Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model

AbstractSmall cell lung cancer (SCLC) is a highly aggressive human tumor with a more than 95% mortality rate. Its ontogeny and molecular pathogenesis remains poorly understood. We established a mouse model for neuroendocrine (NE) lung tumors by conditional inactivation of Rb1 and Trp53 in mouse lung epithelial cells. Mice carrying conditional alleles for both Rb1 and Trp53 developed with high incidence aggressive lung tumors with striking morphologic and immunophenotypic similarities to SCLC. Most of these tumors, which we designate MSCLC (murine small cell lung carcinoma), diffusely spread through the lung and gave rise to extrapulmonary metastases. In our model, inactivation of both Rb1 and p53 was a prerequisite for the pathogenesis of SCLC

The influence of adjuvant systemic regimens on contralateral breast cancer risk and receptor subtype

Background: An increasing number of breast cancer (BC) survivors are at risk of developing contralateral breast cancer (CBC). We aimed to investigate the influence of various adjuvant systemic regimens on, subtype-specific, risk of CBC. Methods: This population-based cohort study included female patients diagnosed with first invasive BC between 2003 and 2010; follow-up was complete until 2016. Clinico-pathological data were obtained from the Netherlands Cancer Registry and additional data on receptor status through linkage with PALGA: the Dutch Pathology Registry. Cumulative incidences (death and distant metastases as competing risk) and hazard ratios (HRs) were estimated for all invasive metachronous CBC and CBC subtypes. Results: Of 83 144 BC patients, 2816 developed a CBC; the 10-year cumulative incidence was 3.8% (95% confidence interval [CI]=3.7% to 4.0%). Overall, adjuvant chemotherapy (HR=0.70, 95% CI=0.62 to 0.80), endocrine therapy (HR=0.46, 95% CI=0.41 to 0.52), and trastuzumab with chemotherapy (HR=0.57, 95% CI=0.45 to 0.73) were strongly associated with a reduced CBC risk. Specifically, taxane-containing chemotherapy (HR=0.48, 95% CI=0.36 to 0.62) and aromatase inhibitors (HR=0.32, 95% CI=0.23 to 0.44) were associated with a large CBC risk reduction. More detailed analyses showed that endocrine therapy statistically significantly decreased the risk of estrogen receptor (ER)-positive CBC (HR=0.41, 95% CI=0.36 to 0.47) but not ER-negative CBC (HR=1.32, 95% CI=0.90 to 1.93) compared with no endocrine therapy. Patients receiving chemotherapy for ER-negative first BC had a higher risk of ER-negative CBC from 5years of follow-up (HR=2.84, 95% CI=1.62 to 4.99) compared with patients not receiving chemotherapy for ER-negative first BC. Conclusion: Endocrine therapy, chemotherapy, as well as trastuzumab with chemotherapy reduce CBC risk. However, each adjuvant therapy regimen had a different impact on the CBC subtype distribution. Taxane-containing chemotherapy and aromatase inhibitors were associated with the largest CBC risk reduction

Safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive advanced breast cancer: Primary results from the KAMILLA study cohort 1

Abstract Background Many patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) are candidates for trastuzumab emtansine (T-DM1) treatment sometime in their disease history. KAMILLA evaluated safety of T-DM1 in patients with previously treated HER2-positive locally advanced or metastatic BC (advanced BC). Methods KAMILLA (NCT01702571) is a single-arm, open-label, international, phase IIIb safety study of patients with HER2-positive advanced BC with progression after prior treatment with chemotherapy and a HER2-directed agent for MBC or within 6 months of completing adjuvant therapy. Patients received T-DM1 (3.6 mg/kg every 3 weeks) until unacceptable toxicity, withdrawal or disease progression. Results Among 2002 treated patients, median age was 55 years (range, 26–88; 373 [18.6%] aged ≥65 years), 1321 (66.0%) received ≥2 prior metastatic treatment lines and 398 (19.9%) had baseline central nervous system metastases. Adverse events (AEs) and serious AEs occurred in 1862 (93.0%) and 427 (21.3%) patients, respectively. Grade ≥3 AEs occurred in 751 (37.5%) patients; the three most common (individual Medical Dictionary for Regulatory Activity terms) were anaemia (3.0%), thrombocytopaenia (2.7%) and fatigue (2.5%). Median progression-free survival (PFS) was 6.9 months (95% confidence interval [CI], 6.0–7.6). Median overall survival (OS) was 27.2 months (95% CI, 25.5–28.7). With increasing lines of prior advanced therapy (0–1 versus 4+), median PFS and OS decreased numerically from 8.3 to 5.6 months and from 31.3 to 22.5 months, respectively. Conclusions KAMILLA is the largest cohort of T-DM1–treated patients studied to date. Results are consistent with prior randomised studies, thereby supporting T-DM1 as safe, tolerable and efficacious treatment for patients with previously treated HER2-positive advanced BC

