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BACKGROUND: Pathologic complete response after neoadjuvant chemoradiotherapy for rectal cancer is associated with improved survival. It is unclear whether residual carcinoma in situ portends a similar outcome. OBJECTIVE: To compare the survival of patients with locally advanced rectal cancer who received neoadjuvant therapy and achieved pathologic carcinoma in situ versus pathologic complete response. DESIGN: Retrospective cohort study. SETTING: National public database. PATIENTS: A total of 4594 patients in the National Cancer Database from 2006 to 2016 with locally advanced rectal cancer who received neoadjuvant therapy, underwent surgery, and had node-negative ypTis or ypT0 on final pathology were included. Of these, 4321 patients (94.1%) had ypT0 and 273 (5.9%) had ypTis on final pathology. MAIN OUTCOME MEASURE: Overall survival. RESULTS: The median age was 60 years, and 1822 patients (39.7%) were women. On initial staging, 54.5% (n = 2503) had stage II disease and 45.5% (n = 2091) had stage III disease. The ypTis group had decreased overall survival compared to the ypT0 group (HR 1.42; 95% CI, 1.04-1.95; p = 0.028). Other factors associated with decreased overall survival were older age at diagnosis, increasing Charlson-Deyo score, and poorly differentiated tumor grade. Variables associated with improved survival were female sex, private insurance, and receipt of both neoadjuvant and adjuvant chemotherapy. For the total cohort, there was no difference in survival between clinical stage II and stage III. LIMITATIONS: Standard therapy versus total neoadjuvant therapy could not be abstracted. Overall survival was defined as the time from surgery to death from any cause or last contact, allowing for some erroneously misclassified deaths. CONCLUSIONS: ypTis is associated with worse overall survival than ypT0 for patients with locally advanced rectal cancer who receive neoadjuvant chemoradiotherapy followed by surgery. For this cohort, clinical stage was not a significant predictor of survival. Prospective trials comparing survival for these pathologic outcomes are needed. See Video Abstract . SUPERVIVENCIA DEL CNCER DE RECTO PARA EL CARCINOMA RESIDUAL IN SITU VS RESPUESTA PATOLGICA COMPLETA DESPUS DE LA TERAPIA NEOADYUVANTE: ANTECEDENTESLa respuesta patológica completa después de la quimiorradioterapia neoadyuvante para el cáncer de recto se asocia con una mayor supervivencia. No está claro si el carcinoma residual in situ presagia un resultado similar.OBJETIVOComparar la supervivencia de pacientes con cáncer de recto localmente avanzado que recibieron terapia neoadyuvante y lograron un carcinoma patológico in situ versus una respuesta patológica completa.DISEÑOEstudio de cohorte retrospectivo.ESCENARIOBase de datos pública nacional.PACIENTESSe incluyeron 4,594 pacientes de la Base de Datos Nacional de Cáncer de 2006 a 2016 con cáncer de recto localmente avanzado que recibieron terapia neoadyuvante, fueron sometidos a cirugía y tuvieron ganglios negativos, ypTis o ypT0 en el reporte patológico final. 4.321 (94,1%) tuvieron ypT0 y 273 (5,9%) tuvieron ypTis en el reporte final.PRINCIPALES MEDIDAS DE RESULTADOSupervivencia general.RESULTADOSLa mediana de edad fue de 60 años. 1.822 pacientes (39,7%) fueron mujeres. El 54,5% (n = 2.503) tuvo la enfermedad en estadio II y el 45,5% (n = 2.091) tuvo la enfermedad en estadio III según la estadificación inicial. El grupo ypTis tuvo una supervivencia general reducida en comparación con el grupo ypT0 (HR 1,42, IC 95 % 1,04-1,95, p = 0,028). Otros factores asociados con una menor supervivencia general fueron una edad más avanzada al momento del diagnóstico, un aumento de la puntuación de Charlson-Deyo y un grado tumoral poco diferenciado. Las variables asociadas con una mejor supervivencia fueron el sexo femenino, el seguro privado y la recepción de quimioterapia neoadyuvante y adyuvante. Para la cohorte total, no hubo diferencias en la supervivencia entre el estadio clínico 2 y el estadio 3.LIMITACIONESNo se pudo resumir el tratamiento estándar versus el tratamiento neoadyuvante total. La supervivencia general se definió como el tiempo transcurrido desde la cirugía hasta la muerte por cualquier causa o último contacto, lo que permite algunas muertes erróneamente clasificadas.CONCLUSIONESypTis se asocia con una peor supervivencia general que ypT0 en pacientes con cáncer de recto localmente avanzado que reciben quimiorradioterapia neoadyuvante seguida de cirugía. Para esta cohorte, el estadio clínico no fue un predictor significativo de supervivencia. Se necesitan ensayos prospectivos que comparen la supervivencia de estos resultados patológicos. ( Traducción-Dr Osvaldo Gauto ).
