Tolerability and toxicity of trastuzumab or trastuzumab + lapatinib in older patients: a sub-analysis of the ALTTO trial (BIG 2-06; NCCTG (Alliance) N063D).

PURPOSE: Little is known about the use of trastuzumab or trastuzumab + lapatinib in older patients. We have performed a sub-analysis of the Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation (ALTTO) trial focused on toxicity and treatment completion of both regimens in older patients (≥ 65 years old) METHODS: The ALTTO trial randomised 8381 patients with early HER2-positive BC in 4 arms. Eligible patients for this study were those having received at least one dose of assigned treatment in either the trastuzumab or trastuzumab + lapatinib arms. Treatment completion was evaluated through the rate of temporary treatment interruptions, permanent treatment discontinuations and lapatinib dose reductions. Toxicity was evaluated via a selected subset of adverse events of interest (AEI). Risk factors for both treatment completion outcomes and toxicity were investigated, including comorbidities and use of 5 or more co-medications at randomization. RESULTS: A total of 430 patients ≥ 65 year were eligible. Median age was 68 (range 65-80). In comparison with the younger cohort, older patients had a significantly higher number of comorbidities at randomization (p < 0.001). Treatment completion outcomes were worse, particularly in the trastuzumab + lapatinib arm. Adverse events of interest were likewise more common in the trastuzumab + lapatinib arm with higher AEI rates (63.4% in younger vs 78.0% in older, p < 0.001). Concomitant chemotherapy was associated with worse treatment completion outcomes among older patients. CONCLUSION: Trastuzumab plus lapatinib was significantly more toxic among older patients and had worse treatment completion. Trastuzumab was generally well tolerated.

HER2-low status and response to neoadjuvant chemotherapy in HER2 negative early breast cancer.

PURPOSE: Knowledge on whether low expressions of HER2 have prognostic impact in early-stage breast cancer (BC) and on its response to current chemotherapy protocols can contribute to medical practice and development of new drugs for this subset of patients, changing treatment paradigms. This study aims to evaluate the impact of HER2-low status on response to neoadjuvant chemotherapy (NACT) and survival outcomes in early-stage HER2-negative BC. METHODS: Records from all BC patients treated with NACT from January 2007 to December 2018 in a single cancer center were retrospectively reviewed. HER2-negative (immunohistochemistry [IHC] 0, + 1, or + 2 non-amplified by in situ hybridization [ISH]) patients were included. HER2-low was defined by IHC + 1 or + 2 ISH non-amplified and HER2-0 by IHC 0. The coprimary objectives were to compare pathological complete response (pCR) and relapse-free survival (RFS) between luminal/HER2-low versus luminal/HER2-0 populations and between triple negative (TNBC)/HER2-low versus TNBC/HER2-0. RESULTS: In total, 855 HER2-negative patients were identified. The median follow-up was 59 months. 542 patients had luminal subtype (63.4%) and 313 had TNBC (36.6%). 285 (33.3%) were HER2-low. Among luminal patients, 145 had HER2 IHC + 1 (26.8%) and 91 had IHC + 2/ISH non-amplified (16.8%). In TNBC, 36 had HER2 IHC + 1 (11.5%) and 13 had IHC + 2/ISH non-amplified (4.2%). Most patients had locally advanced tumors, regardless of subtype or HER2-low status. For luminal disease, pCR was achieved in 13% of HER2-low tumors versus 9.5% of HER2-0 (p = 0.27). Similarly, there was no difference in pCR rates among TNBC: 51% versus 47% in HER2-low versus HER2-0, respectively (p = 0.64). HER2-low was also not prognostic for RFS, with 5-year RFS rates of 72.1% versus 71.7% (p = 0.47) for luminal HER2-low/HER2-0, respectively, and 75.6% versus 70.8% (p = 0.23) for TNBC HER2-low/HER2-0. CONCLUSION: Our data does not support HER2-low as a biologically distinct BC subtype, with no prognostic value on survival outcomes and no predictive effect for pCR after conventional NACT.

Body Mass Index and Weight Change in Patients With HER2-Positive Early Breast Cancer: Exploratory Analysis of the ALTTO BIG 2-06 Trial.

