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PURPOSE: Late alopecia, defined as incomplete hair regrowth > 6 months following cytotoxic chemotherapy or > 6 months from initiation of endocrine therapy, negatively impacts quality of life and may affect dose intensity of adjuvant therapy. This study investigates the effect of oral minoxidil in women with chemotherapy and/or endocrine therapy-induced late alopecia. METHODS: The rate of clinical response was assessed by standardized photography and quantitated with trichoscopy. RESULTS: Two hundred and sixteen patients (mean age 57.8 ± 13.7) were included. The most common cancer diagnosis was breast, in 170 patients (79.1%). Alopecia developed after chemotherapy in 31 (14.4%) patients, endocrine monotherapy in 65 (30.1%) patients, and chemotherapy followed by endocrine therapy in 120 (55.6%) patients. In 119 patients, standardized photography assessments were used to determine clinical change in alopecia after a median of 105 (IQR = 70) days on oral minoxidil and revealed improvement in 88 (74%) patients. Forty-two patients received quantitative trichoscopic assessments at baseline and at follow-up after a median of 91 (IQR = 126) days on oral minoxidil. Patients had clinically and statistically significant increases in frontal hair shaft density (from 124.2 hairs/cm2 at initial to 153.2 hairs/cm2 at follow-up assessment, p = 0.008) and occipital shaft density (from 100.3 hairs/cm2 at initial to 123.5 hairs/cm2 at follow-up assessment. p = 0.004). No patients discontinued oral minoxidil due to adverse events. CONCLUSIONS: Overall, oral minoxidil was well tolerated by patients and may benefit both frontal and occipital late alopecia in cancer survivors treated with cytotoxic and/or endocrine therapy by increasing hair shaft and follicle density.
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PURPOSE: HER2 +- amplified breast cancer patients derive benefit from treatment with anti-HER2-targeted therapy. Though adjuvant treatment is based on final pathology, decisions regarding neoadjuvant chemotherapy are made in the preoperative setting with imaging playing a key role in staging. We examined the accuracy of pre-operative imaging in determining pathological tumor size (pT) in patients undergoing upfront surgery. METHODS: Early (cT1-T2N0) HER2 + breast cancer patients who underwent upfront surgery between 2015 and 2016 were identified from a prospective institutional database. We compared data for both clinical and final pathologic stage. Only those who underwent magnetic resonance imaging (MRI), mammography, and ultrasound in the preoperative setting were included in the analysis. Adjuvant treatment regimens were reviewed. RESULTS: We identified 87 cT1-2N0 patients with invasive HER2 + breast cancer who underwent upfront surgery. Median age was 52 years (IQR 43, 58) and median tumor size was 1.1 cm (IQR 0.5, 1.6). Fifteen patients (17%) were upstaged to stage II/III based on final pathology. Thirty-seven patients were T1cN0 on final pathology; 8 were cT1a-bN0 preop and 12 had pT overestimated by MRI by an average of 1.5 cm (> 0.5-1.5 cm). Compared to both mammography and MRI, the imaging modality most predictive of pT was ultrasound (p = 0.000072 ultrasound vs mammography and 0.000042 ultrasound vs MRI). CONCLUSION: For small HER2 + cN0 tumors undergoing upfront surgery, ultrasound was the imaging modality most predictive of pT. MRI overestimated tumor size in approximately 40% of patients. MRI may not accurately discriminate low-volume tumor burden in the breast and carries the potential of overtreatment in the upfront setting.
