support, and unmet psychosocial and emotional needs correlated with increased anxiety symptoms. Additionally, lower quality of life, higher FCR, diminished resilience, and limited social support were associated with higher depression symptomatology. Conclusions: Our study of Slovenian breast cancer survivors one to five years post-treatment observed a significant increase in anxiety and depression symptoms, possibly exacerbated by the COVID-19 pandemic. The demographic and psychosocial factors identified in this study offer valuable insights for future research. The study emphasises the importance of recognising and addressing the psychological needs of breast cancer survivors and the need to follow them throughout their cancer journey.

Evaluation of an Early Individualized Integrated Rehabilitation Program versus Standard Rehabilitation Program for Smoking Cessation in 115 Smokers Among 467 Female Breast Cancer Patients 2019-2021 in Slovenia.

BACKGROUND Cigarette smoking affects cancer risk and cardiovascular risk. Smoking cessation is very beneficial for health. This study aimed to evaluate an early individualized integrated rehabilitation program and standard rehabilitation program for smoking cessation in breast cancer patients. MATERIAL AND METHODS This prospective study included 467 breast cancer patients (29-65 (mean 52) years of age) treated at the Institute of Oncology Ljubljana from 2019 to 2021 and were followed longer than 1 year. The control group and intervention group included 282 and 185 patients, respectively. Three questionnaires were completed by patients before and 1 year after the beginning of oncological treatment. The intervention group received interventions according to the patient's needs, while the control group underwent standard rehabilitation. The data obtained from the survey were analyzed using the chi-square test and analysis of variance. RESULTS In total, 115 patients were tobacco smokers before the beginning of cancer treatment. There were no differences between the intervention and control group in the prevalence of smoking before the treatment. Before the cancer treatment, smoking was present in the intervention group in 22% and in control group in 27% (P=0.27). One year after the beginning of cancer treatment, smoking was present in the intervention group in only 10% of cases, while it was present in control group in 20% of cases. Smoking was significantly less common in the intervention group than in the control group (P=0.004). CONCLUSIONS Smoking cessation was more common after early integrated rehabilitation than after standard rehabilitation.

Axillary ultrasound for predicting response to neoadjuvant treatment in breast cancer patients-a single institution experience.

BACKGROUND: In node-positive breast cancer patients at diagnosis (cN +) that render node-negative after neoadjuvant systemic treatment (NAST), axillary lymph node dissection (ALND) can be avoided in selected cases. Axillary ultrasound (AUS) is most often used for re-staging after NAST. We aimed to determine sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of AUS after NAST for predicting nodal response at the Institute of Oncology, Ljubljana. METHODS: Biopsy-confirmed cN + patients consecutively diagnosed at our institution between 2008 and 2021, who received NAST, followed by surgery were identified retrospectively. Only patients that underwent AUS after NAST were included. AUS results were compared to definite nodal histopathology results. We calculated sensitivity, specificity, PPV and NPV of AUS. We also calculated the proportion of patients with false-positive AUS that results in surgical overtreatment (unnecessary ALND). RESULTS: We identified 437 cN + patients. In 244 (55.8%) AUS after NAST was performed. Among those, 42/244 (17.2%) were triple negative (TN), 78/244 (32.0%) Her-2 positive (Her-2 +), and 124/244 (50,8%) luminal Her-2 negative cancers. AUS was negative in 179/244 (73.4%), suspicious/positive in 65/244 (26.6%) (11/42 (26.2%) TN, 19/78 (24.4%) Her-2 + , and 35/124 (28.2%) luminal Her-2 negative cancers). On definite histopathology, nodal complete response (pCR) was observed in 89/244 (36.5%) (19/42 (45.2%) TN, 55/78 (70.5%) Her-2 + , and 15/124 (12.1%) luminal Her-2 negative cancers). Among patients with suspicious/positive AUS, pCR was observed in 20/65 (30.8%) (6/11 (54.5%) TN, 13/19 (68.4%) Her-2 + and 1/35 (2.9%) luminal Her-2 negative cancers). Sensitivity was 29.0%, specificity 77,5%, PPV 69.2%, NPV 38.5%. Specificity and PPV in TN was 68.4% and 45.4%, in Her-2 + 76.4% and 31.6%, in luminal Her-2 negative 93,3% and 97,1%, respectively. CONCLUSION: In approximately half of the patients, AUS falsely predicts nodal response after NAST and may lead to overtreatment in 30% of the cases (ALND). However, AUS has to be interpreted in context with tumor subtype. In luminal Her-2 negative cancers, it has a high PPV and is therefore useful.

Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer.

BACKGROUND: Prospective data on the risk of recurrence among women with hormone receptor-positive early breast cancer who temporarily discontinue endocrine therapy to attempt pregnancy are lacking. METHODS: We conducted a single-group trial in which we evaluated the temporary interruption of adjuvant endocrine therapy to attempt pregnancy in young women with previous breast cancer. Eligible women were 42 years of age or younger; had had stage I, II, or III disease; had received adjuvant endocrine therapy for 18 to 30 months; and desired pregnancy. The primary end point was the number of breast cancer events (defined as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer) during follow-up. The primary analysis was planned to be performed after 1600 patient-years of follow-up. The prespecified safety threshold was the occurrence of 46 breast cancer events during this period. Breast cancer outcomes in this treatment-interruption group were compared with those in an external control cohort consisting of women who would have met the entry criteria for the current trial. RESULTS: Among 516 women, the median age was 37 years, the median time from breast cancer diagnosis to enrollment was 29 months, and 93.4% had stage I or II disease. Among 497 women who were followed for pregnancy status, 368 (74.0%) had at least one pregnancy and 317 (63.8%) had at least one live birth. In total, 365 babies were born. At 1638 patient-years of follow-up (median follow-up, 41 months), 44 patients had a breast cancer event, a result that did not exceed the safety threshold. The 3-year incidence of breast cancer events was 8.9% (95% confidence interval [CI], 6.3 to 11.6) in the treatment-interruption group and 9.2% (95% CI, 7.6 to 10.8) in the control cohort. CONCLUSIONS: Among select women with previous hormone receptor-positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort. Further follow-up is critical to inform longer-term safety. (Funded by ETOP IBCSG Partners Foundation and others; POSITIVE ClinicalTrials.gov number, NCT02308085.).

Complete response in the axilla and the non-triple negative subtype are favourable prognostic factors for survival outcomes in inflammatory breast cancer.

AIM: To assess real-world outcomes and prognostic factors of non-metastatic inflammatory breast cancer according to immunohistochemistry (IHC)-based subtype and treatment regimen. METHODS: An institutional retrospective analysis of patients treated with neoadjuvant systemic treatment (NAST) for stage III inflammatory breast cancer diagnosed between 2001 and 2018 was performed. The survival outcomes in relation to patient characteristics, tumour characteristics, treatment modality and response to NAST were analyzed. RESULTS: 225 patients fulfilled the inclusion criteria, 90% of patients were node-positive. IHC-based subtypes: 39.1% were HR+/HER2-, 19.1% HR+/HER2+, 23.1% HR-/HER2+ and 18.7% HR-/HER2-. Treatment was multimodal: NAST (100%), surgery (94.2%) and radiotherapy (94.2%). 53.3% of patients received adjuvant endocrine therapy, 34.3% (neo)adjuvant trastuzumab. Tri-modality therapy was applied in 89.3% of patients. Following NAST, a pathologic complete remission (pCR) in the breast was found in 16.9%, in the axilla in 29.7% and in both the breast and axilla in 10.3% of patients. The axillary pCR rate was significantly higher in HR- subtypes. Median overall survival (OS) was 8.9, 7.2, 5.8 and 2.3 years (p < 0.001) for HR+/HER2-, HR+/HER2+, HR-/HER2+ and HR-/HER2- subtype, respectively. On multivariate analysis, IHC-based subtype, age and axillary pCR were found as independent prognostic factors for RFS and OS. pCR rate and median OS improved over time, 5.8% vs 14.7% and 4.7 vs 10.0 years (2001-2009 vs. 2010-2018), respectively. CONCLUSIONS: Axillary pCR and the non-triple-negative IHC-based subtype are favourable prognostic factors for RFS and OS in inflammatory breast cancer. Introduction of taxanes and antiHER2 drugs contributed to improved pCR rate and OS.

