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PURPOSE: We investigated time to pregnancy, efficacy and safety of fertility preservation, and assisted reproductive technologies (ARTs) in women with early hormone receptor-positive breast cancer (BC) desiring future pregnancy. PATIENTS AND METHODS: POSITIVE is an international, single-arm, prospective trial, in which 518 women temporarily interrupted adjuvant endocrine therapy to attempt pregnancy. We evaluated menstruation recovery and factors associated with time to pregnancy and investigated if ART use was associated with achieving pregnancy. The cumulative incidence of BC-free interval (BCFI) events was estimated according to the use of ovarian stimulation at diagnosis. The median follow-up was 41 months. RESULTS: Two hundred seventy-three patients (53%) reported amenorrhea at enrollment, of whom 94% resumed menses within 12 months. Among 497 patients evaluable for pregnancy, 368 (74%) reported at least one pregnancy. Young age was the main factor associated with shorter time to pregnancy with cumulative incidences of pregnancy by 1 year of 63.5%, 54.3%, and 37.7% for patients age <35, 35-39, and 40-42 years, respectively. One hundred and seventy-nine patients (36%) had embryo/oocyte cryopreservation at diagnosis, of whom 68 reported embryo transfer after enrollment. Cryopreserved embryo transfer was the only ART associated with higher chance of pregnancy (odds ratio, 2.41 [95% CI, 1.75 to 4.95]). The cumulative incidence of BCFI events at 3 years was similar for women who underwent ovarian stimulation for cryopreservation at diagnosis, 9.7% (95% CI, 6.0 to 15.4), compared with those who did not, 8.7% (95% CI, 6.0 to 12.5). CONCLUSION: In POSITIVE, fertility preservation using ovarian stimulation was not associated with short-term detrimental impact on cancer prognosis. Pregnancy rates were highest among those who underwent embryo/oocyte cryopreservation followed by embryo transfer.
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Neoplasias de la Mama , Preservación de la Fertilidad , Técnicas Reproductivas Asistidas , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Embarazo , Preservación de la Fertilidad/métodos , Estudios Prospectivos , Quimioterapia Adyuvante/efectos adversos , Inducción de la Ovulación/métodos , Inducción de la Ovulación/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/uso terapéutico , Persona de Mediana Edad , CriopreservaciónRESUMEN
BACKGROUND: Immune checkpoint inhibitors have shown minimal clinical activity in hormone receptor-positive metastatic breast cancer (HR+mBC). Doxorubicin and low-dose cyclophosphamide are reported to induce immune responses and counter regulatory T cells (Tregs). Here, we report the efficacy and safety of combined programmed cell death protein-1/cytotoxic T-lymphocyte-associated protein 4 blockade concomitant with or after immunomodulatory chemotherapy for HR+mBC. METHODS: Patients with HR+mBC starting first-/second- line chemotherapy (chemo) were randomized 2:3 to chemotherapy (pegylated liposomal doxorubicin 20 mg/m2 every second week plus cyclophosphamide 50 mg by mouth/day in every other 2-week cycle) with or without concomitant ipilimumab (ipi; 1 mg/kg every sixth week) and nivolumab (nivo; 240 mg every second week). Patients in the chemo-only arm were offered cross-over to ipi/nivo without chemotherapy. Co-primary endpoints were safety in all patients starting therapy and progression-free survival (PFS) in the per-protocol (PP) population, defined as all patients evaluated for response and receiving at least two treatment cycles. Secondary endpoints included objective response rate, clinical benefit rate, Treg changes during therapy and assessment of programmed death-ligand 1 (PD-L1), mutational burden and immune gene signatures as biomarkers. RESULTS: Eighty-two patients were randomized and received immune-chemo (N=49) or chemo-only (N=33), 16 patients continued to the ipi/nivo-only cross-over arm. Median follow-up was 41.4 months. Serious adverse events occurred in 63% in the immune-chemo arm, 39% in the chemo-only arm and 31% in the cross-over-arm. In the PP population (N=78) median PFS in the immune-chemo arm was 5.1 months, compared with 3.6 months in the chemo-only arm, with HR 0.94 (95% CI 0.59 to 1.51). Clinical benefit rates were 55% (26/47) and 48% (15/31) in the immune-chemo and chemo-only arms, respectively. In the cross-over-arm (ipi/nivo-only), objective responses were observed in 19% of patients (3/16) and clinical benefit in 25% (4/16). Treg levels in blood decreased after study chemotherapy. High-grade immune-related adverse events were associated with prolonged PFS. PD-L1 status and mutational burden were not associated with ipi/nivo benefit, whereas a numerical PFS advantage was observed for patients with a high Treg gene signature in tumor. CONCLUSION: The addition of ipi/nivo to chemotherapy increased toxicity without improving efficacy. Ipi/nivo administered sequentially to chemotherapy was tolerable and induced clinical responses. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT03409198.