Adjuvant capecitabine-containing chemotherapy benefit and homologous recombination deficiency in early-stage triple-negative breast cancer patients

Background The addition of adjuvant capecitabine to standard chemotherapy of early-stage triple-negative breast cancer (TNBC) patients has improved survival in a few randomised trials and in meta-analyses. However, many patients did not benefit. We evaluated the BRCA1-like DNA copy number signature, indicative of homologous recombination deficiency, as a predictive biomarker for capecitabine benefit in the TNBC subgroup of the FinXX trial. Methods Early-stage TNBC patients were randomised between adjuvant capecitabine-containing (TX + CEX: capecitabine-docetaxel, followed by cyclophosphamide-epirubicin-capecitabine) and conventional chemotherapy (T + CEF: docetaxel, followed by cyclophosphamide-epirubicin-fluorouracil). Tumour BRCA1-like status was determined on low-coverage, whole genome next-generation sequencing data using an established DNA comparative genomic hybridisation algorithm. Results For 129/202 (63.9%) patients the BRCA1-like status could be determined, mostly due to lack of tissue. During a median follow-up of 10.7 years, 35 recurrences and 32 deaths occurred. Addition of capecitabine appears to improve recurrence-free survival more among 61 (47.3%) patients with non-BRCA1-like tumours (HR 0.23, 95% CI 0.08-0.70) compared to 68 (52.7%) patients with BRCA1-like tumours (HR 0.66, 95% CI 0.24-1.81) (P-interaction = 0.17). Conclusion Based on our data, patients with non-BRCA1-like TNBC appear to benefit from the addition of capecitabine to adjuvant chemotherapy. Patients with BRCA1-like TNBC may also benefit. Additional research is needed to define the subgroup within BRCA1-like TNBC patients who may not benefit from adjuvant capecitabine.Peer reviewe

External validation and clinical utility assessment of PREDICT breast cancer prognostic model in young, systemic treatment-naïve women with node-negative breast cancer

Background: The validity of the PREDICT breast cancer prognostic model is unclear for young patients without adjuvant systemic treatment. This study aimed to validate PREDICT and assess its clinical utility in young women with node-negative breast cancer who did not receive systemic treatment. Methods: We selected all women from the Netherlands Cancer Registry who were diagnosed with node-negative breast cancer under age 40 between 1989 and 2000, a period when adjuvant systemic treatment was not standard practice for women with node-negative disease. We evaluated the calibration and discrimination of PREDICT using the observed/expected (O/E) mortality ratio, and the area under the receiver operating characteristic curve (AUC), respectively. Additionally, we compared the potential clinical utility of PREDICT for selectively administering chemotherapy to the chemotherapy-to-all strategy using decision curve analysis at predefined thresholds. Results: A total of 2264 women with a median age at diagnosis of 36 years were included. Of them, 71.2% had estrogen receptor (ER)-positive tumors and 44.0% had grade 3 tumors. Median tumor size was 16 mm. PREDICT v2.2 underestimated 10-year all-cause mortality by 33% in all women (O/E ratio:1.33, 95%CI:1.22–1.43). Model discrimination was moderate overall (AUC10-year:0.65, 95%CI:0.62–0.68), and poor for women with ER-negative tumors (AUC10-year:0.56, 95%CI:0.51–0.62). Compared to the chemotherapy-to-all strategy, PREDICT only showed a slightly higher net benefit in women with ER-positive tumors, but not in women with ER-negative tumors. Conclusions: PREDICT yields unreliable predictions for young women with node-negative breast cancer. Further model updates are needed before PREDICT can be routinely used in this patient subset.</p

Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy

Introduction: BRCA-mutated breast cancer cells lack the DNA-repair mechanism homologous recombination that is required for error-free DNA double-strand break (DSB) repair. Homologous recombination deficiency (HRD) may cause hypersensitivity to DNA DSB-inducing agents, such as bifunctional alkylating agents and platinum salts. HRD can be caused by BRCA mutations, and by other mechanisms. To identify HRD, studies have focused on triple-negative (TN) breast cancers as these resemble BRCA1-mutated breast cancer closely and might also share this hypersensitivity. However, ways to identify HRD in non-BRCA-mutated, estrogen receptor (ER)-positive breast cancers have remained elusive. The current study provides evidence that genomic patterns resembling BRCA1- or BRCA2- mutated breast cancers can identify breast cancer patients with TN as well as ER-positive, HER2-negative tumors that are sensitive to intensified, DSB-inducing chemotherapy. Methods: Array comparative genomic hybridization (aCGH) was used to classify breast cancers. Patients with tumors with similar aCGH patterns as BRCA1- and/or BRCA2-mutated breast cancers were defined as having a BRCA-like(CGH) status, others as non-BCRA-like(CGH). Stage-III patients (n = 249) had participated in a randomized controlled trial of adjuvant high-dose (HD) cyclophosphamide-thiotepa-carboplatin (CTC) versus 5-fluorouracil-epirubicin-cyclophosphamide (FE90C) chemotherapy. Results: Among patients with BRCA-like(CGH) tumors (81/249, 32%), a significant benefit of HD-CTC compared to FE90C was observed regarding overall survival (adjusted hazard ratio 0.19, 95% CI: 0.08 to 0.48) that was not seen for patients with non-BRCA-like(CGH) tumors (adjusted hazard ratio 0.90, 95% CI: 0.53 to 1.54) (P = 0.004). Half of all BRCA-like(CGH) tumors were ER-positive. Conclusions: Distinct aCGH patterns differentiated between HER2-negative patients with a markedly improved outcome after adjuvant treatment with an intensified DNA-DSB-inducing regimen (BRCA-like(CGH) patients) and those without benefit (non-BRCA-like(CGH) patients)

IHC-based Ki67 as response biomarker to tamoxifen in breast cancer window trials enrolling premenopausal women

Window studies are gaining traction to assess (molecular) changes in short timeframes. Decreased tumor cell positivity for the proliferation marker Ki67 is often used as a proxy for treatment response. Immunohistochemistry (IHC)-based Ki67 on tissue from neo-adjuvant trials was previously reported to be predictive for long-term response to endocrine therapy for breast cancer in postmenopausal women, but none of these trials enrolled premenopausal women. Nonetheless, the marker is being used on this subpopulation. We compared pathologist assessed IHC-based Ki67 in samples from pre- and postmenopausal women in a neo-adjuvant, endocrine therapy focused trial (NCT00738777), randomized between tamoxifen, anastrozole, or fulvestrant. These results were compared with (1) IHC-based Ki67 scoring by AI, (2) mitotic figures, (3) mRNA-based Ki67, (4) five independent gene expression signatures capturing proliferation, and (5) blood levels for tamoxifen and its metabolites as well as estradiol. Upon tamoxifen, IHC-based Ki67 levels were decreased in both pre- and postmenopausal breast cancer patients, which was confirmed using mRNA-based cell proliferation markers. The magnitude of decrease of Ki67 IHC was smaller in pre- versus postmenopausal women. We found a direct relationship between post-treatment estradiol levels and the magnitude of the Ki67 decrease in tumors. These data suggest IHC-based Ki67 may be an appropriate biomarker for tamoxifen response in premenopausal breast cancer patients, but anti-proliferative effect size depends on estradiol levels.</p