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Terapia Neoadyuvante , Estadificación de Neoplasias , Neoplasia Residual , Neoplasias del Recto , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias del Recto/terapia , Neoplasias del Recto/patología , Neoplasias del Recto/mortalidad , Terapia Neoadyuvante/métodos , Terapia Neoadyuvante/estadística & datos numéricos , Estudios Retrospectivos , Anciano , Tasa de Supervivencia , Proctectomía , Respuesta Patológica CompletaRESUMEN
BACKGROUND: Patients with HER2-positive metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases. A potent and selective HER2 inhibitor with good blood-brain barrier (BBB) penetration is highly desirable. METHODS: The design and structure-activity relationship of DZD1516 was described. The potency and selectivity of DZD1516 were determined by enzymatic and cellular assays. The antitumor activity of DZD1516 monotherapy or in combination with HER2 antibody-drug conjugate was assessed in CNS and subcutaneous xenograft mouse models. A phase 1 first-in-human study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DZD1516 in patients with HER2+ MBC who relapsed from standard of care. RESULTS: DZD1516 showed good selectivity against HER2 over wild-type EGFR in vitro and potent antitumor activity in vivo. Twenty-three patients were enrolled and received DZD1516 monotherapy treatment across six dose levels (25-300 mg, twice daily). Dose-limiting toxicities were reported at 300 mg, and thus 250 mg was defined as the maximum tolerated dose. The most common adverse events included headache, vomiting, and hemoglobin decreased. No diarrhea or skin rash was observed at ≤ 250 mg. The mean Kp,uu,CSF was 2.1 for DZD1516 and 0.76 for its active metabolite DZ2678. With median seven lines of prior systemic therapy, the best antitumor efficacy in intracranial, extracranial and overall lesions was stable disease. CONCLUSIONS: DZD1516 provides positive proof of concept for an optimal HER2 inhibitor with high BBB penetration and HER2 selectivity. Further clinical evaluation of DZD1516 is warranted, with the RP2D being 250 mg BID. CLINICALTRIALS: gov identifier NCT04509596. Registered on August 12, 2020; Chinadrugtrial: CTR20202424 Registered on December 18, 2020.
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Neoplasias de la Mama , Neoplasias del Sistema Nervioso Central , Humanos , Animales , Ratones , Femenino , Neoplasias de la Mama/patología , Receptor ErbB-2/metabolismo , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Inhibidores de Proteínas Quinasas/efectos adversos , Neoplasias del Sistema Nervioso Central/secundario , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Systemic therapy for both early-stage and metastatic human epidermal growth factor receptor-2-positive (HER2+) breast cancer has seen significant evolution over the last 20 or more years. Innovative trials leveraging the prognostic and predictive information that neoadjuvant chemotherapy provides has led to preoperative systemic therapy becoming the overwhelmingly favored sequencing in the early-stage setting. However, deintensification of therapy is important to consider for patients with good-risk disease or significant comorbidities. Finally, with the abundance of newly approved agents, drug sequencing in the second-line setting has become an important and individualized decision for patients with metastatic disease.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Terapia Neoadyuvante , Quimioterapia Adyuvante , PronósticoRESUMEN
Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor prognosis and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) breast cancer. Here we report the results of a phase 2 single-arm Simon 2-stage trial combining Ruxolitinib, an oral selective inhibitor of JAK1/2, with exemestane, a steroidal AI, in patients with HR+ metastatic breast cancer (MBC) after progression on non-steroidal AI (NSAI). Safety and efficacy were primary objectives, and analysis of inflammatory markers as predictors of response was a key secondary objective. Twenty-five subjects enrolled. The combination of ruxolitinib and exemestane was safe, though anemia requiring transfusion in 5/15 (33%) at the 25 mg dose in stage 1 led to a reduction to 15 mg twice daily in stage 2 (with no additional transfusions). Clinical benefit rate (CBR) in the overall study population was 24% (95% CI 9.4-45.1); 6/25 patients demonstrated stable disease for ≥6 months. Median progression-free survival was 2.8 months (95% CI 2.6-3.9). Exploratory biomarkers revealed high levels of systemic inflammation and 60% harbored a high-risk IL-6 genotype. Pharmacodynamics demonstrated modest on-target inhibition of phosphorylated-STAT3 by ruxolitinib at a tolerable dose. Thus, ruxolitinib combined with exemestane at a tolerable dose was safe but minimally active in AI-resistant tumors of patients with high levels of systemic inflammation. These findings highlight the need for more potent and specific therapies targeting inflammation in MBC.