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Neoplasias de la Mama , Terapia Neoadyuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Femenino , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Prospectivos , Receptor ErbB-2RESUMEN
BACKGROUND: We assessed the antitumor activity of cabozantinib, a potent multireceptor oral tyrosine kinase inhibitor, in patients with hormone receptor-positive breast cancer with bone metastases. PATIENTS AND METHODS: In this single-arm multicenter phase II study, patients received an initial starting dose of 100 mg, later reduced to 60 mg, per day. The primary endpoint was the bone scan response rate. Secondary endpoints included objective response rate by RECIST, progression-free survival (PFS), and overall survival (OS). RESULTS: Of 52 women enrolled, 20 (38%) experienced a partial response on bone scan and 6 (12%) had stable disease. Prior to the first repeat bone scan at 12 weeks, 19 (35%) patients discontinued study treatment because of early clinical progression or unacceptable toxicity. RECIST evaluation based on best overall response by computed tomography revealed stable disease in extraosseous tissues in 26 patients (50%) but no complete or partial responses. In 25 patients with disease control on bone scan at 12 weeks, only 3 (12%) patients developed extraosseous progression. The median PFS was 4.3 months, and median OS was 19.6 months. The most common grade 3 or 4 toxicities were hypertension (10%), anorexia (6%), diarrhea (6%), fatigue (4%), and hypophosphatemia (4%). CONCLUSION: Bone scans improved in 38% of patients with metastatic hormone receptor-positive breast cancer and remained stable in an additional 12% for a minimum duration of 12 weeks on cabozantinib. Further investigations should assess the activity of cabozantinib in combination with other hormonal and other breast cancer therapies and determine whether bone scan responses correlate with meaningful antitumor effects. ClinicalTrials.gov identifier. NCT01441947 IMPLICATIONS FOR PRACTICE: Most patients with metastatic hormone receptor-positive (HR+) breast cancer have bone involvement, and many have bone-only disease, which is difficult to evaluate for response. This phase II single-arm study evaluated the clinical activity of the small molecule MET/RET/VEGFR2 inhibitor cabozantinib in patients with metastatic HR+ breast cancer with bone metastases. This study met its primary endpoint, and cabozantinib treatment resulted in a significant bone scan response rate correlating with improved survival. This is the first study to use bone scan response as a primary endpoint in breast cancer. The results support further study of cabozantinib in HR+ breast cancer.
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Neoplasias de la Mama , Anilidas/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Hormonas , Humanos , Piridinas/uso terapéuticoRESUMEN
BACKGROUND: Neoadjuvant endocrine therapy (NET) is effective in downstaging large hormone receptor-positive (HR+) breast cancers and increasing rates of breast-conserving surgery (BCS), but data regarding nodal pathologic complete response (pCR) are sparse. We reported nodal and breast downstaging rates with NET, and compared axillary response rates following NET and neoadjuvant chemotherapy (NAC). METHODS: Consecutive stage I-III breast cancer patients treated with NET and surgery from January 2009 to December 2019 were identified from a prospectively maintained database. Nodal pCR rates were compared between biopsy-proven node-positive patients treated with NET, and HR+/HER2- patients treated with NAC from November 2013 to July 2019. RESULTS: 127 cancers treated with NET and 338 with NAC were included. NET recipients were older, more likely to have lobular and lower-grade tumors, and higher HR expression. With NET, the nodal pCR rate was 11% (4/38) of biopsy-proven cases, and the breast pCR rate was 1.6% (2/126). Nodal-dowstaging rates with NET and NAC were not significantly different (11% vs 18%; P = 0.37). Patients achieving nodal pCR with NET versus NAC were older (median age 70 vs 50, P = 0.004) and had greater progesterone receptor (PR) expression (85% vs 13%, P = 0.031), respectively. Of patients not candidates for BCS due to a large tumor relative to breast size, 36/47 (77%) became BCS-eligible with NET (median PR expression 55% vs 5% in those remaining ineligible, P < 0.05). CONCLUSION: Although nodal pCR is more frequent than breast pCR, NET is more likely to de-escalate breast surgery than axillary surgery. However, with a nodal pCR rate of 11%, NET remains an option for downstaging node-positive patients without clear indications for NAC.
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Neoplasias de la Mama , Terapia Neoadyuvante , Anciano , Axila/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Femenino , Humanos , Mastectomía Segmentaria , Persona de Mediana Edad , Estadificación de Neoplasias , Receptor ErbB-2RESUMEN
