Cellular proliferation, growth, and division following DNA (deoxyribonucleic acid) damage are tightly controlled by the cell-cycle regulatory machinery. This machinery includes cyclin-dependent ...kinases (CDKs) which complex with their cyclin partners, allowing the cell cycle to progress. The cell-cycle regulatory process plays a critical role in oncogenesis and in the development of therapeutic resistance; it is frequently disrupted in breast cancer, providing a rational target for therapeutic development. Palbociclib is a potent and selective inhibitor of CDK4 and -6 with significant activity in breast cancer models. Furthermore, it has been shown to significantly prolong progression-free survival when combined with letrozole in the management of estrogen receptor-positive metastatic breast cancer. In this article we review the cell cycle and its regulatory processes, their role in breast cancer, and the rationale for CDK inhibition in this disease. We describe the preclinical and clinical data relating to the activity of palbociclib in breast cancer and the plans for the future development of this agent.
We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving ...neoadjuvant chemotherapy.
We identified responders (RCB 0/1) and matched non-responders (RCB 2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel versus cisplatin in TNBC. We collected plasma samples at baseline, 3 weeks and 12 weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence.
Of 139 patients, 68 had complete samples and no additional neoadjuvant chemotherapy. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000 variants) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3 and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10−4 (range 7.9 × 10−7-4.9 × 10−1). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10 of 11 patients with RCB 0, 3 of 8 with RCB 1, 4 of 15 with RCB 2 and 0 of 4 with RCB 3. Among six patients with known recurrence, five had persistent ctDNA at week 12.
Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine whether ctDNA-guided approaches can improve outcomes.
•We carried out a case-control study of patients with TNBC receiving neoadjuvant chemotherapy enrolled on the TBCRC030 trial.•Using a highly sensitive mutation enrichment approach (MAESTRO), we showed a strong association between ctDNA TFx and RCB.•Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders.•In 58% of patients, TFx dropped below the threshold of commercially available assays, showing the need for sensitive tests.
We previously reported progression-free survival (PFS) results on a phase II trial of weekly paclitaxel, trastuzumab, and pertuzumab in patients with human epidermal growth factor receptor ...2(HER2)–positive metastatic breast cancer (MBC) treated in the first- and second-line setting. Here, we report results for overall survival (OS) and updated PFS after an additional year of follow-up. Patients with HER2-positive MBC with 0–1 prior treatment were eligible. Treatment consisted of paclitaxel (80 mg/m
2
) weekly, and trastuzumab (loading dose 8 mg/kg → 6 mg/kg) and pertuzumab (loading dose 840 mg → 420 mg) every 3 weeks, all given intravenously. Primary endpoint was 6-month PFS. Secondary endpoints included median PFS, 6-month and median OS. Evaluable patients received at least one full dose of treatment. From January 2011 to December 2013, 69 patients were enrolled: 51 (74 %) and 18 (26 %) treated in first- and second-line metastatic settings, respectively. As of July 1, 2015, the median follow-up was 33 months (range 3–49 months; 67 patients were evaluable for efficacy). The median OS was 44 months (95 % CI 37.5–NR) overall and 44 months (95 % CI 38.3–NR) and 37.5 months (95 % CI 30.3–NR) for patients with 0 and 1 prior metastatic treatment, respectively; 6-month OS was 98 % (95 % CI 90-1). The 6-month PFS was 86 % (95 % CI 75–93) overall and 89 % (95 % CI 76–95) and 78 % (95 % CI 51–91) for patients with 0 and 1 prior therapy, respectively; and median PFS was 21.4 months (95 % CI 14.1–NR) overall and 25.7 months (95 % CI 14.1–NR) and 16.9 months (95 % CI 8.5–NR) for patients with 0–1 prior treatment, respectively. Treatment was well tolerated. Updated analysis demonstrates that weekly paclitaxel, when added to trastuzumab and pertuzumab, is associated with a favorable OS and PFS and offers an alternative to docetaxel-based therapy.
http://www.ClinicalTrials.gov
NCT0127604
We integrated the genomic sequencing of 1,918 breast cancers, including 1,501 hormone receptor-positive tumors, with detailed clinical information and treatment outcomes. In 692 tumors previously ...exposed to hormonal therapy, we identified an increased number of alterations in genes involved in the mitogen-activated protein kinase (MAPK) pathway and in the estrogen receptor transcriptional machinery. Activating ERBB2 mutations and NF1 loss-of-function mutations were more than twice as common in endocrine resistant tumors. Alterations in other MAPK pathway genes (EGFR, KRAS, among others) and estrogen receptor transcriptional regulators (MYC, CTCF, FOXA1, and TBX3) were also enriched. Altogether, these alterations were present in 22% of tumors, mutually exclusive with ESR1 mutations, and associated with a shorter duration of response to subsequent hormonal therapies.
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•We performed prospective sequencing of 1,501 HR+ breast cancers in the clinical setting•MAPK and TF alterations were present in 22% of 692 HR+ post-endocrine therapy tumors•MAPK and TF alterations were mutually exclusive with ESR1 mutations•MAPK and TF alterations were associated with shorter response to endocrine therapies
Razavi et al. identify mutations in the MAPK pathway and the estrogen receptor transcriptional program in 22% of hormone receptor-positive breast cancers after hormone therapy. These mutations are mutually exclusive with ESR1 mutations and correlate with a shorter response duration to subsequent hormone therapies.
Background: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for ...patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Delta 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Delta 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Delta 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion: With 35 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDES and DDFS with no new safety signals.