BACKGROUND: The association between obesity and prognosis in HER2-positive early breast cancer remains unclear, with limited data available. This study aimed to determine the impact of body mass index (BMI) at baseline and weight change after 2 years on outcomes of patients with HER2-positive early breast cancer. METHODS: ALTTO was a randomized phase III trial in patients with HER2-positive early breast cancer. BMI was collected at randomization and 2 years after. WHO BMI categories were used: underweight, <18.5 kg/m2; normal weight, 18.5 to <25 kg/m2; overweight, ≥25 to <30 kg/m2; and obese ≥30 kg/m2. A weight change from baseline of ≥5.0% and ≤5.0% was categorized as weight gain and weight loss. The impact of BMI at randomization and of weight change on disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were investigated with multivariate analyses, adjusting for baseline patients and tumor characteristics. RESULTS: A total of 8,381 patients were included: 187 (2.2%), 3,797 (45.3%), 2,690 (32.1%), and 1,707 (20.4%) were underweight, normal weight, overweight, and obese at baseline, respectively. Compared with normal weight, being obese at randomization was associated with a significantly worse DDFS (adjusted hazard ratio [aHR], 1.25; 95% CI, 1.04-1.50) and OS (aHR, 1.27; 95% CI, 1.01-1.60), but no significant difference in DFS (aHR, 1.14; 95% CI, 0.97-1.32). Weight loss ≥5.0% at 2 years after randomization was associated with significantly poorer DFS (aHR, 1.34; 95% CI, 1.05-1.71), DDFS (aHR, 1.46; 95% CI, 1.07-1.98), and OS (aHR, 1.83; 95% CI, 1.18-2.84). Hormone receptor and menopausal status but not anti-HER2 treatment type influenced outcomes. Toxicities were more frequent in obese patients. CONCLUSIONS: In patients with HER2-positive early breast cancer, obesity at baseline is a poor prognostic factor. Weight loss during treatment and follow-up negatively impacts clinical outcomes. Dietary counseling should be part of survivorship care programs.

Reactive stroma and trastuzumab resistance in HER2-positive early breast cancer.

We investigated the value of reactive stroma as a predictor for trastuzumab resistance in patients with early HER2-positive breast cancer receiving adjuvant therapy. The pathological reactive stroma and the mRNA gene signatures that reflect reactive stroma in 209 HER2-positive breast cancer samples from the FinHer adjuvant trial were evaluated. Levels of stromal gene signatures were determined as a continuous parameter, and pathological reactive stromal findings were defined as stromal predominant breast cancer (SPBC; ≥50% stromal) and correlated with distant disease-free survival. Gene signatures associated with reactive stroma in HER2-positive early breast cancer (N = 209) were significantly associated with trastuzumab resistance in estrogen receptor (ER)-negative tumors (hazard ratio [HR] = 1.27 p interaction = 0.014 [DCN], HR = 1.58, p interaction = 0.027 [PLAU], HR = 1.71, p interaction = 0.019 [HER2STROMA, novel HER2 stromal signature]), but not in ER-positive tumors (HR = 0.73 p interaction = 0.47 [DCN], HR = 0.71, p interaction = 0.73 [PLAU], HR = 0.84; p interaction = 0.36 [HER2STROMA]). Pathological evaluation of HER2-positive/ER-negative tumors suggested an association between SPBC and trastuzumab resistance. Reactive stroma did not correlate with tumor-infiltrating lymphocytes (TILs), and the expected benefit from trastuzumab in patients with high levels of TILs was pronounced only in tumors with low stromal reactivity (SPBC <50%). In conclusion, reactive stroma in HER2-positive/ER-negative early breast cancer tumors may predict resistance to adjuvant trastuzumab therapy.

Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial.

BACKGROUND: Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting. METHODS: This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm. RESULTS: With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68-1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4-11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54-6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25-2.75]), BMI > 30 kg/m2 (vs < 25 mg/kg2, OR 2.21 [95% CI 1.40-3.49]), cumulative dose of doxorubicin ≥240 mg/m2 (OR 1.36 [95% CI 1.01-1.82]) and of epirubicin≥ 480 mg/m2 (OR 2.33 [95% CI 1.55-3.51]). CONCLUSIONS: Dual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006-000562-36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2-06 /EGF106708/N063D.

A pooled analysis of the cardiac events in the trastuzumab adjuvant trials.