BACKGROUND: Endocrine therapy-based neoadjuvant treatment for luminal breast cancer allows efficient testing of new combinations before surgery. The activation of the phosphatidylinositol-3-kinase (PI3K) pathway is a known mechanism of resistance to endocrine therapy. Taselisib is an oral, selective PI3K inhibitor with enhanced activity against PIK3CA-mutant cancer cells. The LORELEI trial tested whether taselisib in combination with letrozole would result in an increased proportion of objective responses and pathological complete responses. METHODS: In this multicentre, randomised, double-blind, parallel-cohort, placebo-controlled phase 2, study, we enrolled postmenopausal women (aged ≥18 years) with histologically confirmed, oestrogen receptor (ER)-positive, HER2-negative, stage I-III, operable breast cancer, from 85 hospitals in 22 countries worldwide. To be eligible, patients had have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1, adequate organ function, and had to have evaluable tumour tissue for PIK3CA genotyping. Patients were randomly assigned (1:1) by means of a permuted block algorithm (block size of four) via an interactive voice or web-based response system, to receive letrozole (2·5 mg/day orally, continuously) with either 4 mg of oral taselisib or placebo (on a 5 days-on, 2 days-off schedule) for 16 weeks, followed by surgery. Randomisation was stratified by tumour size and nodal status. Site staff, patients, and the sponsor were masked to treatment assignment. Coprimary endpoints were the proportion of patients who achieved an objective response by centrally assessed breast MRI and a locally assessed pathological complete response in the breast and axilla (ypT0/Tis, ypN0) at surgery in all randomly assigned patients and in patients with PIK3CA-mutant tumours. Analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02273973, and is closed to accrual. FINDINGS: Between Nov 12, 2014, and Aug 12, 2016, 334 participants were enrolled and randomly assigned to receive letrozole and placebo (n=168) or letrozole and taselisib (n=166). Median follow-up was 4·9 months (IQR 4·7-5·1). The study met one of its primary endpoints: the addition of taselisib to letrozole was associated with a higher proportion of patients achieving an objective response in all randomly assigned patients (66 [39%] of 168 patients in the placebo group vs 83 [50%] of 166 in the taselisib group; odds ratio [OR] 1·55, 95% CI 1·00-2·38; p=0·049) and in the PIK3CA-mutant subset (30 [38%] of 79 vs 41 [56%] of 73; OR 2·03, 95% CI 1·06-3·88; p=0·033). No significant differences were observed in pathological complete response between the two groups, either in the overall population (three [2%] of 166 in the taselisib group vs one [1%] of 168 in the placebo group; OR 3·07 [95% CI 0·32-29·85], p=0·37) or in the PIK3CA-mutant cohort (one patient [1%) vs none [0%]; OR not estimable, p=0·48). The most common grade 3-4 adverse events in the taselisib group were gastrointestinal (13 [8%] of 167 patients), infections (eight [5%]), and skin-subcutaneous tissue disorders (eight [5%]). In the placebo group, four (2%) of 167 patients had grade 3 or worse vascular disorders, two (1%) had gastrointestinal disorders, and two (1%) patients had grade 3 or worse infections and infestations. There was no grade 4 hyperglycaemia and grade 3 cases were asymptomatic. Serious adverse events were more common in the taselisib group (eight [5%] patients with infections and seven [4%] with gastrointestinal effects) than in the placebo group (one [1%] patient each with grade 3 postoperative wound and haematoma infection, grade 4 hypertensive encephalopathy, grade 3 acute cardiac failure, and grade 3 breast pain). One death occurred in the taselisib group, which was not considered to be treatment-related. INTERPRETATION: The increase in the proportion of patients who achieved an objective response from the addition of taselisib to endocrine therapy in a neoadjuvant setting is consistent with the clinical benefit observed in hormone receptor-positive, HER2-negative, metastatic breast cancer. FUNDING: Genentech and F Hoffmann-La Roche.
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Neoplasias de la Mama/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa Clase I/genética , Imidazoles/administración & dosificación , Letrozol/administración & dosificación , Oxazepinas/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Método Doble Ciego , Receptor alfa de Estrógeno/genética , Femenino , Humanos , Imidazoles/efectos adversos , Letrozol/efectos adversos , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Oxazepinas/efectos adversos , Posmenopausia , Receptor ErbB-2/genética , Resultado del TratamientoRESUMEN
Bone health and maintenance of bone integrity are important components of comprehensive cancer care. Many patients with cancer are at risk for therapy-induced bone loss, with resultant osteoporotic fractures, or skeletal metastases, which may result in pathologic fractures, hypercalcemia, bone pain, and decline in motility and performance status. Effective screening and timely interventions are essential for reducing bone-related morbidity. Management of long-term bone health requires a broad knowledge base. A multidisciplinary health care team may be needed for optimal assessment and treatment of bone-related issues in patients with cancer. Since publication of the previous NCCN Task Force Report: Bone Health in Cancer Care in 2009, new data have emerged on bone health and treatment, prompting NCCN to convene this multidisciplinary task force to discuss the progress made in optimizing bone health in patients with cancer. In December 2012, the panel members provided didactic presentations on various topics, integrating expert judgment with a review of the key literature. This report summarizes issues surrounding bone health in cancer care presented and discussed during this NCCN Bone Health in Cancer Care Task Force meeting.