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Neoplasias de la Mama , Nivolumab , Femenino , Humanos , Antraciclinas , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1 , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inducido químicamente , Ciclofosfamida , Ipilimumab/farmacología , Ipilimumab/uso terapéutico , Nivolumab/farmacología , Nivolumab/uso terapéuticoRESUMEN
BACKGROUND: Luminal B breast cancer (BC) presents a worse prognosis when compared with luminal A BC and exhibits a lower sensitivity to chemotherapy and a lower immunogenicity in contrast to non-luminal BC subtypes. The Neo-CheckRay clinical trial investigates the use of stereotactic body radiation therapy (SBRT) directed to the primary tumor in combination with the adenosine pathway inhibitor oleclumab to improve the response to neo-adjuvant immuno-chemotherapy in luminal B BC. The trial consists of a safety run-in followed by a randomized phase II trial. Here, we present the results of the first-in-human safety run-in. METHODS: The safety run-in was an open-label, single-arm trial in which six patients with early-stage luminal B BC received the following neo-adjuvant regimen: paclitaxel q1w×12 â doxorubicin/cyclophosphamide q2w×4; durvalumab (anti-programmed cell death receptor ligand 1 (PD-L1)) q4w×5; oleclumab (anti-CD73) q2w×4 â q4w×3 and 3×8 Gy SBRT to the primary tumor at week 5. Surgery must be performed 2-6 weeks after primary systemic treatment and adjuvant therapy was given per local guidelines, RT boost to the tumor bed was not allowed. Key inclusion criteria were: luminal BC, Ki67≥15% or histological grade 3, MammaPrint high risk, tumor size≥1.5 cm. Primary tumor tissue samples were collected at three timepoints: baseline, 1 week after SBRT and at surgery. Tumor-infiltrating lymphocytes, PD-L1 and CD73 were evaluated at each timepoint, and residual cancer burden (RCB) was calculated at surgery. RESULTS: Six patients were included between November 2019 and March 2020. Median age was 53 years, range 37-69. All patients received SBRT and underwent surgery 2-4 weeks after the last treatment. After a median follow-up time of 2 years after surgery, one grade 3 adverse event (AE) was reported: pericarditis with rapid resolution under corticosteroids. No grade 4-5 AE were documented. Overall cosmetical breast evaluation after surgery was 'excellent' in four patients and 'good' in two patients. RCB results were 2/6 RCB 0; 2/6 RCB 1; 1/6 RCB 2 and 1/6 RCB 3. CONCLUSIONS: This novel treatment combination was considered safe and is worth further investigation in a randomized phase II trial. TRIAL REGISTRATION NUMBER: NCT03875573.
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Neoplasias de la Mama , Radiocirugia , Humanos , Adulto , Persona de Mediana Edad , Anciano , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/radioterapia , Antígeno B7-H1/uso terapéutico , Radiocirugia/métodos , Pronóstico , Terapia CombinadaRESUMEN
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.).