Factors associated with a high level of unmet needs and their prevalence in the breast cancer survivors 1-5 years after post local treatment and (neo)adjuvant chemotherapy during the COVID-19: A cross-sectional study.

Objective: To assess the prevalence of unmet needs in post-treatment breast cancer survivors and identify sociodemographic, clinical, and psychosocial variables associated with reported unmet needs during the COVID-19 pandemic. Materials and methods: In this cross-sectional study, 430 post-treatment breast cancer survivors, ranging between 1 and 5 years after the procedure, completed the Cancer Survivors' Unmet Needs (CaSUN) questionnaire from September 2021 and January 2022. The multivariate logistic analysis identified factors associated with at least one reported unmet need in the total CaSUN scale and specific domains. Results: A total of 67% of survivors reported at least one unmet need. The most frequently reported unmet needs were the lack of accessible hospital parking (43%) and recurrence concerns (39.5%). The majority of reported unmet needs relate to comprehensive care (44%), followed by the psychological and emotional support domain (35.3%). Younger age (OR = 0.95, 95% CI = 0.92-0.99; p < 0.001), three or more comorbidities (OR = 0.27, 95% CI = 0.11-0.71, p < 0.01), a lower quality of life (OR = 0.06, 95% CI = 0.01-0.47, p < 0.01) and low resilience (OR = 0.95, 95% CI = 0.93-0.99) were associated with a high level of unmet needs in the multivariate regression model. Results are presented for factors associated with a high level of unmet needs for comprehensive cancer care and psychological and emotional support domain. Conclusion: A high prevalence found in our study could be attributed to the COVID-19 pandemic, where patients may have missed adequate follow-up care, although comparing to studies done in non-pandemic time is difficult. Family physicians should be more attentive toward younger cancer survivors and those with more comorbidities as both characteristics can be easily recognized in the family practice.

Ribociclib plus letrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer with no prior endocrine therapy: subgroup safety analysis from the phase 3b CompLEEment-1 trial.

BACKGROUND: The CDK4/6 inhibitor, ribociclib in combination with endocrine therapy significantly improved progression-free survival in the first line setting in post-menopausal patients with HR+/HER2- advanced breast cancer (ABC) in a pivotal phase 3, placebo-controlled trial (MONALEESA-2) and demonstrated superior overall survival in premenopausal patients with HR+/HER2- ABC (MONALEESA-7). The multinational, phase 3b, CompLEEment-1 trial, which assessed the safety and efficacy of ribociclib plus letrozole in a broader population of patients who have not received prior endocrine therapy for advanced disease, is the largest phase 3 clinical trial to date to evaluate the safety and efficacy of a CDK4/6 inhibitor. We report a subanalysis of data from patients (N = 339) enrolled in the central and south European countries of the SERCE (Southern Europe, RUC, Central Europe) cluster of CompLEEment-1. PATIENTS AND METHODS: Men and women of any menopausal status with HR+/HER2- ABC received once-daily oral ribociclib 600 mg (3-weeks on/1-week-off), plus letrozole 2.5 mg continuously. Men/premenopausal women also received a GnRH-agonist. The primary outcome was the number of patients with adverse events (AEs) over a timeframe of approximately 36 months. Time-to-progression, overall response rate, and clinical benefit rate were also measured. RESULTS: Safety results in the SERCE subgroup were consistent with those in the pivotal clinical trials of ribociclib in combination with endocrine therapy. Treatment-related AEs leading to dose adjustments/interruption occurred in 63.1% of patients but led to treatment discontinuation in only 10.6%. The most common treatment-related AEs of grade ≥ 3 were neutropenia and transaminase elevations. There were no fatal treatment-related events. CONCLUSIONS: These findings from the SERCE subgroup support the safety and manageable tolerability of ribociclib in a broad range of patients with HR+/HER2- ABC more representative of patients in real-world clinical practice.