BACKGROUND: Trastuzumab-associated cardiotoxicity remains an issue for patients with HER2-positive breast cancer. This pooled analysis of 3 adjuvant trials investigated the incidence, timing, impact on treatment completion, and risk factors for trastuzumab-associated cardiotoxicity. METHODS: This is an individual patient data level pooled analysis of HERA, NSBAP B-31, and NCCTG 9831 (Alliance Trials). Definitions of cardiac events were as per each individual study. RESULTS: A total of 7445 patients enrolled in the 3 trials were included in the analysis, of which 4017 were in the trastuzumab and 3428 in the control (observation) arms, respectively. Median follow-up exceeded 10 years (119.2-137.2 months). Nearly all patients (97.4%) in the trastuzumab arms received anthracycline-based chemotherapy. In total, 452 patients in the trastuzumab arms experienced a cardiac event (11.3%), with most being mildly symptomatic or asymptomatic left ventricular ejection fraction (LVEF) decrease (351 patients, 8.7%). Severe congestive heart failure was more common in the trastuzumab arm (2.3%) than in the control arm (0.8%). Most cardiac events occurred during trastuzumab treatment (78.1%) and cardiac events were the main cause of discontinuation across the sample (10.0%); nevertheless, a large majority of patients completed trastuzumab treatment (76.2%). Baseline risk factors that were significantly associated with the development of cardiac events were baseline LVEF < 60%, hypertension, body mass index > 25, age ≥ 60 and, non-Caucasian ethnicity. CONCLUSION: One year of trastuzumab increases the risk of cardiac events, though most consist of asymptomatic or mildly symptomatic LVEF drops. Adjuvant trastuzumab should be considered a safe treatment from a cardiac standpoint for most patients. Trastuzumab-associated cardiotoxicity is the main cause of discontinuation and further research is needed to individualize prevention and management.

Anti-HER2 therapy for breast cancer in older patients.

Older patients now form between 30 and 40% of breast cancer (BC) patients. Managing older patients with BC is particularly challenging due to the limited availability of high-quality evidence. In this review we discuss the available evidence on the efficacy and safety of anti-HER2 agents in older patients with HER2-positive BC is presented, with a particular look at the latest results of promising new agents such trastuzumab-deruxtecan. The data suggest that older patients can expect similar efficacy when using standard regimens, with higher toxicity, particular cardiac toxicity and diarrhea. Anti-HER2 agents should thus be used in most older patients most as per standard of care as long as adequate follow-up is available to manage toxicities.

Antibody-Drug Conjugates in Breast Cancer: a Comprehensive Review.

OPINION STATEMENT: Antibody-drug conjugates are an elegant approach to cancer treatment that couples the specificity of monoclonal antibodies to the cytotoxicity of classic chemotherapy agents, permitting, at least in theory, increased activity and reduced toxicity. In breast cancer, the early success of trastuzumab-emtansine (T-DM1) in the HER2-positive metastatic setting led to great hopes, later dashed by results in the early setting (KRISTINE trial) and in combination with pertuzumab (MARIANNE trial). Parallel to this, development of ADCs in breast cancer has suffered other setbacks, including the recent failure of other agents (MM-302) as well as the suspension of a few programs (XMT-1522, ADCT-502) with the overall effect of dampening the impetus of this concept and halting/delaying the progress of drugs associated with it, particularly when immunotherapy is at the center of so many efforts. Numerous antibody-drug conjugates remain, however, in development, and could prove successful. Critically, ADCs could permit the introduction of novel concepts such as the expansion of potent anti-HER2 therapy to HER2-low breast cancer, treatment beyond resistance to T-DM1, and synergy in combination with immune checkpoint blockade. In the early setting, the ATEMPT trial may show that T-DM1 reduces toxicity while maintaining good outcomes for lower risk HER2+ patients. ADCs based on bispecific antibodies are also in development. Finally, breakthroughs are occurring in the orphan triple-negative breast cancer subtype with agents targeting surface proteins. The recent results of Sacituzumab govitecan suggest substantial activity in heavily pre-treated patients and underscore the enduring relevance of antibody drug conjugates as a path towards better outcomes.

Mammaprint™: a comprehensive review.

The number of breast cancer (BC) cases is growing worldwide, being most frequently diagnosed in the early-setting. Mammaprint™ is a 70-gene-expression signature, originally designed for selecting early BC patients with low risk of developing metastasis, so that they could be spared adjuvant chemotherapy. Its use as a prognostic biomarker has been extensively validated, both retrospectively and prospectively. However, its value as a predictive tool and as a clinically useful tool remains controversial. This review will describe how the test works, its application in the clinic and its limitations. Cost-effectiveness studies will be summarized. Finally, we will provide a perspective on the use of Mammaprint in the near future, as a valuable tool for personalizing the treatment of early BC patients.

Pertuzumab in HER2-positive early breast cancer: current use and perspectives.

