Lydia Gaba

Clinical implications of the intrinsic molecular subtypes of breast cancer

Gene-expression profiling has had a considerable impact on our understanding of breast cancer biology. During the last 15 years, 5 intrinsic molecular subtypes of breast cancer (Luminal A, Luminal B, HER2-enriched, Basal-like and Claudin-low) have been identified and intensively studied. In this review, we will focus on the current and future clinical implications of the intrinsic molecular subtypes beyond the current pathological-based classification endorsed by the 2013 St. Gallen Consensus Recommendations. Within hormone receptor-positive and HER2-negative early breast cancer, the Luminal A and B subtypes predict 10-year outcome regardless of systemic treatment administered as well as residual risk of distant recurrence after 5 years of endocrine therapy. Within clinically HER2-positive disease, the 4 main intrinsic subtypes can be identified and dominate the biological and clinical phenotype. From a clinical perspective, patients with HER2+/HER2-enriched disease seem to benefit the most from neoadjuvant trastuzumab, or dual HER2 blockade with trastuzumab/lapatinib, in combination with chemotherapy, and patients with HER2+/Luminal A disease seem to have a relative better outcome compared to the other subtypes. Finally, within triple-negative breast cancer (TNBC), the Basal-like disease predominates (70-80%) and, from a biological perspective, should be considered a cancer-type by itself. Importantly, the distinction between Basal-like versus non-Basal-like within TNBC might predict survival following (neo)adjvuvant multi-agent chemotherapy, bevacizumab benefit in the neoadjuvant setting (CALGB40603), and docetaxel vs. carboplatin benefit in first-line metastatic disease (TNT study). Overall, this data suggests that intrinsic molecular profiling provides clinically relevant information beyond current pathology-based classifications.

Immune-related gene expression profiling after PD-1 blockade in non–small cell lung carcinoma, head and neck squamous cell carcinoma, and melanoma

Antibody targeting of the immune checkpoint receptor PD1 produces therapeutic activity in a variety of solid tumors, but most patients exhibit partial or complete resistance to treatment for reasons that are unclear. In this study, we evaluated tumor specimens from 65 patients with melanoma, lung nonsquamous, squamous cell lung or head and neck cancers who were treated with the approved PD1-targeting antibodies pembrolizumab or nivolumab. Tumor RNA before anti-PD1 therapy was analyzed on the nCounter system using the PanCancer 730-Immune Panel, and we identified 23 immune-related genes or signatures linked to response and progression-free survival (PFS). In addition, we evaluated intra- and interbiopsy variability of PD1, PD-L1, CD8A, and CD4 mRNAs and their relationship with tumor-infiltrating lymphocytes (TIL) and PD-L1 IHC expression. Among the biomarkers examined, PD1 gene expression along with 12 signatures tracking CD8 and CD4 T-cell activation, natural killer cells, and IFN activation associated significantly with nonprogressive disease and PFS. These associations were independent of sample timing, drug used, or cancer type. TIL correlated moderately (∼0.50) with PD1 and CD8A mRNA levels and weakly (∼0.35) with CD4 and PD-L1. IHC expression of PD-L1 correlated strongly with PD-L1 (0.90), moderately with CD4 and CD8A, and weakly with PD1. Reproducibility of gene expression in intra- and interbiopsy specimens was very high (total SD <3%). Overall, our results support the hypothesis that identification of a preexisting and stable adaptive immune response as defined by mRNA expression pattern is reproducible and sufficient to predict clinical outcome, regardless of the type of cancer or the PD1 therapeutic antibody administered to patients. Cancer Res; 77(13); 3540-50. ©2017 AACR.