Management Strategies for Hyperglycemia Associated with the α-Selective PI3K Inhibitor Alpelisib for the Treatment of Breast Cancer.

Alpelisib is an α-selective phosphatidylinositol 3-kinase inhibitor used for treating hormone receptor-positive (HR+), human epidermal growth receptor 2-negative (HER2-), PIK3CA-mutated locally advanced or metastatic breast cancer following disease progression on or after endocrine therapy. Hyperglycemia is an on-target effect of alpelisib affecting approximately 60% of treated patients, and sometimes necessitating dose reductions, treatment interruptions, or discontinuation of alpelisib. Early detection of hyperglycemia and timely intervention have a key role in achieving optimal glycemic control and maintaining alpelisib dose intensity to optimize the benefit of this drug. A glycemic support program implemented by an endocrinology-oncology collaborative team may be very useful in this regard. Lifestyle modifications, mainly comprising a reduced-carbohydrate diet, and a designated stepwise, personalized antihyperglycemic regimen, based on metformin, sodium-glucose co-transporter 2 inhibitors, and pioglitazone, are the main tools required to address the insulin-resistant hyperglycemia induced by alpelisib. In this report, based on the consensus of 14 oncologists and seven endocrinologists, we provide guidance for hyperglycemia management strategies before, during, and after alpelisib therapy for HR+, HER2-, PIK3CA-mutated breast cancer, with a focus on a proactive, multidisciplinary approach.

Intraoperative Touch Imprint Cytology in Breast Cancer Patients After Neoadjuvant Chemotherapy.

BACKGROUND: Intraoperative touch imprint cytology (ITIC) is used for intraoperative detection of sentinel lymph node (SLN) metastases with intention to spare the patients another surgery. However, ITIC prolongs surgery, and ads costs. It is less likely positive in breast cancer (BC) patients after neoadjuvant chemotherapy (NAC) due to low axillary tumor burden. We aimed to evaluate ITIC in patients after NAC and assess how often it changes the ongoing surgery. MATERIALS AND METHODS: BC patients treated with NAC followed by surgery at the Institute of Oncology Ljubljana, Slovenia, from January 2008 to July 2020 with ITIC performed were selected for analysis. Sensitivity, specificity, and the proportion of positive ITIC were calculated for different subgroups. RESULTS: Overall, 144 patients were identified. 73 of 144 (50.7%) patients were N0 before NAC and 71 of 144 (49.3%) were initially N1 and downstaged to N0 after NAC. ITIC was positive in 30 of 144 (20.8%) of patients, 7 of 73 (9.6%) in N0 group and 23 of 71 (32.4%) in N1 group. In N0 group, ITIC was positive in 1 of 20 (5%) if the tumor size was ≤ 20 mm after NAC, and 2 of 39 (5.1%) if the tumor was triple negative (TN) or Her-2+. In the N1 group ITIC was positive in > 20% in all subgroups. The sensitivity and specificity of ITIC was 50.8% and 100%, respectively and did not differ between groups. CONCLUSION: ITIC after NAC is accurate with comparable sensitivity to ITIC in upfront surgery. We suggest omission of ITIC after NAC in initially N0 patients, particularly for tumors ≤ 20 mm after NAC, and in TN or Her-2+ subtypes.