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Huesos/fisiopatología , Terapia Neoadyuvante/efectos adversos , Neoplasias/complicaciones , Osteoporosis/fisiopatología , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/efectos adversos , Densidad Ósea , Calcio/administración & dosificación , Suplementos Dietéticos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/epidemiología , Neoplasias/patología , Osteoporosis/inducido químicamente , Osteoporosis/complicaciones , Osteoporosis/epidemiología , Medición de Riesgo , Vitamina D/administración & dosificaciónRESUMEN
PURPOSE: Dose-limiting neuropathy is a major adverse event associated with most of the microtubule-stabilizing agent-based chemotherapy regimens. Ixabepilone, a semisynthetic analogue of the natural epothilone B, has activity against a wide range of tumor types. Peripheral neuropathy (PN), associated with ixabepilone treatment, is usually mild to moderate, predominantly sensory and cumulative. Preclinical studies demonstrate that ixabepilone and taxanes produce a similar neurotoxicity profile. METHODS: We searched databases of phase II/III clinical trials involving patients receiving ixabepilone as a monotherapy or in combination with capecitabine for incidences of neuropathy. Potential risk factors for grade 3/4 PN were identified by a Cox regression analysis on a dataset of 1,540 patients with different tumor types across multiple studies. RESULTS: Rates for incidence of ixabepilone-induced severe PN (Common Terminology Criteria for Adverse Events grade 3/4) ranged from 1% in early untreated breast cancer up to 24% in heavily pretreated metastatic breast cancer; grade 4 PN was rare (≤ 1%). Common symptoms included numbness, paresthesias, and sometimes dysesthesias. Cox regression analysis identified only preexisting neuropathy as a risk factor for increased ixabepilone-associated PN. The management of PN has been primarily through dose adjustments (dose delays and/or dose reduction). Patients had resolution of their neuropathy within a median time of 5 to 6 weeks. CONCLUSIONS: PN is a dose-limiting toxicity associated with ixabepilone treatment, is reversible in most patients, and can be managed with dose reduction and delays.
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Epotilonas/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Moduladores de Tubulina/efectos adversos , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Bases de Datos Factuales , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Relación Dosis-Respuesta a Droga , Epotilonas/administración & dosificación , Epotilonas/uso terapéutico , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Modelos de Riesgos Proporcionales , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Moduladores de Tubulina/administración & dosificación , Moduladores de Tubulina/uso terapéutico , Adulto JovenRESUMEN
Breast cancer that lacks expression of estrogen/progesterone receptors and overexpression of the human epidermal growth factor receptor2 (HER2), i.e. triple-negative breast cancer (TNBC), is not amenable to current targeted therapies and carries a poor prognosis. This review discusses the natural history of TNBC and published literature in the relevant treatment landscape, with a focus on newer therapies. Compared with other subtypes of breast cancer, TN tumors have higher response rates to neoadjuvant chemotherapy; however, this advantage is not clearly translated into the metastatic setting and has not improved these patients' overall survival. Numerous cytotoxic and targeted strategies have demonstrated efficacy or are under investigation. Strategies showing promise in this difficult-to-treat group of patients include cytotoxic therapy with platinum-containing agents, ixabepilone, and novel targeted approaches such as poly(ADP-ribose) polymerase inhibitors.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Cisplatino/uso terapéutico , Reactivos de Enlaces Cruzados/uso terapéutico , Epotilonas/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Femenino , Humanos , Terapia Neoadyuvante , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Pronóstico , Tasa de SupervivenciaRESUMEN
Patients with breast cancer, which lacks ER, PR, and HER2; "triple negative" (TNBC), are at increased risk of brain metastases (BMs). However, the impact of modern therapy on the risk of BMs and outcomes remains largely unknown. In this retrospective, single-institution study we assessed the incidence of BMs, the therapeutic options, and overall survival, in a recent cohort of patients with TNBC. Women diagnosed with early stage TNBC from January 1, 1998 to December 31, 2007 were identified through institutional databases. Electronic medical records were reviewed to assess patterns of recurrence, treatment, and survival. In total, 1,323 patients, median age 53 years (range 20-91), were identified. There were 298 patients (23%) who developed metastatic disease, of whom, 99 (33%) developed BMs, representing 7.5% of the entire cohort. Following BM diagnosis, treatment consisted of: radiotherapy 87 (88%) patients, resection 26 (26%) patients, and systemic chemotherapy 70 (71%) patients, with a median of 1.0 (range 0-8) chemotherapy regimens. The actuarial median survival from diagnosis of BMs is 5 months (95% CI 4-7 months). This single-institution, retrospective study confirms that the prognosis for patients with BMs from TNBC remains poor. This group of patients urgently needs improved therapies.