Although the prognosis of HER2-positive breast cancer patients has dramatically improved with modern chemotherapy and the monoclonal antibody trastuzumab, up to 31% of them will experience a recurrence in the long term. After the unprecedented benefit in overall survival with the addition of the second monoclonal antibody pertuzumab for patients with metastatic disease, the drug was tested with various degrees of success in the preoperative and postoperative settings. In this review, we will focus on the pharmacologic aspects of the drug, including mechanism of action and toxicities, and discuss clinical data regarding its use in advanced and early stage HER2-positive breast cancer, placing in perspective the pros and cons regarding other available drugs and biomarkers.

Cardiac biomarkers for early detection and prediction of trastuzumab and/or lapatinib-induced cardiotoxicity in patients with HER2-positive early-stage breast cancer: a NeoALTTO sub-study (BIG 1-06).

BACKGROUND: Biomarkers of cardiac damages, such as troponin T (TnT) and the amino-terminal fragment of brain natriuretic peptide (NT-proBNP), may be useful as early predictors of cardiac dysfunction. The role of these biomarkers in patients receiving lapatinib and/or trastuzumab before anthracyclines is unknown. This study explores TnT and NT-proBNP as predictors of early cardiac toxicity in neoadjuvant breast cancer patients. METHODS: This sub-study of the NEOALTTO trial tested if changes in the levels of TnT and NT-proBNP occurred after 2 weeks of anti-HER2 therapy (lapatinib, trastuzumab or their combination) alone and/or after 18 weeks of anti-HER2 therapy plus weekly paclitaxel. RESULTS: 173 and 172 were tested at all three timepoints for NT-proBNP and TnT, respectively. The incidence of biomarker elevation was overall low at all timepoints for all the three treatment arms. A total of 13 CEs in 11 patients occurred. Biomarker elevations in patients with CEs were very rare; only one patient with subsequent CE had a NT-proBNP elevation at baseline and at week 2. CONCLUSION: These results suggest that TnT and proBNP may not be useful as early predictors of cardiac toxicity in anthracycline-naïve patients receiving trastuzumab and/or lapatinib.

Ovarian Function Suppression in Premenopausal Women with Early-Stage Breast Cancer.

OPINION STATEMENT: Breast cancers arising in young women are biologically more aggressive, and most of these patients are candidates to receive aggressive treatments that include the use of chemotherapy. As most of these tumors express the hormone receptors (i.e., luminal disease), these patients are also candidates to adjuvant endocrine therapy. Chemotherapy-induced amenorrhea showed to be prognostic in young patients with luminal breast cancer. However, the role of ovarian function suppression (OFS) in addition to standard adjuvant treatments has been largely debated over the past years. Recently, several studies have provided important insights on the role of OFS. Currently, the use of tamoxifen alone without prior cytotoxic therapy can be considered a very effective treatment option in young patients with hormone receptor-positive breast cancer at low risk of relapse. On the other hand, for patients at higher risk of relapse as those who are candidates to (neo)adjuvant chemotherapy, OFS proved to be beneficial, and therefore luteinizing hormone-releasing hormone agonists (LHRHa) should be considered in addition to tamoxifen or aromatase inhibitors (AI). However, toxicity is considerable and patients should be actively engaged in decision-making. Finally, in young breast cancer patients who are candidates to (neo)adjuvant chemotherapy, loss of ovarian function and fertility may be a concern. Besides other techniques, recent results showed that temporary OFS with LHRHa during cytotoxic treatment can be considered a reliable strategy to preserve gonadal function and fertility. Despite the recent advances in the field, several gray zones remain unanswered: the role of OFS plus AI in women who remained premenopausal after 5 years of tamoxifen, the optimal extended approach in women treated with 5 years of OFS plus AI, and the role of temporary OFS with LHRHa during chemotherapy in the specific subgroup of patients with BRCA mutations and in women undergoing this strategy after prior embryo/oocyte cryopreservation.

Synergistic actions of Alpelisib and Melatonin in breast cancer cell lines with PIK3CA gene mutation.