TMPRSS2-ERG in Blood and Docetaxel Resistance in Metastatic Castration-resistant Prostate Cancer

TMPRSS2-ERG rearrangement is a genetic alteration exclusive to prostate cancer, associated with taxane resistance in preclinical models. Its detection in blood samples of metastatic resistant prostate cancer (mCRPC) patients may indicate the presence of circulating tumour cells with this genetic alteration and may predict taxane resistance. To test this hypothesis, we evaluated TMPRSS2-ERG expression using quantitative reverse transcription polymerase chain reaction in peripheral blood mononuclear cells and tumour tissue from mCPRC patients treated with taxanes. We examined peripheral blood mononuclear cells from 24 healthy controls, 50 patients treated with docetaxel, and 22 with cabazitaxel. TMPRSS2-ERG was detected in 0%, 16%, and 22.7% of them, respectively. In docetaxel-treated patients TMPRSS2-ERG detection correlated with lower prostatic-specific antigen (PSA) response rate (12.5% vs 68.3%, p=0.005), PSA-progression-free survival (PFS; 3.1 mo vs 7.5 mo, p<0.001), clinical/radiological-PFS (3.1 mo vs 8.2 mo, p<0.001), and it was independently associated with PSA-PFS (hazard ratio 3.7; p=0.009) and clinical/radiological-PFS (hazard ratio 6.3; p<0.001). Moreover, TMPRSS2-ERG also predicted low PSA-PFS to cabazitaxel. At progression, a switch from negative to positive TMPRSS2-ERG was observed in 41% of patients with undetected TMPRSS2-ERG at the baseline sample. Tissue TMPRSS2-ERG expression correlated with lower PSA-PFS (p=0.02) to docetaxel. Our findings support the potential role of TMPRSS2-ERG detection as a biomarker to tailor treatment strategies. PATIENT SUMMARY Taxanes are the most active chemotherapy agents in metastatic resistant prostate cancer. However, not all patients respond to this therapy. In the present study we show that the detection of TMPRSS2-ERG in blood from metastatic resistant prostate cancer patients predicts resistance to docetaxel and it may be useful to select treatment and to avoid possible toxicities in refractory patients.

Development of Cutaneous Toxicities During Selective Anti-BRAF Therapies: Preventive Role of Combination with MEK Inhibitors.

Activated BRAF mutations affecting the mitogen-activated protein kinases (MAPK) pathway are present in 50% of metastatic melanomas. Targeted therapies have been developed to block such mutations (1, 2). There is a risk of other components of the MAPK signalling pathway, such as MEK, being reactivated after the use of BRAF inhibitors (3–5). Given the evidence of drug resistance and side-effects of BRAF inhibitors, combined treatments with BRAF and MEK inhibitors are being tested in clinical trials for metastatic melanoma. Trametinib is one of these MEK inhibitors. Skin toxicities from BRAF inhibitors, such as photosensitivity, palmoplantar keratoderma (PPK) and keratosis pilaris (KP), have been reported (4, 6–11). Also, non-melanoma skin cancers (NMSC) are considered one of the most significant sideeffects (3, 11). We report here the profile of skin toxicities from vemurafenib, dabrafenib alone, or dabrafenib and trametinib combined treatment.

Pembrolizumab in a BRAF-mutant metastatic melanoma patient following a severe immune-related adverse event with ipilimumab

Currently, limited data exist on the safety of pembrolizumab in patients with metastatic melanoma who have developed severe immune-related adverse events following treatment with ipilimumab. We report a 45-year-old male patient with BRAF-mutant metastatic melanoma who discontinued treatment with ipilimumab due to treatment-related grade 3 colitis and was subsequently treated with the anti-programmed cell death 1 protein (PD-1) antibody pembrolizumab. He has been on treatment with pembrolizumab for more than 20 months with no major toxicities and has achieved an objective partial response, which is ongoing.

