Summary Endometrial cancer is the most common gynaecological malignancy in Europe and North America. Traditional classification of endometrial carcinoma is based either on clinical and endocrine ...features (eg, types I and II) or on histopathological characteristics (eg, endometrioid, serous, or clear-cell adenocarcinoma). Subtypes defined by the different classification systems correlate to some extent, but there is substantial heterogeneity in biological, pathological, and molecular features within tumour types from both classification systems. In this Review we provide an overview of traditional and newer genomic classifications of endometrial cancer. We discuss how a classification system that incorporates genomic and histopathological features to define biologically and clinically relevant subsets of the disease would be useful. Such integrated classification might facilitate development of treatments tailored to specific disease subgroups and could potentially enable delivery of precision medicine to patients with endometrial cancer.
The recent cataloging of the genomic aberrations in breast cancer has revealed the diversity and complexity of the disease at the genetic level. To unravel the functional consequences of specific ...repertoires of mutations and copy number changes on signaling pathways in breast cancer, it is crucial to develop model systems that truly recapitulate the disease. Here we discuss the three-dimensional culture models currently being used or recently developed for the study of normal mammary epithelial cells and breast cancer, including primary tumors and dormancy. We discuss the insights gained from these models in regards to cell signaling and potential therapeutic strategies, and the challenges that need to be met for the generation of heterotypic breast cancer model systems that are amenable for high-throughput approaches.
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Breast cancer is a vastly heterogeneous disease encompassing a panoply of special histological subtypes. Although rare breast tumors have largely not been investigated systematically in large scale ...genomics series, recent studies have shed light on the genetic underpinnings of special histologic subtypes of breast cancer. Genomic analyses of estrogen receptor-positive special histologic types of breast cancer have not resulted in the identification of novel pathognomonic genetic alterations in addition to the confirmation of the presence of CDH1 loss-of-function mutations in invasive lobular carcinomas. By contrast, the analyses of triple-negative breast cancers have demonstrated that low-grade triple-negative breast cancers categorically differ from the common forms of high-grade triple-negative disease biologically and phenotypically and are underpinned by specific fusion genes or hotspot mutations. A subset of low-grade triple-negative disease has been shown to harbor highly recurrent if not pathognomonic genetic alterations, such as ETV6-NTRK3 fusion gene in secretory carcinomas, the MYB-NFIB fusion gene, MYBL1 rearrangements or MYB gene amplification in adenoid cystic carcinomas, and HRAS Q61 hotspot mutations coupled with mutations in PI3K pathway genes in estrogen receptor-negative adenomyoepitheliomas. A subset of these pathognomonic genetic alterations (e.g., NTRK1/2/3 fusion genes) now constitute an FDA approved indication for the use of TRK inhibitors in the advanced/metastatic setting. These studies have also corroborated that salivary gland-like tumors of the breast, other than acinic cell carcinomas, harbor the repertoire of somatic genetic alterations detected in their salivary gland counterparts. Reassuringly, the systematic study of special histologic types of breast cancer utilizing state-of-the-art sequencing approaches, rather than rendering pathology obsolete, has actually strengthened the importance of breast cancer histologic typing and is providing additional ancillary markers for the diagnosis of these rare but fascinating entities.
Metaplastic breast carcinoma (MBC) is a rare and aggressive histologic type of breast cancer, predominantly of triple-negative phenotype, and characterized by the presence of malignant cells showing ...squamous and/or mesenchymal differentiation. We sought to define the repertoire of somatic genetic alterations and the mutational signatures of MBCs.
Whole-exome sequencing was performed in 35 MBCs, with 16, 10, and 9 classified as harboring chondroid, spindle, and squamous metaplasia as the predominant metaplastic component. The genomic landscape of MBCs was compared with that of triple-negative invasive ductal carcinomas of no special type (IDC-NST) from The Cancer Genome Atlas. Wnt and PI3K/AKT/mTOR pathway activity was assessed using a qPCR assay.