AIMS: Breast cancer (BC) presents high mortality rate and about 25-46 % have mutation in the PIK3CA gene. Alpelisib is a PI3K inhibitor that acts on p110α, which is a subunit of the PI3K protein. The melatonin shown important anti-neoplastic effects and may increase the effectiveness of chemotherapy. This study evaluated the synergistic action of Alpelisib and Melatonin in BC lines carrying the H1047R mutation in PIK3CA, relative to the cellular dynamics and the PI3K/AKT/mTOR pathway. MAIN METHODS: MDA-MB-468 (triple-ernegative), MDA-MB-453 (H1047R PIK3CA, HER2+) and T-47D cells (H1047R PIK3CA, ER+/PR+) were divided into four treatment groups: control; Melatonin (1 mM); Alpelisib (1 µM); and Alpelisib (1 µM) + Melatonin (1 mM). Cell viability and migration were investigated using the MTT assay and Transwell assay, respectively. Protein expression of PI3K, p-AKT, mTOR, HIF-1α, and caspase-3, was verified using immunocytochemistry. KEY FINDINGS: MTT assay revealed that MDA-MB-453 and T-47D showed reduction in cell viability in all groups, especially in the MDA-MB-453 treated with Melatonin + Alpelisib. MDA-MB-468 presents reduction in cell migration only with Melatonin, while in the lines with mutation, the treatment of Melatonin + Alpelisib caused inhibition of cell migration. PI3K, p-AKT, mTOR and HIF-1α were inhibited after treatment with Melatonin + Alpelisib in MDA-MB-453 and T-47D lines. The expression of caspase-3 increased in all groups in MDA-MB-453 and T-47D cells, being the increase more pronounced in the Melatonin + Alpelisib group. SIGNIFICANCE: These results indicate that the combined use of Melatonin and Alpelisib may be more effective in inhibiting BC in women carrying the PIK3CA gene mutation than either treatment alone.

Timelines to initiate a phase III trial across the globe: a sub-analysis of the APHINITY trial.

Background: Geographic location and national income may influence access to innovation in healthcare. We aimed to study if geographical location and national income influenced the timelines to activate the global phase III APHINITY trial, evaluating adjuvant pertuzumab in patients with HER2-positive early breast cancer. Methods: Time from regulatory authority (RA) submission to approval (RAA), time to Ethics Committee/Institutional Review Board (EC/IRB) approval, time from study approval by EC/IRB to first randomised patient and from first to last randomised patient were collected. Analyses were conducted grouping countries by geographical region or economic income classification. Results: Forty-one countries (of 42) had data available regarding all relevant timelines. No statistical difference was observed between the time to RAA and geographical region (p = 0.47), although there was a trend to longer time to RAA in upper middle-income economies (p = 0.07). Except for time from first to last patient randomised, there was wide variation in timelines overall and within geographical regions and economic income groups. Conclusions: Geographical location and income classification did not appear to be the major drivers influencing time for clinical trial activation. Wide variability in activation timelines within geographical regions and income groups exists and is worthy of further investigation.

PREDICT underestimates survival of patients with HER2-positive early-stage breast cancer.

The prognostic performance of PREDICT in patients with HER2-positive early breast cancer (EBC) treated in the modern era with effective chemotherapy and anti-HER2 targeted therapies is unclear. Therefore, we investigated its prognostic performance using data extracted from ALTTO, a phase III trial evaluating adjuvant lapatinib ± trastuzumab vs. trastuzumab alone in patients with HER2-positive EBC. Our analysis included 2794 patients. After a median follow-up of 6.0 years (IQR, 5.8-6.7), 182 deaths were observed. Overall, PREDICT underestimated 5-year OS by 6.7% (95% CI, 5.8-7.6): observed 5-year OS was 94.7% vs. predicted 88.0%. The underestimation was consistent across all subgroups, including those according to the type of anti HER2-therapy. The highest absolute differences were observed for patients with hormone receptor negative-disease, nodal involvement, and large tumor size (13.0%, 15.8%, and 15.3%, respectively). AUC under the ROC curve was 73.7% (95% CI 69.7-77.8) in the overall population, ranging between 61.7% and 77.7% across the analyzed subgroups. In conclusion, our analysis showed that PREDICT highly underestimated OS in HER2-positive EBC. Hence, it should be used with caution to give prognostic estimation to HER2-positive EBC patients treated in the modern era with effective chemotherapy and anti-HER2 targeted therapies.

Impact of Age on Clinical Outcomes and Efficacy of Adjuvant Dual Anti-HER2 Targeted Therapy.