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Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Meníngeas/diagnóstico , Persona de Mediana Edad , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Tasa de Supervivencia , Factores de Tiempo , Adulto JovenRESUMEN
PURPOSE: Oversuppression of bone turnover can be a critical factor in the pathogenesis of osteonecrosis of the jaw (ONJ). We investigated N-telopeptide of type I collagen (NTX) and bone-specific alkaline phosphatase (BAP) as potential predictors of ONJ onset. PATIENTS AND METHODS: Patients with ONJ and available stored serum were identified retrospectively from the institutional databases. Four approximate points were examined: point of ONJ diagnosis and 12, 6, and 1 month before the diagnosis. NTX and BAP were measured using enzyme-linked immunosorbent assays and examined as possible predictors of ONJ. RESULTS: From March 1998 to September 2009, we identified 122 patients with ONJ. Of these, 56 (46%) had one or more serum samples available. Overall, 55 patients (98%) received bisphosphonates. Using the exact dates, no obvious patterns in either NTX or BAP were noted. Similarly, using the ordinal points, no evidence of suppression of NTX or BAP over time was seen. The consecutive median values were as follows: The median NTX values were 8.0 nmol/L (range 3.8 to 32.9) at 12 months before ONJ; 9.5 nmol/L (range 4.7 to 42.7) at 6 months; 9.5 nmol/L (range 4.5 to 24.6) at 1 month, and 10.4 nmol/L (range 4.4 to 32.5) at the ONJ diagnosis. The median BAP values were BAP 18.0 U/L (range 7.0 to 74) at 12 months before ONJ; 18.0 U/L (range 4.0 to 134) at 6 months; 14.0 U/L (range 4.0 to 132) at 1 month, and 18.0 U/L (range 0.7 to 375) at the ONJ diagnosis. Only 2 patients (4%) had NTX and 17 (30%) had BAP below the normal range at the ONJ diagnosis. CONCLUSIONS: In the present large retrospective study, no trends were seen in the NTX and BAP levels before the ONJ diagnosis.
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Fosfatasa Alcalina/análisis , Osteonecrosis de los Maxilares Asociada a Difosfonatos/sangre , Neoplasias Óseas/secundario , Huesos/enzimología , Colágeno Tipo I/sangre , Péptidos/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Osteonecrosis de los Maxilares Asociada a Difosfonatos/enzimología , Conservadores de la Densidad Ósea/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Neoplasias de la Mama/patología , Difosfonatos/administración & dosificación , Femenino , Estudios de Seguimiento , Predicción , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/patología , Estudios Retrospectivos , Factores de TiempoRESUMEN
Background: Denosumab is approved to prevent fragility fractures in patients with osteoporosis at high risk for fracture and to prevent bone loss in patients with breast and prostate cancer who receive endocrine therapy. The antiresorptive effect of denosumab rapidly dissipates when it is delayed or discontinued, but the risk for, and incidence of, multiple clinical vertebral fractures in patients with breast cancer after stopping denosumab is currently unclear. Question/Purposes: We sought to identify the incidence of clinical vertebral fractures in patients with breast cancer who received at least 2 doses of denosumab (60 mg) and then discontinued the medication. Methods: We conducted a retrospective chart review to identify patients with a history of breast cancer who were treated with denosumab between June 1, 2010, and July 18, 2018, at Memorial Sloan Kettering Cancer Center. We identified 335 postmenopausal women and 1 man with nonmetastatic breast cancer who received their final denosumab injection at least 6.5 months earlier. Data recorded included baseline bone density and the incidence of vertebral fractures after denosumab discontinuation. Results: The median age of patients was 62 years. Patients received between 2 and 13 denosumab doses before drug discontinuation. Most of the patients (310; 92.3%) were also treated with aromatase inhibitors. Of the 194 patients with baseline bone density data, 50 (25.8%) had normal bone density, 97 (50.0%) had osteopenia, and 47 (24.2%) had osteoporosis. The median follow-up duration from the last denosumab dose was 18.5 months. We identified 1 case of spontaneous vertebral fractures after denosumab stoppage. We found no cases of osteonecrosis of the jaw or atypical femur fracture. Most of the patients (88%) had a gap in denosumab dosing. Conclusions: Clinicians treating patients with breast cancer-especially those continuing to take aromatase inhibitors-should be aware of the possible risks of delaying doses of or discontinuing denosumab and should educate their patients accordingly. Prospective studies are needed to fully evaluate the risks of stopping or delaying denosumab.