MBCs harbored complex genomes with frequent
(69%) mutations. In contrast to triple-negative IDC-NSTs, MBCs more frequently harbored mutations in
(29%),
(11%),
(11%),
(11%), and
(11%).
mutations were not found in MBCs with chondroid metaplasia. Compared with triple-negative IDC-NSTs, MBCs significantly more frequently harbored mutations in PI3K/AKT/mTOR pathway-related (57% vs. 22%) and canonical Wnt pathway-related (51% vs. 28%) genes. MBCs with somatic mutations in PI3K/AKT/mTOR or Wnt pathway-related genes displayed increased activity of the respective pathway.
MBCs are genetically complex and heterogeneous, and are driven by a repertoire of somatic mutations distinct from that of triple-negative IDC-NSTs. Our study highlights the genetic basis and the importance of PI3K/AKT/mTOR and Wnt pathway dysregulation in MBCs and provides a rationale for the metaplastic phenotype and the reported responses to PI3K/AKT/mTOR inhibitors in these tumors.
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BRCA1 and BRCA2 are involved in homologous recombination (HR) DNA repair and are germ-line cancer pre-disposition genes that result in a syndrome of hereditary breast and ovarian cancer (HBOC). ...Whether germ-line or somatic alterations in these genes or other members of the HR pathway and if mono- or bi-allelic alterations of HR-related genes have a phenotypic impact on other cancers remains to be fully elucidated. Here, we perform a pan-cancer analysis of The Cancer Genome Atlas (TCGA) data set and observe that bi-allelic pathogenic alterations in homologous recombination (HR) DNA repair-related genes are prevalent across many malignancies. These bi-allelic alterations often associate with genomic features of HR deficiency. Further, in ovarian, breast and prostate cancers, bi-allelic alterations are mutually exclusive of each other. The combination of these two properties facilitates reclassification of variants of unknown significance affecting DNA repair genes, and may help personalize HR directed therapies in the clinic.Germline mutations in homologous recombination (HR) DNA repair genes are linked to breast and ovarian cancer. Here, the authors show that mutually exclusive bi-allelic inactivation of HR genes are present in other cancer types and associated with genomic features of HR deficiency, expanding the potential use of HR-directed therapies.
The identification of early-stage breast cancer patients at high risk of relapse would allow tailoring of adjuvant therapy approaches. We assessed whether analysis of circulating tumor DNA (ctDNA) in ...plasma can be used to monitor for minimal residual disease (MRD) in breast cancer. In a prospective cohort of 55 early breast cancer patients receiving neoadjuvant chemotherapy, detection of ctDNA in plasma after completion of apparently curative treatment-either at a single postsurgical time point or with serial follow-up plasma samples-predicted metastatic relapse with high accuracy hazard ratio, 25.1 (confidence interval, 4.08 to 130.5; log-rank P < 0.0001) or 12.0 (confidence interval, 3.36 to 43.07; log-rank P < 0.0001), respectively. Mutation tracking in serial samples increased sensitivity for the prediction of relapse, with a median lead time of 7.9 months over clinical relapse. We further demonstrated that targeted capture sequencing analysis of ctDNA could define the genetic events of MRD, and that MRD sequencing predicted the genetic events of the subsequent metastatic relapse more accurately than sequencing of the primary cancer. Mutation tracking can therefore identify early breast cancer patients at high risk of relapse. Subsequent adjuvant therapeutic interventions could be tailored to the genetic events present in the MRD, a therapeutic approach that could in part combat the challenge posed by intratumor genetic heterogeneity.
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.
Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer ...cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression.
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•A large clinico-genomic database to study metastatic patterns across 50 tumor types•Oncogenic alteration frequency and chromosomal instability are increased in metastases•Correlations between chromosomal instability and metastatic burden depend on cancer type•Genomic features associated with metastasis are identified for specific target organs
Clinico-genomic analysis of MSK-MET, a cohort of over 25,000 patients with metastasis across 50 cancer types, identifies somatic alterations associated with organ-specific metastasis and highlights that chromosomal instability correlates with metastatic burden in a cancer type-dependent manner.