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Neoplasias de la Mama , Adulto , Femenino , Humanos , Embarazo , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante , Terapia Combinada , Supervivencia sin Enfermedad , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/prevención & control , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estudios Prospectivos , Privación de TratamientoRESUMEN
BACKGROUND: Dual anti-HER2-targeted therapy in breast cancer (BC) significantly increased the rate of pathological complete response (pCR) compared to single blockade when added to chemotherapy. However, limited data exist on the long-term impact on survival of the additional increase in pCR. METHODS: Neoadjuvant lapatinib and/or trastuzumab treatment optimisation (NCT00553358) is an international, randomised, open-label, phase III study investigating the addition of lapatinib to chemotherapy plus trastuzumab in HER2-positive early BC. Ten-year event-free survival (EFS), overall survival (OS) and safety were assessed on intention-to-treat population. The association between pCR and EFS or OS was investigated in landmark population. RESULTS: A total of 455 patients were randomised to receive lapatinib (154), trastuzumab (149) or the combination (152). Ten-year EFS estimates were 63% (95% confidence interval [CI], 54%-71%) in the lapatinib group, 64% (95% CI, 55%-72%) in the trastuzumab group and 67% (95% CI, 58%-74%) in the combination group. Ten-year OS rates were 76% (95% CI, 67%-83%), 75% (95% CI, 66%-82%) and 80% (95% CI, 73%-86%) in the lapatinib, trastuzumab and combination groups, respectively. Women who achieved a pCR had improved EFS (hazard ratio 0.48, 95% CI, 0.31-0.73) and OS (hazard ratio 0.37, 95% CI, 0.20-0.63) compared with those who did not. The numerical difference in survival according to pCR status was greater in women treated with the combination and those with hormone-receptor-negative tumours. There were no new or long-term safety concerns. CONCLUSIONS: Patients with HER2-positive BC showed a durable survival benefit of neoadjuvant anti-HER2, irrespective of treatment arm. Patients who achieve pCR have significantly better outcomes than patients without pCR.
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Neoplasias de la Mama , Humanos , Femenino , Masculino , Neoplasias de la Mama/patología , Lapatinib/uso terapéutico , Terapia Neoadyuvante , Receptor ErbB-2 , Trastuzumab/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE: Detection of circulating tumor DNA (ctDNA) after neoadjuvant chemotherapy in patients with early-stage breast cancer may allow for early detection of relapse. In this study, we analyzed ctDNA using a personalized, tumor-informed multiplex polymerase chain reaction-based next-generation sequencing assay. METHODS: Plasma samples (n = 157) from 44 patients were collected before neoadjuvant therapy (baseline), after neoadjuvant therapy and before surgery (presurgery), and serially postsurgery including a last follow-up sample. The primary end point was event-free survival (EFS) analyzed using Cox regression models. RESULTS: Thirty-eight (86%), 41 (93%), and 38 (86%) patients had baseline, presurgical, and last follow-up samples, respectively. Twenty patients had hormone receptor-positive/human epidermal growth factor receptor 2-negative, 13 had triple-negative breast cancer, and 11 had human epidermal growth factor receptor 2-positive disease. Baseline ctDNA detection was observed in 22/38 (58%) patients and was significantly associated with Ki67 > 20% (P = .036) and MYC copy-number gain (P = .0025, false discovery rate = 0.036). ctDNA detection at presurgery and at last follow-up was observed in 2/41 (5%) and 2/38 (5%) patients, respectively. Eight relapses (seven distant and one local) were noted (median follow-up 3.03 years [range, 0.39-5.85 years]). After adjusting for pathologic complete response (pCR), ctDNA detection at presurgery and at last follow-up was associated with shorter EFS (hazard ratio [HR], 53; 95% CI, 4.5 to 624; P < .01, and HR, 31; 95% CI, 2.7 to 352; P < .01, respectively). Association between baseline detection and EFS was not observed (HR, 1.4; 95% CI, 0.3 to 5.9; P = .67). CONCLUSION: The presence of ctDNA after neoadjuvant chemotherapy is associated with relapse in early-stage breast cancer, supporting interventional trials for testing the clinical utility of ctDNA monitoring in this setting.
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ADN Tumoral Circulante , Neoplasias de la Mama Triple Negativas , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Humanos , Antígeno Ki-67 , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/genéticaRESUMEN
BACKGROUND: Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers. METHODS: We conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor-positive cohort and among all patients. RESULTS: Of 557 patients who underwent randomization, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease. In the hormone receptor-positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group (hazard ratio for disease progression or death, 0.51; P<0.001), and overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death, 0.64; P = 0.003). Among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician's choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P = 0.001). Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician's choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events. CONCLUSIONS: In this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician's choice of chemotherapy. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast04 ClinicalTrials.gov number, NCT03734029.).
