Molecular Profiling of the Residual Disease of Triple-Negative Breast Cancers after Neoadjuvant Chemotherapy Identifies Actionable Therapeutic Targets

Balko, Justin M.; Giltnane, Jennifer M.; Wang, Kai; Schwarz, Luis J.; Young, Christian D.; Cook, Rebecca S.; Owens, P. C.; Sanders, Melinda E.; Kuba, María G.; Sánchez, Violeta; Kurupi, Richard; Moore, Preston D.; Pinto, Joseph A.; Doimi, Franco D.; Gómez, Henry L.; Horiuchi, Dai; Goga, Andrei; Lehmann, Brian D.; Bauer, Joshua A.; Pietenpol, Jennifer A.; Ross, Jeffrey S.; Palmer, Gary A.; Yelensky, Roman; Cronin, Maureen; Miller, Vincent A.; Stephens, P. J.; Arteaga, Carlos L.

doi:10.1158/2159-8290.cd-13-0286

Cited by 425 publications

(442 citation statements)

References 48 publications

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“…In triple-negative breast cancer, the establishment and molecular profiling of PDXs from residual cancer cells that persist after neoadjuvant treatment (minimal residual disease (MRD)) may lead to the identification of targetable molecular alterations in the chemotherapy-resistant component of the tumour, which may mirror micro-metastases that are destined to clinically recur 68 .…”

Section: Pdx Models Of Treatment-resistant Diseasementioning

confidence: 99%

Interrogating open issues in cancer precision medicine with patient-derived xenografts

et al. 2017

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Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions. This Opinion article discusses aspects of PDX modelling that are relevant to these questions and highlights the merits of shared PDX resources to advance cancer medicine from the 6 perspective of EurOPDX, an international initiative devoted to PDX-based research.Response to anticancer therapies varies owing to the substantial molecular heterogeneity of human tumours and to poorly defined mechanisms of drug efficacy and resistance 1 . Immortalized cancer cell lines, either cultured in vitro or grown as xenografts, cannot interrogate the complexity of human tumours, and only provide determinate insights into human disease, as they are limited in number and diversity, and have been cultured on plastic over decades 2 .This disconnection in scale and biological accuracy contributes considerably to attrition in drug development [3][4][5] .Surgically derived clinical tumour samples that are implanted in mice (known as patient-derived xenografts (PDXs)) are expected to better inform therapeutic development strategies. As intact tissue -in which the tumour architecture and the relative proportion of cancer cells and stromal cells are both maintained -is directly implanted into recipient animals, the alignment with human disease is enhanced. More importantly, PDXs retain the idiosyncratic characteristics of different tumours from different patients; hence, they can effectively recapitulate the intra-tumour and inter-tumour heterogeneity that typifies human cancer 6-9 . 7 Exhaustive information on the key characteristics and the practical applications of PDXs can be found in recent reviews [10][11][12][13] . In this Opinion article, we discuss basic methodological concepts, as well as challenges and opportunities in developing "next-generation" models to improve the reach of PDXs as preclinical tools for in vivo studies (TABLE 1). We also elaborate on the merits of PDXs for exploring the intrinsic heterogeneity and subclonal genetic evolution of individual tumours, and discuss how this may influence therapeutic resistance. Finally, we examine the utility of PDXs in navigating complex variables in clinical decision-making, such as the discovery of predictive and prognostic biomarkers, and the categorization of genotype-drug response correlations in high-throughput formats. Being primarily co-authored by leading members of the EurOPDX Consortium (see Further information), we provide...

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Section: Pdx Models Of Treatment-resistant Diseasementioning

confidence: 99%

Interrogating open issues in cancer precision medicine with patient-derived xenografts

et al. 2017

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“…The PIK3CA mutation frequency in MPBC thus appears to be greater than the 25% frequency listed for all types of breast cancer 50 and for TNBCs as a group. 51 PIK3CA mutations have been linked to improved outcomes in breast cancer. 52 The PI3K pathway is now widely considered a target of therapy for cancer in general 53 and for breast cancer, in particular.…”

Section: Resultsmentioning

confidence: 99%

Genomic Profiling of Advanced-Stage, Metaplastic Breast Carcinoma by Next-Generation Sequencing Reveals Frequent, Targetable Genomic Abnormalities and Potential New Treatment Options