The Place of Chemotherapy in The Evolving Treatment Landscape for Patients With HR-positive/HER2-negative MBC.

Endocrine therapy (ET) for the treatment of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR-positive/HER2-negative) metastatic breast cancer (MBC) has changed markedly over recent years with the emergence of new ETs and the use of molecularly targeted agents. Cytotoxic chemotherapy continues, however, to have an important role in these patients and it is important to maximize its efficacy while minimizing toxicity to optimize outcomes. This review examines current HR-positive/HER2-negative MBC clinical guidelines and addresses key questions around the use of chemotherapy in the face of emerging therapeutic options. Specifically, the indications for chemotherapy in patients with HR-positive/HER2-negative MBC and the choice of optimal chemotherapy are discussed.

Who are the women who enrolled in the POSITIVE trial: A global study to support young hormone receptor positive breast cancer survivors desiring pregnancy.

BACKGROUND: Premenopausal women with early hormone-receptor positive (HR+) breast cancer receive 5-10 years of adjuvant endocrine therapy (ET) during which pregnancy is contraindicated and fertility may wane. The POSITIVE study investigates the impact of temporary ET interruption to allow pregnancy. METHODS: POSITIVE enrolled women with stage I-III HR + early breast cancer, ≤42 years, who had received 18-30 months of adjuvant ET and wished to interrupt ET for pregnancy. Treatment interruption for up to 2 years was permitted to allow pregnancy, delivery and breastfeeding, followed by ET resumption to complete the planned duration. FINDINGS: From 12/2014 to 12/2019, 518 women were enrolled at 116 institutions/20 countries/4 continents. At enrolment, the median age was 37 years and 74.9 % were nulliparous. Fertility preservation was used by 51.5 % of women. 93.2 % of patients had stage I/II disease, 66.0 % were node-negative, 54.7 % had breast conserving surgery, 61.9 % had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed ET (41.8 %), followed by tamoxifen + ovarian function suppression (OFS) (35.4 %). A greater proportion of North American women were <35 years at enrolment (42.7 %), had mastectomy (59.0 %) and received tamoxifen alone (59.8 %). More Asian women were nulliparous (81.0 %), had node-negative disease (76.2%) and received tamoxifen + OFS (56.0 %). More European women had received chemotherapy (69.3 %). INTERPRETATION: The characteristics of participants in the POSITIVE study provide insights to which patients and doctors considered it acceptable to interrupt ET to pursue pregnancy. Similarities and variations from a regional, sociodemographic, disease and treatment standpoint suggest specific sociocultural attitudes across the world.

Full population results from the core phase of CompLEEment-1, a phase 3b study of ribociclib plus letrozole as first-line therapy for advanced breast cancer in an expanded population.

PURPOSE: CompLEEment-1 is a phase 3b trial in an expanded patient population with hormone receptor-positive (HR +), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC), the largest current trial of cyclin-dependent kinase 4 and 6 inhibitors in ABC. METHODS: Patients treated with ≤ 1 line of prior chemotherapy and no prior endocrine therapy for ABC received ribociclib 600 mg/day (3-weeks-on/1-week-off) plus letrozole 2.5 mg/day and additionally monthly goserelin/leuprolide in men and pre-/perimenopausal women. Eligibility criteria allowed inclusion of patients with stable CNS metastases and an Eastern Cooperative Oncology Group performance status of 2. Primary objectives were safety and tolerability, and secondary objectives were efficacy and quality of life (QoL). RESULTS: Overall, 3,246 patients were evaluated (median follow-up 25.4 months). Rates of all-grade and grade ≥ 3 treatment-related adverse events (AEs) were 95.2% and 67.5%, respectively. Treatment-related discontinuations due to all grade and grade ≥ 3 AEs occurred in 12.9% and 7.3% of patients, respectively. Rates of all-grade AEs of special interest (AESI) were as follows: neutropenia (74.5%), increased alanine aminotransferase (16.2%), increased aspartate aminotransferase (14.1%), and QTcF prolongation (6.7%); corresponding values for grade ≥ 3 AESI were 57.2%, 7.7%, 5.7%, and 1.0%, respectively. Median time to progression was 27.1 months (95% confidence interval, 25.7 to not reached). Patient QoL was maintained during treatment. CONCLUSION: Safety and efficacy data in this expanded population were consistent with the MONALEESA-2 and MONALEESA-7 trials and support the use of ribociclib plus letrozole in the first-line setting for patients with HR + , HER2- ABC. TRIAL REGISTRATION: linicalTrials.gov NCT02941926.