Introduction
Quantification of plasma viral load (PVL) is used to monitor disease progression in SIV‐infected macaques. This study was aimed at optimizing of performance characteristics of the ...quantitative PCR (qPCR) PVL assay.
Methods
The PVL quantification procedure was optimized by inclusion of an exogenous control hepatitis C virus armored RNA (aRNA), a plasma concentration step, extended digestion with proteinase K, and a second RNA elution step. Efficiency of viral RNA (vRNA) extraction was compared using several commercial vRNA extraction kits. Various parameters of qPCR targeting the gag region of SIVmac239, SIVsmE660, and the LTR region of SIVagmSAB were also optimized.
Results
Modifications of the SIV PVL qPCR procedure increased vRNA recovery, reduced inhibition and improved analytical sensitivity. The PVL values determined by this SIV PVL qPCR correlated with quantification results of SIV RNA in the same samples using the ‘industry standard’ method of branched‐DNA (bDNA) signal amplification.
Conclusions
Quantification of SIV genomic RNA in plasma of rhesus macaques using this optimized SIV PVL qPCR is equivalent to the bDNA signal amplification method, less costly and more versatile. Use of heterologous aRNA as an internal control is useful for optimizing performance characteristics of PVL qPCRs.
A doença do enxerto contra o hospedeiro crônica (DECHc) é uma importante complicação tardia do transplante alogênico de células-tronco hematopoiéticas (alo-TCTH). A identificação de marcadores que ...possibilitem o diagnóstico precoce, predizer risco ou gravidade da DECHc é de suma importância. A utilização da saliva para análise de biomarcadores é pouco relatada e pode ser uma estratégia promissora quando comparada ao plasma. O objetivo deste trabalho foi avaliar o perfil de citocinas inflamatórias no plasma e na saliva de pacientes submetidos ao alo-TCTH que desenvolveram ou não a DECHc. Para isso, foi realizado um estudo de coorte prospectivo no qual amostras de plasma, saliva, índices de saúde bucal, medida de dor e de fluxo salivar foram coletados no pré transplante (T0), no momento do diagnóstico da DECH crônica (T1-DECHc), ou ao completar 1 ano pós TCTH nos pacientes que não desenvolveram a doença (T1- Não DECHc). Foram incluídos 41 pacientes, 26 do sexo masculino, média de 34,04 (± 15,96) anos, 31% deles desenvolveram DECHc. Os pacientes que desenvolveram DECHc apresentaram maior expressão de IL-6 (0,036 ± 0,0171 × 0,025 ± 0,0189, p = 0,034) em plasma e de IL-8 (0,434 ± 0,198 × 0,425 ± 0,549, p = 0,055) e IL-6 (0,146 ± 0,208 × 0,0624 ± 0,145;, p = 0,009) em saliva no momento do diagnóstico da doença, quando comparado ao T1-Não DECHc. Maior expressão de TNF-α em saliva (0,442 ± 1,00E0 × 0,000 ± 0,000; p = 0,026) foi observada no T0 de pacientes que não desenvolveram DECHc. Pacientes que desenvolveram DECHc em boca + outros órgãos apresentaram maior expressão sérica de IL-8 (0,018 ± 0,012 × 0,012 ± 0,010; p = 0,04), IL-1β (0,158 ± 0,090 × 0,057 ± 0,064; p = 0,045), IL-6 (0,051 ± 0,011 × 0,027 ± 0,0179; p= 0,053); e de IL-8 (0,677 ± 0,128 × 0,404 ± 0,453; p = 0,024), IL-6 (0,345 ± 0,391 × 0,070 ± 0,126; p = 0,057) em saliva no diagnóstico, quando comparado ao T1 não DECH. O desenvolvimento de DECHc em outros órgãos (não incluindo a boca) se relacionou com maior expressão de IL-6 salivar (0,132 ± 0,0887 × 0,089 ± 0,186; p = 0,047) e menor de lactoferrina em saliva (0,194 ± 0,191 × 0,067 ± 0,030; p = 0,016) em T1. Adicionalmente, observamos maior expressão das citocinas inflamatórias em saliva quando comparado ao plasma: IL-8, IL-1β, lactoferrina (p < 0,000) em T0 e IL-8 (p < 0,0000), IL-1β (p = 0,001), IL-6 (p = 0,048) e lactoferrina (p < 0,0000) em T1, incluindo DECHc e não DECHc. Na avaliação da expressão de citocinas entre os diferentes tempos (T0 × T1), os pacientes que não desenvolveram DECHc apresentaram maior quantificação de citocinas no pré transplante: IL-1β sérica (p = 0,003), IL-8 salivar (p = 0,007) e IL-1β salivar (p = 0,013). Entre os pacientes que desenvolveram DECHc, não houve diferença estatística na quantificação de citocinas entre T0 e T1. Acreditamos que a maior expressão de citocinas em T0 quando comparado ao T1 nos pacientes sem DECHc se deva à terapia sistêmica utilizada no tratamento onco-hematológico antes do TCTH e que, a ausência de diferença na quantificação de citocinas em T0 e T1 de pacientes com DECHc evidencie altos níveis de citocinas encontradas no desenvolvimento da DECHc, contrastado com a queda nos pacientes que não desenvolveram DECHc. Tais achados nos permitem concluir o potencial do uso da saliva para avaliação de marcadores infamatórios da DECHc, mesmo quando a manifestação ocorra de forma sistêmica, não envolvendo a boca.
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