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Antineoplásicos Inmunológicos , Neoplasias de la Mama , Receptor ErbB-2 , Trastuzumab , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/secundario , Camptotecina/análogos & derivados , Progresión de la Enfermedad , Femenino , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/uso terapéutico , Inmunohistoquímica , Receptor ErbB-2/análisis , Receptor ErbB-2/biosíntesis , Receptor ErbB-2/genética , Trastuzumab/efectos adversos , Trastuzumab/uso terapéuticoRESUMEN
BACKGROUND: Neoadjuvant therapy with dual HER2 blockade improved pathological complete response (pCR) rate in HER2-positive breast cancer patients. Nevertheless, it would be desirable to identify patients exquisitely responsive to single agent trastuzumab to minimize or avoid overtreatment. Herein, we evaluated the predictive and prognostic value of basal primary tumor miRNA expression profile within the trastuzumab arm of NeoALTTO study (ClinicalTrials.gov Identifier: NCT00553358). METHODS: RNA samples from baseline biopsies were randomized into training (n = 45) and testing (n = 47) sets. After normalization, miRNAs associated with Event-free survival (EFS) and pCR were identified by univariate analysis. Multivariate models were implemented to generate specific signatures which were first confirmed, and then analyzed together with other clinical and pathological variables. RESULTS: We identified a prognostic signature including hsa-miR-153-3p (HR 1.831, 95% CI: 1.34-2.50) and hsa-miR-219a-5p (HR 0.629, 95% CI: 0.50-0.78). For two additional miRNAs (miR-215-5p and miR-30c-2-3p), we found a statistically significant interaction term with pCR (p.interaction: 0.017 and 0.038, respectively). Besides, a two-miRNA signature was predictive of pCR (hsa-miR-31-3p, OR 0.70, 95% CI: 0.53-0.92, and hsa-miR-382-3p, OR: 1.39, 95% CI: 1.01-1.91). Notably, the performance of this predictive miRNA signature resembled that of the genomic classifiers PAM50 and TRAR, and did not improve when the extended models were fitted. CONCLUSION: Analyses of primary tumor tissue miRNAs hold the potential of a parsimonious tool to identify patients with differential clinical outcomes after trastuzumab based neoadjuvant therapy.
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Biomarcadores de Tumor , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , MicroARNs/genética , Receptor ErbB-2/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Pronóstico , Modelos de Riesgos Proporcionales , Receptor ErbB-2/antagonistas & inhibidores , Trastuzumab/administración & dosificación , Trastuzumab/efectos adversos , Trastuzumab/uso terapéutico , Resultado del Tratamiento , Carga TumoralRESUMEN
Biomarkers to identify patients without benefit from adding everolimus to endocrine treatment in metastatic breast cancer (MBC) are needed. We report the results of the Pearl trial conducted in five Belgian centers assessing 18F-FDG-PET/CT non-response (n = 45) and ctDNA detection (n = 46) after 14 days of exemestane-everolimus (EXE-EVE) to identify MBC patients who will not benefit. The metabolic non-response rate was 66.6%. Median PFS in non-responding patients (using as cut-off 25% for SUVmax decrease) was 3.1 months compared to 6.0 months in those showing response (HR: 0.77, 95% CI: 0.40-1.50, p = 0.44). The difference was significant when using a "post-hoc" cut-off of 15% (PFS 2.2 months vs 6.4 months). ctDNA detection at D14 was associated with PFS: 2.1 months vs 5.0 months (HR-2.5, 95% CI: 1.3-5.0, p = 0.012). Detection of ctDNA and/or the absence of 18F-FDG-PET/CT response after 14 days of EXE-EVE identifies patients with a low probability of benefiting from treatment. Independent validation is needed.
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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.
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Neoplasias de la Mama , Supervivientes de Cáncer , Adulto , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante , Femenino , Hormonas/uso terapéutico , Humanos , Mastectomía , Embarazo , Premenopausia , Tamoxifeno/uso terapéuticoRESUMEN
AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA, and RB1 mutations; MDM4 and MYC amplifications; and ARID1A deletions. An increase in clonality was observed in driver genes such as ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR+/HER2- cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC. SIGNIFICANCE: The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic samples from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients.This article is highlighted in the In This Issue feature, p. 2659.
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Neoplasias de la Mama , Biomarcadores de Tumor/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Proteínas de Ciclo Celular/genética , Detección Precoz del Cáncer , Femenino , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Recurrencia Local de Neoplasia/patología , Proteínas Proto-Oncogénicas/genética , TranscriptomaRESUMEN
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.