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Background: Triple-negative breast cancer (TNBC) is associated with a poor prognosis when compared to hormone receptor-positive breast cancers. Anthracycline-based regimens (ABRs) are mainstay for treatment of non-metastatic TNBC. However, anthracyclines are associated with an increased risk of potentially life-threatening adverse effects. We sought to evaluate outcomes in patients with early TNBC treated with ABRs versus those treated with anthracycline-sparing regimens (ASRs). Methods: All patients treated for stage I-III TNBC who had undergone curative-intent surgery at a large academic medical center between January 2013 and May 2018 were included in this retrospective study. Event-free survival (EFS) and disease-free survival (DFS) were the primary endpoints, with overall survival (OS) as a secondary endpoint and were defined as per standardized STEEP criteria. Kaplan-Meier, multivariable Cox regression, and log-rank tests were used to define key survival and treatment-related differences between subjects treated with ABRs versus ASRs. Results: One hundred thirty-two patients met inclusion criteria with a median follow-up of 55.9 months. Twenty-seven patients (20%) had disease recurrence and 20 (15%) died. Patients in the ABR group were more likely to have nodal involvement (chi-square p = 0.011). Patients treated with ABRs (n = 26, 20%) compared with ASRs (n = 106, 80%) had significantly shorter median EFS (32.4 months vs not reached (NR), p < 0.001), DFS (26.2 months vs NR, p < 0.001), and OS (49.2 months vs NR, p < 0.001). The shorter survival observed in the ABR group persisted after adjusting for nodal status and on multivariate analysis. Of the 26 ABR-treated patients, 9 (35%) had an anthracycline added after suboptimal response to an ASR. Regardless of reason for anthracycline inclusion, the survival outcomes were similar. No cardiac or secondary leukemic events were observed in either group. Conclusion: ABRs were associated with shorter EFS, DFS, and OS, even after adjusting for certain high-risk clinical features.
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PURPOSE OF REVIEW: To highlight recent practice changing clinical trials, focusing on those leading to new drug approvals, in human epidermal growth factor receptor 2-positive (HER2+) breast cancer. RECENT FINDINGS: The improved disease-free survival of adjuvant trastuzumab emtansine (T-DM1) over trastuzumab in patients with residual disease has made neoadjuvant sequencing of therapy standard for most patients with early stage disease. In patients with metastatic HER2+ breast cancer, trastuzumab deruxtecan has recently shown dramatically improved efficacy over T-DM1. Tucatinib is an oral tyrosine kinase inhibitor with best in class blood-brain barrier penetration. Margetuximab, a novel HER2-targeted chimeric monoclonal antibody with an engineered Fc receptor designed to activate local immune response, was recently approved in heavily pretreated patients based on modest but significant improvement in progression-free survival. SUMMARY: Patients with HER2+ breast cancer have a variety of therapeutic options in the early stage and metastatic setting. Optimal sequencing of therapy will depend on patient-specific factors such as site of tumor progression and underlying comorbidities. De-escalation of the first-line metastatic regimen may be considered in select patients with hormone positive/HER2+ breast cancer, by using endocrine therapy instead of chemotherapy in combination with HER2-targeted therapy, which may improve side effects without sacrificing efficacy.
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Neoplasias de la Mama , Ado-Trastuzumab Emtansina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Femenino , Humanos , Terapia Neoadyuvante , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapéuticoRESUMEN
The natural history of hormone receptor-positive breast cancer tends to be more favorable than other subtypes such as human epidermal growth factor receptor 2-amplified and triple-negative. In addition, the natural dependence on steroid hormone signaling has allowed for therapeutic targeting of this pathway and significant improvements in survival while maintaining quality of life: the two main goals in management of the disease. The sequential use of endocrine agents including the selective estrogen receptor modulators (tamoxifen), aromatase inhibitors (letrozole, anastrozole, and exemestane) and the selective estrogen receptor degrader fulvestrant has been the backbone of management for years. In the past decade, the introduction of molecularly targeted agents against intracellular targets such as mammalian target of rapamycin (everolimus), cyclin-dependent kinases 4 and 6 (palbociclib, ribociclib, and abemaciclib), and phosphatidylinositol 3-kinase (alpelisib) has offered patients effective nonchemotherapy-based options, which are improving outcomes. Although knowledge gaps still exist in regard to the optimal sequencing of these new regimens, they have expanded our repertoire of options for patients and have shifted the need for cytotoxic chemotherapy and its associated complications to later lines. Still, formatting a plan for these patients includes taking into account traditional prognostic factors such as menopausal status, previous treatments, disease-free interval for those patients with early breast cancer that has recurred, and tumor burden. To assist in developing this treatment plan, we will review the current data with systemic agents in the management of these patients.