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PURPOSE: Activating mutations in PIK3CA promote resistance to HER2-targeted therapy in breast cancer; however, inhibition of PI3K alone leads to escape via feedback upregulation of HER3. Combined inhibition of HER2, HER3, and PI3K overcomes this mechanism preclinically. PATIENTS AND METHODS: This phase I study investigated the MTD of alpelisib given in combination with trastuzumab and LJM716 (a HER3-targeted antibody) in patients with PIK3CA-mutant HER2-positive (HER2+) metastatic breast cancer (MBC) using the continual reassessment method. Secondary analyses included efficacy and exploratory correlative studies. RESULTS: Ten patients were treated initially with daily alpelisib (arm A). Grade ≥3 adverse events seen in ≥2 patients included diarrhea (n = 6), hypokalemia (n = 3), abnormal liver enzymes (n = 3), hyperglycemia (n = 2), mucositis (n = 2), and elevated lipase (n = 2). The MTD of alpelisib in arm A was 250 mg daily. This prompted the opening of arm B in which 11 patients received intermittently dosed alpelisib. Grade ≥3 adverse events seen in ≥2 patients included diarrhea (n = 5), hypokalemia (n = 3), and hypomagnesemia (n = 2). The MTD of alpelisib in arm B was 350 mg given 4 days on, 3 days off. Among 17 patients assessed, 1 had a partial response, 14 had stable disease, and 2 had disease progression at best response. Five patients had stable disease for >30 weeks. mRNA profiling of pre- and on-treatment tissue demonstrated PIK3CA target engagement by alpelisib via induction of downstream signaling and feedback pathways. CONCLUSIONS: Combination treatment with alpelisib, trastuzumab, and LJM716 was limited by gastrointestinal toxicity. Further efforts are warranted to target the PI3K pathway in HER2+ MBC.
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Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Mutación , Tiazoles/administración & dosificación , Trastuzumab/administración & dosificación , Adulto , Anciano , Neoplasias de la Mama/química , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Receptor ErbB-2/análisisRESUMEN
Bone marrow myelotoxicity is a major limitation of chemotherapy. While granulocyte colony stimulating factor (G-CSF) treatment is effective, alternative approaches to support hematopoietic recovery are sought. We previously found that a beta-glucan extract from maitake mushroom Grifola frondosa (MBG) enhanced colony forming unit-granulocyte monocyte (CFU-GM) activity of mouse bone marrow and human hematopoietic progenitor cells (HPC), stimulated G-CSF production and spared HPC from doxorubicin toxicity in vitro. This investigation assessed the effects of MBG on leukocyte recovery and granulocyte/monocyte function in vivo after dose intensive paclitaxel (Ptx) in a normal mouse. After a cumulative dose of Ptx (90-120 mg/kg) given to B6D2F1mice, daily oral MBG (4 or 6 mg/kg), intravenous G-CSF (80 microg/kg) or Ptx alone were compared for effects on the dynamics of leukocyte recovery in blood, CFU-GM activity in bone marrow and spleen, and granulocyte/monocyte production of reactive oxygen species (ROS). Leukocyte counts declined less in Ptx + MBG mice compared to Ptx-alone (p = 0.024) or Ptx + G-CSF treatment (p = 0.031). Lymphocyte levels were higher after Ptx + MBG but not Ptx + G-CSF treatment compared to Ptx alone (p < 0.01). MBG increased CFU-GM activity in bone marrow and spleen (p < 0.001, p = 0.002) 2 days after Ptx. After two additional days (Ptx post-day 4), MBG restored granulocyte/monocyte ROS response to normal levels compared to Ptx-alone and increased ROS response compared to Ptx-alone or Ptx + G-CSF (p < 0.01, both). The studies indicate that oral MBG promoted maturation of HPC to become functionally active myeloid cells and enhanced peripheral blood leukocyte recovery after chemotoxic bone marrow injury.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Células Progenitoras de Granulocitos y Macrófagos/metabolismo , Grifola , Leucocitos/metabolismo , Paclitaxel/administración & dosificación , beta-Glucanos/administración & dosificación , Animales , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Línea Celular Tumoral , Carbohidratos de la Dieta/administración & dosificación , Antagonismo de Drogas , Quimioterapia Combinada , Células Progenitoras de Granulocitos y Macrófagos/efectos de los fármacos , Células Progenitoras de Granulocitos y Macrófagos/inmunología , Células Progenitoras de Granulocitos y Macrófagos/patología , Humanos , Leucocitos/efectos de los fármacos , Leucocitos/inmunología , Leucocitos/patología , Leucopoyesis/efectos de los fármacos , Ratones , Oxidación-Reducción/efectos de los fármacos , Paclitaxel/efectos adversos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The outlook for patients with HER2-positive breast cancer was revolutionized by