BACKGROUND: Young age at breast cancer (BC) diagnosis has historically been a rationale for overtreatment. Limited data with short follow-up exist on the prognostic value of age at diagnosis in HER2-positive BC and the benefit of anti-HER2 therapy in young patients. METHODS: APHINITY (NCT01358877) is an international, placebo-controlled, double-blind randomized phase III trial in HER2-positive early BC patients investigating the addition of pertuzumab to adjuvant chemotherapy plus trastuzumab. The prognostic and predictive value of age on invasive disease-free survival (IDFS) as continuous and dichotomous variable (aged 40 years or younger and older than 40 years) was assessed. A subpopulation treatment effect pattern plot analysis was conducted to illustrate possible treatment-effect heterogeneity based on age as a continuous factor. RESULTS: Of 4804 included patients, 768 (16.0%) were aged 40 years or younger at enrollment. Median follow-up was 74 (interquartile range = 62-75) months. Young age was not prognostic either as dichotomous (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 0.84 to 1.33) or continuous (HR = 1.00, 95% CI = 1.00 to 1.01) variable. Lack of prognostic effect of age was observed irrespective of hormone receptor status and treatment arm. No statistically significant interaction was observed between age and pertuzumab effect (Pinteraction = 0.61). Adding pertuzumab improved IDFS for patients in the young (HR = 0.86, 95% CI = 0.56 to 1.32) and older (HR = 0.75, 95% CI = 0.62 to 0.92) cohorts. Similar results were observed irrespective of hormone receptor status. Subpopulation treatment effect pattern plot analysis confirmed the benefit of pertuzumab in 6-year IDFS across age subpopulations. CONCLUSIONS: In patients with HER2-positive early BC treated with modern anticancer therapies, young age did not demonstrate either prognostic or predictive value, irrespective of hormone receptor status.

Knowledge, Practice, and Attitudes of Physicians in Low- and Middle-Income Countries on Fertility and Pregnancy-Related Issues in Young Women With Breast Cancer.

PURPOSE: Fertility and pregnancy-related issues are highly relevant for young (≤ 40 years) patients with breast cancer. Limited evidence exists on knowledge, practice, and attitudes of physicians from low- and middle-income countries (LMICs) regarding these issues. METHODS: A 19-item questionnaire adapted from an international survey exploring issues about fertility preservation and pregnancy after breast cancer was sent by e-mail between November 2019 and January 2020 to physicians from LMICs involved in breast cancer care. Descriptive analyses were performed. RESULTS: A total of 288 physicians from Asia, Africa, America, and Europe completed the survey. Median age was 38 years. Responders were mainly medical oncologists (44.4%) working in an academic setting (46.9%). Among responders, 40.2% and 53.8% reported having never consulted the available international guidelines on fertility preservation and pregnancy after breast cancer, respectively. 25.0%, 19.1%, and 24.3% of responders answered to be not at all knowledgeable about embryo, oocyte, or ovarian tissue cryopreservation, respectively; 29.2%, 23.6%, and 31.3% declared that embryo, oocyte, and ovarian tissue cryopreservation were not available in their countries, respectively. 57.6% of responders disagreed or were neutral on the statement that controlled ovarian stimulation can be considered safe in patients with breast cancer. 49.7% and 58.6% of responders agreed or were neutral on the statement that pregnancy in breast cancer survivors may increase the risk of recurrence overall or only in those with hormone receptor-positive disease, respectively. CONCLUSION: This survey showed suboptimal knowledge, practice, and attitudes of physicians from LMICs on fertility preservation and pregnancy after treatment completion in young women with breast cancer. Increasing awareness and education on these aspects are needed to improve adherence to available guidelines and to promote patients' oncofertility counseling.

Combined endocrine and targeted therapy in luminal breast cancer.

Introduction: For decades, endocrine therapy has been the cornerstone of management for luminal breast cancer. Despite the substantial benefit derived by patients from endocrine therapy, primary and secondary resistances to endocrine therapy are serious clinical issues.Areas covered: Today, in the advanced setting, three distinct classes of targeted agents mTOR, CDK 4/6, and PI3K inhibitors, are approved for use. CDK 4/6 inhibitors have improved outcomes substantially, changing the natural history of advanced luminal breast cancer. Current studies seek to bring CDK 4/6 inhibitors to the early setting. This review will cover all available data on target therapy combinations with endocrine therapy for both the early and advanced settings, including approved drugs and agents in development.Expert opinion: Combined endocrine and target therapy has changed the landscape in advanced disease. In early disease, it is possible to have a large impact, particularly in patients with higher risk of relapse. Trials like ADAPTCYCLE seek to leverage neoadjuvant data to de-escalate treatment, substituting chemotherapy for CDK 4/6 inhibitors. In advanced diseases, studies such as PADA-1 point toward a future in which ctDNA will be used to define management before clinical progression occurs.