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Neoplasias de la Mama , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Femenino , Humanos , Letrozol/uso terapéutico , Calidad de VidaRESUMEN
It has been over three decades since anthracyclines took their place as the standard chemotherapy backbone for breast cancer in the curative setting. Though the efficacy of anthracycline chemotherapy is not debatable, potentially life-threatening and long-term risks accompany this class of agents, leading some to question their widespread use, especially when newer agents with improved therapeutic indices have become available. Critically assessing when to incorporate an anthracycline is made more relevant in an era where molecular classification is enabling not only the development of biologically targeted therapeutics but also is improving the ability to better select those who would benefit from cytotoxic agents. This comprehensive analysis will present the problem of overtreatment in early-stage breast cancer, review evidence supporting the use of anthracyclines in the pre-taxane era, analyze comparative trials evaluating taxanes with or without anthracyclines in biologically unselected and selected patient populations, and explore published work aimed at defining anthracycline-sensitive tumor types.
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Chronic inflammation has been a proposed mechanism of resistance to aromatase inhibitors in breast cancer. Stratifying by HER2 status, a matched case-control study from the Wellness After Breast Cancer-II cohort was performed to assess whether or not elevated serum inflammatory biomarkers (C-Reactive protein [CRP], interleukin-6 [IL-6], and serum amyloid A [SAA]) and/or the presence of a high-risk IL-6 promoter genotype were associated with recurrence of hormone receptor positive (HR+) early breast cancer. Estrogen levels were also measured and correlated with biomarkers and disease outcomes. CRP and SAA were significantly associated with an increased risk of recurrence in the HR+/HER2- group, but not the HR+/HER2+ group. Mean serum estrogen levels were non-significantly elevated in patients who relapsed vs. non-relapsed patients. Surprisingly, high-risk IL-6 promoter polymorphisms were strongly associated with HER2+ breast cancer relapse, which has potential therapeutic implications, as elevated intracellular IL-6 has been associated with trastuzumab resistance in pre-clinical models.
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There are over 2 million cases a year of breast cancer, leading to over 600,000 deaths globally [1]. Despite these large numbers, increasingly more women are being cured with early stage disease and women with advanced disease are living longer [2]. The appreciation for molecular subtypes of the disease has led to significant therapeutic advances and estrogen receptor positive (ER+) breast cancer represents the largest of these subgroups. An appreciation for the importance of estrogen signaling in ER+ dates back to 1896 when Dr. George Thomas Beatson observed impressive disease responses after performing bilateral oophorectomy in 3 women at Glasgow Cancer Hospital [3]. The evolution of treatment for advanced disease from progestins, to the selective estrogen receptor modulator tamoxifen, and subsequently the aromatase inhibitors and the selective estrogen receptor degrader fulvestrant, has been accompanied by improved efficacy and decreased side effects. While the use of these drugs has changed the natural history of both early and advanced disease, it has been long recognized that many patients will develop resistance to this approach. After many years of trying to improve on single-agent endocrine treatment, since 2012 there has been an explosion of new drugs that have shown improved efficacy in combination with endocrine approaches. The first of these to receive FDA approval was the mTOR inhibitor everolimus (2012) [4], followed by the approval of 3 cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors [palbociclib (2015) [5], ribociclib (2018) [6], and abemaciclib (2018) [7]], and more recently the PI3-kinase inhibitor alpelisib (2019) [8]. In addition, chemotherapy is still used frequently when endocrine manipulations have been exhausted. Like other incurable malignancies, the goal in advanced ER+ breast cancer is to prolong survival and maintain quality of life. Currently, we have more tools available to achieve this than ever before and we will review the efficacy and side effect data with these agents that are driving physician choices for individual patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Receptores de Estrógenos/genética , Estrógenos/genética , Femenino , Humanos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Palbociclib is highly active in oestrogen-receptor positive (ER+) metastatic breast cancer, but neutropenia is dose limiting. The goal of this study was to determine whether early neutropenia is associated with disease response to single-agent palbociclib. METHODS: Blood count and disease-response data were analysed from two Phase 2 clinical trials at different institutions using single-agent palbociclib: advanced solid tumours positive for retinoblastoma protein and advanced liposarcoma. The primary endpoint was PFS. The primary exposure variable was the nadir absolute neutrophil count (ANC) during the first two cycles of treatment. RESULTS: One hundred and ninety-six patients (61 breast, 135 non-breast) were evaluated between the two trials. Development of any grade neutropenia was significantly associated with longer median PFS in both the breast cancer (HR 0.29, 95% CI 0.11-0.74, p = 0.010) and non-breast cancer (HR 0.57, 95% CI 0.38-0.85, p = 0.006) cohorts. Grade 3-4 neutropenia was significantly associated with prolonged PFS in the non-breast cohort (HR 0.57, 95% CI 0.38-0.85, p = 0.006) but not in the breast cohort (HR 0.87, 95% CI 0.51-1.47, p = 0.596). Multivariate analysis yielded similar results. CONCLUSIONS: Treatment-related neutropenia in the first two cycles was significantly and independently associated with prolonged PFS, suggesting that neutropenia may be a useful pharmacodynamic marker to guide individualised palbociclib dosing. CLINICAL TRIALS REGISTRATION INFORMATION: Basket Trial: NCT01037790; Sarcoma Trial: NCT01209598.