Trastuzumab Emtansine Plus Non-Pegylated Liposomal Doxorubicin in HER2-Positive Metastatic Breast Cancer (Thelma): A Single-Arm, Multicenter, Phase Ib Trial.

The paper assesses the dose-limiting toxicities and the maximum tolerated dose (MTD) of trastuzumab emtansine (T-DM1) combined with non-pegylated liposomal doxorubicin (NPLD) in HER2-positive (HER2+) metastatic breast cancer (MBC). This single-arm, open-label, phase Ib trial (NCT02562378) enrolled anthracycline-naïve HER2+ MBC patients who had progressed on trastuzumab and taxanes. Patients received a maximum of 6 cycles of NPLD intravenously (IV) at various dose levels (45, 50, and 60 mg/m2) in the "3 plus 3" dose-escalation part. During expansion, they received 60 mg/m2 of NPLD every 3 weeks (Q3W) plus standard doses of T-DM1. The MTD was T-DM1 3.6 mg/kg plus NPLD 60 mg/m2 administered IV Q3W. No clinically relevant worsening of cardiac function was observed. Among all evaluable patients, the overall response rate was 40.0% (95%CI, 16.3-67.7) with a median duration of response of 6.9 months (95%CI, 4.8-9.1). Clinical benefit rate was 66.7% (95%CI, 38.4-88.2) and median progression-free survival was 7.2 months (95%CI, 4.5-9.6). No significant influence of NPLD on T-DM1 pharmacokinetics was observed. The addition of NPLD to T-DM1 is feasible but does not seem to improve the antitumor efficacy of T-DM1 in HER2+ MBC patients.

Efficacy and safety of selective cyclin-dependent kinases 4/6 inhibitors in hormone-receptor-positive, HER2-negative advanced breast cancer - results from a real-world setting.

BACKGROUND: Selective cyclin-dependent kinases 4/6 inhibitors (CDKi) have become the standard of care in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer (ABC). We performed retrospective analysis in patients treated with CDKi in the first year of their routine clinical use in Slovenia. METHODS: The primary goals were time-to-treatment failure (TTF) and overall survival (OS), analysed via Kaplan-Meier method, the secondary goals were clinical benefit rate (CBR) and safety. RESULTS: Overall, 218 patients' data were evaluated. The median age was 61.8 years (30.6-84.6). The median number of previous ET lines for ABC was 2 (range 0-5). At the time of inclusion, 128 patients (58.7%) had visceral metastases, 45 patients (20.6%) had bone-only disease. At the median follow-up of 15.2 months, disease progressed in 74 patients and 60 patients died. The median TTF was 8.3 months for the whole group, 19.3, 10.3 and 5.5 months for patients treated in the first-, second- and further lines of systemic therapy, respectively. The median OS from the start of CDKi treatment was not reached in any of the groups. CBR was 59.6% for the whole group, 42.7% for further lines of therapy. The most common grade 3/4 adverse event was neutropaenia in 108 patients (49.5%), followed by an increase of hepatic aminotransferases in 13 patients (6.0%). CONCLUSIONS: Even in the diverse real-world population treatment with CDKi in combination with ET showed clinical benefit, most prominently in the first- and second lines of systemic therapy.