Life-threatening colitis and complete response with ipilimumab in a patient with metastatic BRAF-mutant melanoma and rheumatoid arthritis

Immune checkpoint inhibitors, such as ipilimumab (an anti-CTLA4 antibody), have become a commonly used therapy in cancer. To date, safety data of patients with underlying autoimmune disease is limited. We present a case of a patient with rheumatoid arthritis who was diagnosed of a BRAF-mutant metastatic melanoma. The patient was treated with ipilimumab and presented with high-grade colitis requiring immunosuppressors. Despite of the immune-related adverse event, no exacerbation of the rheumatoid arthritis was observed and the patient achieved a complete response. This case report contributes to the scarce literature on the use of immune checkpoint inhibitors in patients with an underlying autoimmune condition.

Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer

Background:Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving.Methods:We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation.Results:Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R.Conclusions:Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.

Motor polyradiculopathy during pembrolizumab treatment of metastatic melanoma

Pembrolizumab, a monoclonal antibody directed against the immune checkpoint programmed cell death‐1 receptor (PD‐1), has improved survival in patients with advanced melanoma. Neuromuscular immune‐mediated side effects have been rarely reported.

Ipilimumab, una causa de hipofisitis autoinmunitaria

Hypophysitis represents a heterogeneous group of inflammatory lesions affecting the pituitary gland with a complex pathogenesis and is insufficiently characterized. The different types belong to the group of non-hormone secreting sellar masses, with which they share clinical, and sometimes also radiographic, presentation. These similarities make differential diagnosis difficult in the absence of surgery, which is not indicated in hypophysitis but allows for pathological study. The clinical signs of hypophysitis are similar to those of other sellar masses and include headache, visual disturbances, and variable degrees of hypopituitarism and diabetes insipidus. Hypophysitis may be classified based on various criteria. Adenohypophysitis, infundibuloneurohypophysitis, and panhypophysitis are distinguished based on the anatomical location of the condition. There may be lymphocytic, granulomatous, xanthomatous, and mixed hypophysitis depending on the histopathological characteristics. Based on etiology, a distinction between primary hypophysitis, either isolated or as part of a systemic disease; hypophysitis secondary to sellar diseases such as germinoma, Rathke cyst, craniopharyngioma, or pituitary adenoma, or occurring in the setting of systemic diseases such as Wegener’s granulomatosis, tuberculosis, sarcoidosis, and syphilis; finally, hypophysitis secondary to immunomodulatory drugs such as interferon and antibodies to cytotoxic T-lymphocyte antigen-4 (CTLA-4) has been reported. In the context of the use of immunomodulatory therapies, we report three cases of autoimmune hypophysitis secondary to ipilimumab occurring during the treatment of metastatic melanoma. Thirteen patients with metastatic melanoma have been treated to date with ipilimumab at our hospital. Table 1 summarizes the clinical and laboratory data. Case 1: A 41-year-old male with stage IV melanoma and hepatic and nodal metastases. After the third dose

Paraneoplastic cerebellar degeneration associated with thymic germinoma.

Paraneoplastic cerebellar degeneration (PCD) is characterized by a subacute, severe pancerebellar syndrome, which is related to an underlying tumor. The presence of CSF or serum onconeural antibodies confirms the diagnosis and indicates the underlying tumor type. However, the association between PCD and extragonadal germ cell tumors with the absence of an onconeural antibody has rarely been described. We present a 55-year-old man who developed a pancerebellar syndrome, which made him unable to walk alone after 10months. Routine blood analysis, brain MRI and CSF examination were normal. Despite onconeural antibodies were negative, a whole body PET-CT scan showed a hypermetabolic nodule in the thymus, which was removed, and a hypometabolic presacral mass. The pathologic study revealed a germinoma surrounded by a pronounced inflammatory infiltrate. Shortly after, the patient clearly improved his symptoms, before receiving chemotherapy and prednisone. The cerebellar ataxia worsened when steroids were reduced below 30mg/day. Testicular sonography showed a suspicious lesion in one testicle, but no malignancy was found after orchiectomy. The presacral mass was removed after chemotherapy disclosing a mature teratoma. Our patient emphasizes that despite the absence of onconeural antibodies, studies to rule out an underlying tumor are mandatory in patients with subacute cerebellar ataxia.