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Neoplasias/tratamiento farmacológico , Neutropenia/inducido químicamente , Piperazinas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Piridinas/efectos adversos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/mortalidad , Modelos de Riesgos Proporcionales , Adulto JovenRESUMEN
PURPOSE: The CDK 4/6 inhibitor palbociclib rapidly and reversibly inhibits the cell cycle. The goal of this study was to exploit the cell cycle through intermittent, alternating dosing with palbociclib/paclitaxel to enhance efficacy. We determined the combination dose-limiting toxicity (DLT) in patients with Rb protein-expressing, advanced breast cancer. PATIENTS AND METHODS: This open-label, phase I trial (NCT01320592) enrolled patients to sequential cohorts of palbociclib orally dosed intermittently between days 1 and 19 of a 28-day cycle alternating with weekly paclitaxel. Dose escalation proceeded in a standard 3 + 3 design. Ten additional patients received the combination at the recommended phase II dose (RP2D). Those who reached response plateau ≥6 cycles could continue on palbociclib alone on a 3 week on/1 week off schedule at one dose level above their combination dose. RESULTS: Twenty-seven patients enrolled. Although there was only 1 DLT (grade 3 alanine aminotransferase/aspartate aminotransferase at 125 mg), neutropenia (NTP) requiring dose modification in cycle 1 (C1) resulted in an RP2D of 75 mg palbociclib/80 mg/m2 paclitaxel. During C1, the most common adverse event was NTP, occurring in 15 patients (55.6%); grade 1 or 2 nausea and peripheral neuropathy were also observed in 8 patients each (29.6%). The clinical benefit rate was 55% at the RP2D; benefit was observed across all receptor subtypes. CONCLUSIONS: Alternating sequential palbociclib/paclitaxel in patients with Rb+ advanced breast cancer is feasible and safe, without evidence of additive toxicity. This represents a new application for CDK 4/6 inhibitors in Rb+ breast cancer regardless of subtype; efficacy trials are warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/etiología , Neoplasias de la Mama/terapia , Esquema de Medicación , Femenino , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Piperazinas/administración & dosificación , Piridinas/administración & dosificación , Retratamiento , Resultado del TratamientoRESUMEN
Primary and recurrent retroperitoneal tumors can involve the aortoiliac vasculature. They are often considered inoperable or incurable because of the locally advanced nature of the disease or the technical aspects involved in safely resecting the lesion. Safe resection of these lesions requires experience and extensive preoperative planning for success. A retrospective database review of 76 patients with retroperitoneal tumors identified tumors involving major vascular structures in the abdomen and pelvis undergoing resection of tumor en bloc with the aortoiliac vasculature. Preoperative planning and intraoperative technical maneuvers are reviewed. Patients were followed until time of this report. Four patients with retroperitoneal tumors involving the aortoiliac vessels underwent surgery: two patients with sarcoma (one primary and one recurrent), one with metastatic renal cell carcinoma, and one with a paraganglioma. All patients had resection of the aorta and vena cava or the iliac artery and vein. Arterial reconstruction (anatomic or extra-anatomic) was performed in all cases. The patient with renal cell carcinoma also required venous reconstruction to support a renal autotransplant. Veno-venous bypass was required in one patient. Local control was achieved in 3 of 4 cases. Surgery for retroperitoneal tumors involving major vascular structures is technically feasible with appropriate planning and technique. Multiple disciplines are required, including general surgical oncology, vascular surgery, and possibly, cardiothoracic surgery.