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Índice de Masa Corporal , Neoplasias de la Mama , Obesidad/complicaciones , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/terapia , Supervivencia sin Enfermedad , Femenino , Humanos , Sobrepeso/complicaciones , Pronóstico , Receptor ErbB-2 , Tasa de SupervivenciaRESUMEN
INTRODUCTION: The field of metastatic luminal breast cancer (hormone receptor positive, HER-2 negative) is dynamic and evolving, harboring some of the most significant therapeutic advances in medical oncology. Over the last decade, many pivotal trials showed excellent results with drastic improvements in survival as well as the quality of life of metastatic luminal breast cancer patients. AREAS COVERED: The successful inhibition of the cyclinD/cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma protein (RB) pathway with potent CDK4/6 inhibitors improved the outcome of advanced luminal breast cancers. Abemaciclib is the third CDK 4/6 inhibitor arriving to the market after palbociclib and ribociclib. Here, we describe the biology of the CDK4/6 pathway and summarize clinical data of previously published pivotal trials emphasizing the efficacy and toxicity of abemaciclib. The aim was to define its place in the current guidelines and to make a brief comparison with other available drugs of same class in the absence of cross trials comparison. EXPERT OPINION: As there are no available biomarkers to predict response or resistance to abemaciclib, the promising overall survival data of MONARCH-2 could possibly impact the clinician's choice to optimize treatment for endocrine-resistant metastatic breast cancer.
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Aminopiridinas/administración & dosificación , Bencimidazoles/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Aminopiridinas/efectos adversos , Aminopiridinas/farmacología , Bencimidazoles/efectos adversos , Bencimidazoles/farmacología , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Femenino , Humanos , Guías de Práctica Clínica como Asunto , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacología , Calidad de VidaRESUMEN
PURPOSE: Women with hormone receptor-positive early breast cancers have a persistent risk of relapse and biomarkers for late recurrence are needed. We sought to identify tumor genomic aberrations associated with increased late-recurrence risk. EXPERIMENTAL DESIGN: In a secondary analysis of Study of Letrozole Extension trial, a case-cohort-like sampling selected 598 primary breast cancers for targeted next-generation sequencing analysis of gene mutations and copy-number gains (CNGs). Correlations of genomic aberrations with clinicopathologic factors and breast and distant recurrence-free intervals (BCFIs and DRFIs) were analyzed using weighted Cox models. RESULTS: Analysis of mutations and CNGs was successfully performed for 403 and 350 samples, including 148 and 134 patients with breast cancer recurrences (median follow-up time, 5.2 years), respectively. The most frequent alterations were PIK3CA mutations (42%) and CNGs of CCND1 (15%), ERBB2 (10%), FGFR1 (8%), and MYC (8%). PIK3CA mutations and MYC CNGs were associated with lower (P = 0.03) and higher (P = 0.004) tumor grade, respectively; a higher Ki-67 was seen in tumor with CCND1, ERBB2, and MYC CNGs (P = 0.01, P < 0.001, and P = 0.03, respectively). FGFR1 CNG was associated with an increased risk of late events in univariate analyses [17/29 patients; BCFI: HR, 3.2; 95% confidence interval (CI), 1.48-6.92; P = 0.003 and DRFI: HR, 3.5; 95% CI, 1.61-7.75; P = 0.002) and in multivariable models adjusted for clinicopathologic factors. CONCLUSIONS: Postmenopausal women with hormone receptor-positive early breast cancer harboring FGFR1 CNG had an increased risk of late recurrence despite extended therapy. FGFR1 CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.