Ross

Badve

Wang

et al. 2015

Archives of Pathology &Amp; Laboratory Medicine

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Context.-Metastatic metaplastic breast carcinoma (MPBC) is an uncommon, but aggressive, tumor resistant to conventional chemotherapy.Objective.-To learn whether next-generation sequencing could identify potential targets of therapy for patients with relapsed and metastatic MPBC.Design.-Hybridization capture of 3769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to a minimum of 50 ng of DNA extracted from 20 MPBC formalin-fixed, paraffinembedded specimens and sequenced to high uniform coverage.Results.-The 20 patients with MPBC had a median age of 62 years (range, 42-86 years). There were 9 squamous (45%), 9 chondroid (45%), and 2 spindle cell (10%) MPBCs, all of which were high grade. Ninety-three genomic alterations were identified, (range, 1-11) with 19 of the 20 cases (95%) harboring an alteration that could potentially lead to a targeted treatment option. The mostcommon alterations were in TP53 (n ¼ 69; 75%), PIK3CA (n ¼ 37; 40%), MYC (n ¼ 28; 30%), MLL2 (n ¼ 28; 30%), PTEN (n ¼ 23; 25%), CDKN2A/B (n ¼ 19; 20%), CCND3 (n ¼ 14; 15%), CCNE1 (n ¼ 9; 10%), EGFR (n ¼ 9; 10%), and KDM6A (n ¼ 9; 10%); AKT3, CCND1, CCND2, CDK4, FBXW7, FGFR1, HRAS, NF1, PIK3R1, and SRC were each altered in a single case. All 16 MPBCs (100%) that were negative for ERBB2 (HER2) overexpression by immunohistochemistry and/or ERBB2 (HER2) amplification by fluorescence in situ hybridization were also uniformly (100%) negative for ERBB2 amplification by next-generation sequencing-based copy-number assessment.Conclusions.-Our results indicate that genomic profiling using next-generation sequencing can identify clinically meaningful alterations that have the potential to guide targeted treatment decisions in most patients with metastatic MPBC.

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“…TNBC subtype was more likely to develop bone metastases among Spanish patients (25.4 vs 18.5%) [80]. Balko et al evaluated 111 Peruvian TNBC who received chemotherapy and did not achieve pathologic complete response (pCR), and found that 57% belonged to basal-like, 18% to HER2-enriched, 5% to luminal A, 5% to luminal B and 4% to normal-like [81].…”

Section: Differences In Tumor Clinicopathological Featuresmentioning

confidence: 99%

Genetics, Tumor Features and Treatment Response of Breast Cancer in Latinas

Castañeda

Castillo

Villarreal‐Garza

et al. 2018

Breast Cancer Manag.

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Practice pointsr Latinas with breast cancer have been associated with lower prevalence and higher mortality rates. r The access to healthcare system for Latinas has been described as lower than for white women. r Rates of grade III and triple-negative phenotype breast cancer are higher for Latinas than for white women. r BRCA mutation prevalence appears to be higher in Latinas than white women in the American population. r Distribution of BRCA mutation differs by country in Central, Latin America or Caribbean and recurrent mutations have been described in Mexico. r Finally, evaluated information about treatment efficacy and toxicity in Latinas with breast cancer indicate similar effects than in the white race.Breast cancer is a heterogeneous and genetic disease that has variability according to ethnicity and race with respect to incidence, clinical characteristics and prognosis. The incidence of breast cancer is lower but mortality is higher in Latinas than Caucasians in the US series. Risk factors appear to have different prevalence and impact in Latinas. Breast cancer in Latinas has particular clinic-pathological features including younger age, higher rates of triple-negative subtype and advanced stages. Molecular studies find that Latinas from every region have a specific BRCA incidence and a recurrent mutation, as well as differences in activity of molecular pathways. Treatment response rates and toxicity have also been compared, and no difference was found between Latinas and other ethnic groups.

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Molecular Profiling of the Residual Disease of Triple-Negative Breast Cancers after Neoadjuvant Chemotherapy Identifies Actionable Therapeutic Targets

Cited by 425 publications

References 48 publications

Interrogating open issues in cancer precision medicine with patient-derived xenografts

Interrogating open issues in cancer precision medicine with patient-derived xenografts

Genomic Profiling of Advanced-Stage, Metaplastic Breast Carcinoma by Next-Generation Sequencing Reveals Frequent, Targetable Genomic Abnormalities and Potential New Treatment Options

Genetics, Tumor Features and Treatment Response of Breast Cancer in Latinas

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