Resistance to anti-HER2 therapies in HER2
breast cancer can occur through activation of alternative survival pathways or reactivation of the HER signaling network. Here we employed BT474 parental and ...treatment-resistant cell line models to investigate a mechanism by which HER2
breast cancer can reactivate the HER network under potent HER2-targeted therapies.
Resistant derivatives to lapatinib (L), trastuzumab (T), or the combination (LR/TR/LTR) were developed independently from two independent estrogen receptor ER
/HER2
BT474 cell lines (AZ/ATCC). Two derivatives resistant to the lapatinib-containing regimens (BT474/AZ-LR and BT474/ATCC-LTR lines) that showed HER2 reactivation at the time of resistance were subjected to massive parallel sequencing and compared with parental lines. Ectopic expression and mutant-specific siRNA interference were applied to analyze the mutation functionally.
and
experiments were performed to test alternative therapies for mutant HER2 inhibition.
Genomic analyses revealed that the
L755S mutation was the only common somatic mutation gained in the BT474/AZ-LR and BT474/ATCC-LTR lines. Ectopic expression of
L755S induced acquired lapatinib resistance in the BT474/AZ, SK-BR-3, and AU565 parental cell lines.
L755S-specific siRNA knockdown reversed the resistance in BT474/AZ-LR and BT474/ATCC-LTR lines. The HER1/2-irreversible inhibitors afatinib and neratinib substantially inhibited both resistant cell growth and the HER2 and downstream AKT/MAPK signaling driven by
L755S
and
HER2 reactivation through acquisition of the
L755S mutation was identified as a mechanism of acquired resistance to lapatinib-containing HER2-targeted therapy in preclinical HER2-amplified breast cancer models, which can be overcome by irreversible HER1/2 inhibitors.
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Gastric-type cervical adenocarcinoma (GCA) is an aggressive type of endocervical adenocarcinoma characterized by mucinous morphology, gastric-type mucin, lack of association with human papillomavirus ...(HPV) and resistance to chemo/radiotherapy. We characterized the landscape of genetic alterations in a large cohort of GCAs, and compared it with that of usual-type HPV-associated endocervical adenocarcinomas (UEAs), pancreatic adenocarcinomas (PAs) and intestinal-type gastric adenocarcinomas (IGAs). GCAs (n = 68) were subjected to massively parallel sequencing targeting 410–468 cancer-related genes. Somatic mutations and copy number alterations (CNAs) were determined using validated bioinformatics methods. Mutational data for UEAs (n = 21), PAs (n = 178), and IGAs (n = 148) from The Cancer Genome Atlas (TCGA) were obtained from cBioPortal. GCAs most frequently harbored somatic mutations in TP53 (41%), CDKN2A (18%), KRAS (18%), and STK11 (10%). Potentially targetable mutations were identified in ERBB3 (10%), ERBB2 (8%), and BRAF (4%). GCAs displayed low levels of CNAs with no recurrent amplifications or homozygous deletions. In contrast to UEAs, GCAs harbored more frequent mutations affecting cell cycle-related genes including TP53 (41% vs 5%, p < 0.01) and CDKN2A (18% vs 0%, p = 0.01), and fewer PIK3CA mutations (7% vs 33%, p = 0.01). TP53 mutations were less prevalent in GCAs compared to PAs (41% vs 56%, p < 0.05) and IGAs (41% vs 57%, p < 0.05). GCAs showed a higher frequency of STK11 mutations than PAs (10% vs 2%, p < 0.05) and IGAs (10% vs 1%, p < 0.05). GCAs harbored more frequent mutations in ERBB2 and ERBB3 (9% vs 1%, and 10% vs 0.5%, both p < 0.01) compared to PAs, and in CDKN2A (18% vs 1%, p < 0.05) and KRAS (18% vs 6%, p < 0.05) compared to IGAs. GCAs harbor recurrent somatic mutations in cell cycle-related genes and in potentially targetable genes, including ERBB2/3. Mutations in genes such as STK11 may be used as supportive evidence to help distinguish GCAs from other adenocarcinomas with similar morphology in metastatic sites.
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