the development of trastuzumab (Herceptin), a humanized murine monoclonal antibody. Use of this agent led to improved overall survival when it was added to chemotherapy for the treatment of metastatic breast cancer. Improved understanding of mechanisms of resistance to trastuzumab has facilitated the development of novel agents for HER2-positive breast cancer, and also resulted in superior outcomes when added to chemotherapy in the adjuvant setting. This review explores the use of several such agents, including lapatinib (Tykerb), HSP90 inhibitors, T-DM1, and other tyrosine kinase inhibitors. Emerging data from trials of these agents indicate that the HER2 pathway remains a valid therapeutic target following disease progression on trastuzumab, and suggest a promising role for combined HER2 blockade with two or more agents.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Antineoplásicos/administración & dosificación , Quimioterapia Adyuvante , Resistencia a Antineoplásicos , Femenino , Humanos , Lapatinib , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinazolinas/administración & dosificación , Quinazolinas/uso terapéutico , TrastuzumabRESUMEN
PURPOSE: Epichaperome network maintenance is vital to survival of tumors that express it. PU-H71 is an epichaperome inhibitor that binds to the ATP-binding site of HSP90 and has demonstrated antitumor activity in breast cancer xenograft models and clinical safety in patients. PU-positron emission tomography (PET) is a theragnostic imaging tool that allows visualization of the epichaperome target. In this phase Ib trial, we present safety and tolerability for PU-H71 plus nab-paclitaxel in HER2-negative patients with metastatic breast cancer (MBC) and the utility of PU-PET as a noninvasive predictive biomarker. METHODS: We performed a 3 + 3 dose-escalation study with escalating PU-H71 doses and standard nab-paclitaxel. The primary objective was to establish safety and determine maximum tolerated dose (MTD)/recommended phase 2 dose. Secondary objectives were to assess pharmacokinetics and clinical efficacy. Patients could enroll in a companion PU-PET protocol to measure epichaperome expression before treatment initiation to allow exploratory correlation with treatment benefit. RESULTS: Of the 12 patients enrolled, dose-limiting toxicity occurred in one patient (G3 neutropenic fever) at dose level 1; MTD of PU-H71 was 300 mg/m2 plus nab-paclitaxel 260 mg/m2 administered every 3 weeks. Common toxicities included diarrhea, fatigue, peripheral neuropathy, and nausea. PU-H71 systemic exposure was not altered by nab-paclitaxel administration. Two of 12 patients had partial response (overall response rate, 17%) and the clinical benefit rate was 42% (5 of 12). Time to progression was associated with baseline epichaperome positivity and PU-H71 peak standard uptake value (SUV), with more durable disease control observed with high epichaperome levels. CONCLUSION: The combination of PU-H71 and nab-paclitaxel was well tolerated, with evidence of clinical activity. More durable disease control without progression was observed in patients with high baseline epichaperome expression. A phase II trial of this combination with PU-PET as a companion diagnostic for patient selection is currently planned.
RESUMEN
We developed a first-of-kind dasatinib-derivative imaging agent, 18F-SKI-249380 (18F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assessed the feasibility of using 18F-SKI for PET imaging in patients with malignancies. Methods: Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min after injection of 18F-SKI (mean, 241.24 ± 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney (n = 2) or three 10-min whole-body PET/CT scans (n = 3) immediately after injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of 3 patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. Results: No adverse events occurred after injection of 18F-SKI. In total, 27 tumor lesions were analyzed, with a median SUVpeak of 1.4 (range, 0.7-2.3) and tumor-to-blood ratios of 1.6 (range, 0.8-2.5) at 90 min after injection. The intratumoral drug concentrations calculated for 4 reference lesions ranged from 0.03 to 0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30 and 90 min after injection. A blood radioassay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time, 1.31 ± 0.81 min; plasma, 1.07 ± 0.66 min; n = 4), followed variably by either a prolonged terminal phase (blood half-time, 285 ± 148.49 min; plasma, 240 ± 84.85 min; n = 2) or a small rise to a plateau (n = 2). Like dasatinib, 18F-SKI underwent extensive metabolism after administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 ± 0.04) and small intestine (0.153 ± 0.03). The effective dose was 0.0258 mSv/MBq (SD, 0.0034 mSv/MBq). Conclusion:18F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood.