Cannabinoids and Hormone Receptor-Positive Breast Cancer Treatment.

Breast cancer (BC) is the most common cancer in women worldwide. Approximately 70-80% of BCs express estrogen receptors (ER), which predict the response to endocrine therapy (ET), and are therefore hormone receptor-positive (HR+). Endogenous cannabinoids together with cannabinoid receptor 1 and 2 (CB1, CB2) constitute the basis of the endocannabinoid system. Interactions of cannabinoids with hypothalamic-pituitary-gonadal axis hormones are well documented, and two studies found a positive correlation between peak plasma endogenous cannabinoid anandamide with peak plasma 17ß-estradiol, luteinizing hormone and follicle-stimulating hormone levels at ovulation in healthy premenopausal women. Do cannabinoids have an effect on HR+ BC? In this paper we review known and possible interactions between cannabinoids and specific HR+ BC treatments. In preclinical studies, CB1 and CB2 agonists (i.e., anandamide, THC) have been shown to inhibit the proliferation of ER positive BC cell lines. There is less evidence for antitumor cannabinoid action in HR+ BC in animal models and there are no clinical trials exploring the effects of cannabinoids on HR+ BC treatment outcomes. Two studies have shown that tamoxifen and several other selective estrogen receptor modulators (SERM) can act as inverse agonists on CB1 and CB2, an interaction with possible clinical consequences. In addition, cannabinoid action could interact with other commonly used endocrine and targeted therapies used in the treatment of HR+ BC.

Early Cardiotoxicity after Adjuvant Concomitant Treatment with Radiotherapy and Trastuzumab in Patients with Breast Cancer.

BACKGROUND: The purpose of the study was to find out whether there is a difference in the early parameters of cardiotoxicity (left ventricular ejection fraction [LVEF] and N-terminal pro-B-type natriuretic peptide [NT-proBNP]) between the two groups of patients: the patients treated for left breast cancer (left breast cancer group) and those treated for the right breast cancer (right breast cancer group), after the treatment had been completed. PATIENTS AND METHODS: The study included 175 consecutive patients with human epidermal growth factor receptor-2 (HER2) positive early breast cancer, treated concurrently with trastuzumab and radiotherapy (RT), between June 2005 and December 2010. Echocardiography with LVEF measurement was performed before adjuvant RT (LVEF0) and after the completed treatment (LVEF1,). After the treatment NT-proBNP measurement was done as well. The difference (Δ) between LVEF0 and LVEF1 was analysed (Δ LVEF = LVEF0 - LVEF1) and compared between the two groups. RESULTS: There were 84 patients in the left and 91 in the right breast cancer group. Median observation time was 57 (37-71) months. Mean Δ LVEF (%) was -1.786% in the left and -2.607% in the right breast cancer group (p = 0.562, CI: -2.004 to 3.648). Median NT-proBNP were 111.0 ng/l in the left and 90.0 ng/l in the right breast cancer group (p = 0.545). Echocardiography showed that the patients in the left breast cancer group did not have significantly worse systolic and diastolic left ventricular function in comparison with the patients in the right breast cancer group, but, they had higher incidence of pericardial effusion (9 [11%] vs. 1 [1%]) (p = 0.007). CONCLUSIONS: We did not find any significant differences in the early parameters of cardiotoxicity (LVEF, NT-proBNP) between the observed groups. Patients who received left breast/chest wall irradiation had higher incidence of pericardial effusion.

Outcomes of Treatment in Slovene Follicular Lymphoma Patients.