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Neoplasias de la Mama/tratamiento farmacológico , Letrozol/uso terapéutico , Posmenopausia , Receptores de Estrógenos/metabolismo , Anciano , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Aberraciones Cromosómicas , Femenino , Predisposición Genética a la Enfermedad/genética , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia , Polimorfismo de Nucleótido Simple , Resultado del TratamientoRESUMEN
BACKGROUND: Although data from preclinical and clinical studies provide a strong rationale for combining capecitabine with anti-angiogenic agents, clinical development of this fluoropyrimidine in combination with aflibercept has lagged behind other treatments. We conducted a nonrandomized, noncomparative, 2-arm, phase I trial to address this unmet need. PATIENTS AND METHODS: Patients with chemorefractory gastrointestinal and breast cancer were sequentially recruited into a continuous (Arm A, starting dose 1100 mg/m2/day) or intermittent (Arm B, 2 weeks on/1 week off, starting dose 1700 mg/m2/day) capecitabine dosing arm. Aflibercept was administered at a flat dose of 6 mg/kg every 3 weeks in both arms. A classical 3 + 3, dose-escalation design was used. The primary objective was to establish the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended dose for phase II trials. RESULTS: Thirty-eight eligible patients were recruited of whom 33 were assessable for DLTs (15 in arm A and 18 in arm B). Fourteen had colorectal cancer, 8 gastric cancer, and 11 breast cancer. DLTs included grade 2 hand-foot syndrome, grade 2 anorexia considered unacceptable by the patient, and grade 3 hypertension. The recommended dose for phase II trials for capecitabine was established at 1300 mg/m2/day in Arm A and 2500 mg/m2/day in Arm B with treatment-related grade ≥ 3 adverse events occurring in 47% and 50% of patients, respectively. Among 26 assessable patients, the objective response rate was 15.4% in Arm A and 7.7% in Arm B. CONCLUSION: Combining capecitabine with aflibercept is feasible and associated with a manageable safety profile and some anti-tumor activity in patients with chemorefractory gastrointestinal and breast cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Capecitabina/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Anorexia/inducido químicamente , Anorexia/diagnóstico , Anorexia/epidemiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Capecitabina/efectos adversos , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Estudios de Factibilidad , Femenino , Síndrome Mano-Pie/diagnóstico , Síndrome Mano-Pie/epidemiología , Síndrome Mano-Pie/etiología , Humanos , Hipertensión/inducido químicamente , Hipertensión/diagnóstico , Hipertensión/epidemiología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Proteínas Recombinantes de Fusión/efectos adversos , Criterios de Evaluación de Respuesta en Tumores Sólidos , Índice de Severidad de la Enfermedad , Neoplasias Gástricas/patologíaRESUMEN
PURPOSE OF REVIEW: Estrogen receptor-positive breast cancer accounts for 70% of all breast cancers. Sequential endocrine treatment in monotherapy or in combination with CDK 4/6 or m-TOR inhibitors is the mainstay of recommended treatment options in the management of metastatic breast cancer even in the presence of visceral metastasis. There is an emerging need to address endocrine resistance, which despite highly efficacious treatment combinations still can develop. RECENT FINDINGS: One of the mechanisms of endocrine resistance is molecular alteration of the oestrogen receptor itself, such as ESR1 mutations affecting the ligand-binding domain. These mutations emerge under the selective pressure of aromatase inhibitors. The efficacy of selective oestrogen receptor degraders (SERDs) might not be affected by the presence of molecular alterations of oestrogen receptor. Fulvestrant is the only SERD used in current clinical practice. Numerous novel, nonsteroidal orally available SERDs are currently in clinical development. Efficacious oestrogen receptor target engagement and promising clinical activity was shown in early phase clinical trials. SUMMARY: Therefore, a new class of orally available nonsteroidal SERDs gains high interest in tackling endocrine resistance in oestrogen receptor-positive (ER+) advanced breast cancer. Clinical efficacy needs to be confirmed in larger patient populations.
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Neoplasias de la Mama/tratamiento farmacológico , Antagonistas del Receptor de Estrógeno/administración & dosificación , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/administración & dosificación , Neoplasias de la Mama/metabolismo , Ensayos Clínicos como Asunto , Antagonistas del Receptor de Estrógeno/farmacología , Femenino , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Moduladores Selectivos de los Receptores de Estrógeno/farmacologíaRESUMEN
INTRODUCTION: Despite improvements in the management of HER2+ breast cancer, metastatic disease is still fatal. Usually, these patients receive several lines of chemotherapy associated with HER2 targeted treatments. Most of the trials using innovative approaches are positioning themselves in disease that is resistant to pertuzumab and trastuzumab emtansine (TDM1). AREAS COVERED: We describe the recent advances in clinical development of anti-HER2 treatments. To this aim, we used literature search via Pubmed and made an inventory of abstracts published during the last two years in major oncology conferences. EXPERT OPINION: Further changes will probably occur during the next decade in the management of metastatic HER2-positive breast cancer. This is mainly driven by the fact that the two mainstay drugs (pertuzumab and TDM-1) that confer prolonged survival (56 months) to these patients are currently being used in the treatment of early-stage disease in a subset of patients. Thus, there is an urgent need to develop new, innovative approaches in those patients whose disease has become resistant to these highly potent drugs. Several new antibody-drug conjugates, bispecific antibodies or new generation tyrosine kinase inhibitor (TKIs) hold promise and should be assessed and compared with drugs currently used.