Asunto(s)
Dasatinib/análogos & derivados , Radioisótopos de Flúor/farmacocinética , Neoplasias/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Proteínas Tirosina Quinasas/metabolismo , Radiofármacos/farmacocinética , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Imagen de Cuerpo EnteroRESUMEN
PURPOSE: Granulocyte-colony stimulating factor (G-CSF) was used in CALGB 9741 to support dose-dense sequential chemotherapy with doxorubicin and cyclophosphamide (AC) followed by paclitaxel (P) (Citron et al. J Clin Oncol 21:1431-1439, 2003). However, myelosuppression is not known to be dose or schedule limiting for paclitaxel. We therefore conducted this trial to determine the need for routine G-CSF, using the pegylated product (pG-CSF), support during the paclitaxel component of dose-dense sequential chemotherapy in women with early stage breast carcinoma (BC). PATIENTS AND METHODS: Eligible patients received dose-dense chemotherapy consisting of four cycles of AC followed by four cycles of P at two week intervals. pG-CSF (Neulasta) was administered after each of four cycles of AC but was held after P. Planned enrollment was 59 pts. RESULTS: Of the first 15 patients, nine completed therapy without delays due to neutropenia but 6 (40%) did not, leading to implementation of the pre-specified early termination rule. Overall, 85% of P doses were successfully delivered on time. The mean treatment delay for the entire group due to neutropenia was 0.75 days. There was no significant correlation between neutropenia and prior WBC, ANC, or concurrent treatment with trastuzumab. Pts with neutropenia tended to be younger (Mean age 43.5) and have a lower BSA (1.65 m(2)). There were no febrile episodes due to omission of pG-CSF. CONCLUSION: When paclitaxel is administered in a dose-dense fashion without growth factor support brief treatment delays are common. Further study is needed to identify the minimal pG-CSF administration that will avoid treatment delays.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adolescente , Adulto , Anciano , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Relación Dosis-Respuesta a Droga , Estudios de Factibilidad , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Proyectos Piloto , Polietilenglicoles , Pronóstico , Proteínas Recombinantes , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
A feasibility-phase II study was conducted to assess the cardiotoxicity of weekly trastuzumab, epirubicin, and paclitaxel in patients with human epidermal growth factor receptor-2-positive metastatic breast cancer. Untreated patients with human epidermal growth factor receptor-2-positive advanced breast cancer received trastuzumab (day 1), and epirubicin (25 mg/m2) and paclitaxel (80 mg/m2) (day 2) on a weekly basis. The rate of patients with left-ventricular ejection fraction (L-VEF) reduction greater than 10% after 12 weeks was the primary end point. According to a two-stage model, an initial step with 15 patients was required; after 11 patients without toxicity, a second step with 21 patients was planned. After 255 courses in 15 patients (median treatment weeks: 18), the relative dose intensity was 94.7%. At 12 weeks, three patients (20%) displayed a L-VEF reduction greater than 10%, six and six (40%) patients showed a L-VEF reduction < or =10% or no change, respectively. Baseline, -12 weeks, and -24 weeks median L-VEF was 69% (range 61-77), 65% (range 60-76), and 65% (range 55-73), respectively. No EKG/cardiac signs were present. Thirteen patients had grade 3 alopecia and two patients had grade 3 asthenia, in the absence of severe hematological toxicity. Objective responses were observed in 11 patients (73.3%, 95% confidence interval 51.0-95.7), with 10 partial. The weekly administration of trastuzumab-epirubicin-paclitaxel is extremely tolerable, also with regard to L-VEF reduction. These results allowed entrance to the second step of the study.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Epirrubicina/uso terapéutico , Corazón/efectos de los fármacos , Paclitaxel/uso terapéutico , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Epirrubicina/administración & dosificación , Epirrubicina/efectos adversos , Estudios de Factibilidad , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia/tratamiento farmacológico , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Volumen Sistólico/efectos de los fármacos , Tasa de Supervivencia , Trastuzumab , Resultado del Tratamiento , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Microtubules are essential to cell transport, signaling, and mitosis. An increasing range of anticancer drugs interferes with the normal formation and function of microtubules. Vinca alkaloids act as microtubule destabilizers and the taxanes act as microtubule stabilizers. Taxanes are widely used cytotoxic agents that are active in a range of solid tumor malignancies and are routinely used in a variety of settings. Significant limitations with the taxanes exist, including acquired and intrinsic tumor resistance through the expression of multidrug resistance proteins such as P-glycoprotein, risk of hypersensitivity reactions, dose-limiting hematopoietic toxicity, and cumulative neurotoxicity. Hence, there is a need to develop novel agents that act on the microtubules. Epothilones are macrolide antibiotics that bind near the taxane-binding site on microtubules and have been extensively studied in recent and ongoing clinical trials. A variety of other agents that act on the microtubules at different sites with a variety of structures are at varying stages of development.