BACKGROUND: The outcome of follicular lymphoma (FL) patients has dramatically improved over the last 2 decades by introduction of rituximab in combination chemotherapy and into maintenance setting. We retrospectively analyzed the treatment outcomes in Slovene FL patients in the era of rituximab and compared them to the results reported by pivotal clinical studies. PATIENTS AND METHODS: Two hundred seventy-eight patients with FL treated in Slovenia between 2000 and 2010 with a median follow-up of 5.7 years were included in our retrospective analysis. One hundred ninety-three (69%) received systemic treatment (ST). RESULTS: With a median follow-up of 5.7 years, the 5- and 10-year overall survival (OS) rates for the whole series were 77% and 53%, respectively. The 5-year progression-free survival (PFS) for 193 FL patients treated with ST was 37%. Patients treated with rituximab chemotherapy had a significantly better OS than patients treated with chemotherapy alone, with a 5-year OS of 79% versus 53% (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.22-0.67; P = .001). Adding rituximab to the first-line chemotherapy significantly improved PFS compared to chemotherapy alone (HR, 0.26; 95% CI 0.18-0.36; P < .001). Maintenance rituximab after immunochemotherapy in first-line treatment reduced the risk for progression by 61% and significantly prolonged the time to progression (HR, 0.39; 95% CI 0.20-0.73; P < .003). CONCLUSION: The outcomes in our routinely treated FL patients confirm the benefit of adding rituximab to chemotherapy and are comparable to the results of pivotal clinical studies. The outcome of our FL patients was improved in terms of both PFS and OS.

Combination therapy of lapatinib and Capecitabine for ErbB2-positive metastatic or locally advanced breast cancer: results from the Lapatinib Expanded Access Program (LEAP) in Central and Eastern Europe.

BACKGROUND: The Lapatinib Expanded Access Program (LEAP) was initiated in 45 countries to provide lapatinib in combination with capecitabine to patients with ErbB2 (HER2)-positive breast cancer already treated with anthracyclines, taxanes and trastuzumab. We report the results from 12 Central and Eastern European countries. PATIENTS AND METHODS: By 30 September 2008, 293 patients were enrolled. Patients were monitored for serious adverse events (SAEs) and for any decrease in left ventricular ejection fraction (LVEF). Overall survival and progression-free survival were also assessed. RESULTS: Mean treatment duration was 30 weeks; 107 patients (36.5%) discontinued therapy during the study, mainly due to disease progression (n = 86; 29.4%). A total of 78 SAEs were reported from 47 patients; the most frequently reported was diarrhoea (13 reports). Treatment had a relatively small effect on LVEF. Decreases were minor (0 to < 20%) in 61% of patients at the end of the study. During the study, 3 patients had decreased LVEF meeting the definition of an SAE; these events all resolved. Median overall and median progression-free survival were 37.6 and 21.1 weeks, respectively. CONCLUSIONS: Heavily pretreated patients with ErbB2-positive locally advanced or metastatic breast cancer may benefit from treatment with lapatinib and capecitabine, with a low risk of cardiac toxicity.

Report on isoelectric focusing trial of erythropoietin profiling in two cancer patients during chemotherapy and darbepoetin treatment.

The level of erythropoietin, main regulator of erythropoiesis, is affected by hypoxia, anaemia, application of recombinant erythropoietin, chemotherapy and others. Isoelectric focusing (IEF) combined with double immunobloting is a method that enables distinct analysis of endogenous and recombinant erythropoietin isoforms. Aim of our study was to set up analysis of treatment effects on the pattern of endogenous erythropoietin in anaemic breast cancer patient. Urine and blood samples were collected during and after termination of the treatment and analysed by isoelectric focusing. Endogenous erythropoietin was found lower, but still detectable during darbepoetin treatment. Normal shift of erythropoietin isoforms between serum vs. urine, ordinary seen in healthy volunteers, was not observed indicating kidney damage. The patient was suffering from heavy proteinuria and had low Glomerular filtration rate indicating acute renal failure, probably caused by clinical status or cisplatin chemotherapy. IEF has not yet been used for follow up of erythropoietin profile in cancer patients. It enables to monitor the effects of treatment on the level of endogenous erythropoietin and indirectly indicates kidney function.