Isabel Marugán

Prognostic factors predicting survival from first recurrence in patients with metastatic breast cancer: analysis of 439 patients

We have analyzed retrospectively 439 women with recurrent breast cancer, followed at a single institution, in order to define potential prognostic factors for survival at the time of first recurrence. Median age at the time of first recurrence was 58 and the median disease free interval (DFI) from initial diagnoses to recurrence was 33 months. Thirteen percent of the patients did not receive any adjuvant therapy while 87% received different combinations of chemotherapy, radiotherapy and hormone therapy as adjuvant treatment. With a median follow‐up of 44 months from the time of recurrence the median survival (MSR) was 24 months (SE 1.24) and five‐year overall survival was 18% (SE 2.02). On the univariate analysis, pathological tumor size (pT) at diagnosis (p<0.0006), axillary lymph node status at diagnosis (p<0.00001), negative estrogen receptor (ER) status (p<0.0001), negative progesterone receptor (PgR) status (p<0.0001), adjuvant chemotherapy (p<0.001), disease free interval (p<0.00001), location of recurrence (p<0.0002) and number of metastatic sites (≥3: p, ≤ 0.0003), were significantly associated with shorter survival from first relapse. On the multivariate analysis, only the site of recurrence, axillary lymph node status at diagnosis, ER status and DFI remained independently associated with decreased MSR after first relapse.

Incidence and Prognostic Impact of Secondary Cytogenetic Aberrations in a Series of 145 Patients with Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a mature B‐cell neoplasm with an aggressive behavior, characterized by the t(11;14)(q13;q32). Several secondary genetic abnormalities with a potential role in the oncogenic process have been described. Studies of large MCL series using conventional cytogenetics, and correlating with proliferation and survival, are scarce. We selected 145 MCL cases at diagnosis, displaying an aberrant karyotype, from centers belonging to the Spanish Cooperative Group for Hematological Cytogenetics. Histological subtype, proliferative index and survival data were ascertained. Combined cytogenetic and molecular analyses detected CCND1 translocations in all cases, mostly t(11;14)(q13;q32). Secondary aberrations were present in 58% of patients, the most frequent being deletions of 1p, 13q and 17p, 10p alterations and 3q gains. The most recurrent breakpoints were identified at 1p31‐32, 1p21‐22, 17p13, and 1p36. Aggressive blastoid/pleomorphic variants displayed a higher karyotypic complexity, a higher frequency of 1p and 17p deletions and 10p alterations, a higher proliferation index and poor survival. Gains of 3q and 13q and 17p13 losses were associated with reduced survival times. Interestingly, gains of 3q and 17p losses added prognostic significance to the morphology in a multivariate analysis. Our findings confirm previous observations indicating that proliferation index, morphology and several secondary genetic alterations (3q gains and 13q and 17p losses) have prognostic value in patients with MCL. Additionally, we observed that 3q gains and 17p losses detected by conventional cytogenetics are proliferation‐independent prognostic markers indicating poor outcome.

Response to lenalidomide in myelodysplastic syndromes with del(5q): influence of cytogenetics and mutations

Lenalidomide is an effective drug in low‐risk myelodysplastic syndromes (MDS) with isolated del(5q), although not all patients respond. Studies have suggested a role for TP53 mutations and karyotype complexity in disease progression and outcome. In order to assess the impact of complex karyotypes on treatment response and disease progression in 52 lenalidomide‐treated patients with del(5q) MDS, conventional G‐banding cytogenetics (CC), single nucleotide polymorphism array (SNP‐A), and genomic sequencing methods were used. SNP‐A analysis (with control sample, lymphocytes CD3+, in 30 cases) revealed 5q losses in all cases. Other recurrent abnormalities were infrequent and were not associated with lenalidomide responsiveness. Low karyotype complexity (by CC) and a high baseline platelet count (>280 × 109/l) were associated with the achievement of haematological response (P = 0·020, P = 0·013 respectively). Unmutated TP53 status showed a tendency for haematological response (P = 0·061). Complete cytogenetic response was not observed in any of the mutated TP53 cases. By multivariate analysis, the most important predictor for lenalidomide treatment failure was a platelet count <280 × 109/l (Odds Ratio = 6·17, P = 0·040). This study reveals the importance of a low baseline platelet count, karyotypic complexity and TP53 mutational status for response to lenalidomide treatment. It supports the molecular study of TP53 in MDS patients treated with lenalidomide.

A polymorphism in the XPD gene predisposes to leukemic transformation and new nonmyeloid malignancies in essential thrombocythemia and polycythemia vera

Patients with essential thrombocythemia (ET) and polycythemia vera (PV) have an increased incidence of acute myeloid leukemia and new nonhematologic malignancies compared with the general population. However, information on the factors determining the risk for such complications is limited. In the present study, we investigated whether constitutional genetic variations in DNA repair predispose to leukemic transformation and new nonmyeloid neoplasias in patients with ET and PV. Case-control studies for predisposition to both types of malignancies were nested in a cohort of 422 subjects diagnosed with ET or PV during the period 1973-2010 in several institutions in Spain. A total of 64 incidence cases of leukemia and 50 cases of primary nonmyeloid cancers were accrued. At conditional regression analysis, the Gln/Gln genotype in the XPD codon 751 showed the strongest association with both leukemic transformation (odds ratio [OR] = 4.9; 95% confidence interval [95% CI], 2.0-12) and development of nonmyeloid malignancies (OR = 4.2; 95% CI, 1.5-12). Additional predictive factors were exposure to cytoreductive agents for leukemic transformation (OR = 3.5; 95% CI, 2.0-6.2) and age for nonmyeloid malignancies (OR = 2.0; 95% CI, 1.4-2.8). These findings provide further evidence about the contribution of inherited genetic variations to the pathogenesis and clinical course of myeloproliferative neoplasms.

Cytogenetic response induced by interferon alpha in the myeloproliferative disorder with eosinophilia, T cell lymphoma and the chromosomal translocation t(8;13)(p11;q12)

Cytogenetic response induced by interferon alpha in the myeloproliferative disorder with eosinophilia, T cell lymphoma and the chromosomal translocation t(8;13)(p11;q12)

Prognostic factors in patients with isolated recurrences of breast cancer (stage IV-NED)

Background: One to 10% of women with metastatic breast cancer have a recurrence of their disease as an isolated lesion (local, regional, or distant) which may be treated by surgical resection, irradiation, or both. These are patients with stage IV breast cancer with no evidence of disease, or stage IV-NED. Because natural history and prognostic factors for patients with stage IV-NED are poorly determined, we decided to evaluate a group of patients with stage IV-NED treated at a single institution.Patients and methods: Ninety-six patients with isolated recurrence of stage IV breast cancer were analyzed retrospectively. Treatment of loco-regional or distant recurrence was surgery in 18 patients and surgery plus irradiation in 78 patients. Seventy-nine patients received systemic therapy after loco-regional treatment (24 chemotherapy and 55 hormonotherapy). Prognostic factors were analyzed and correlated with disease-free survival (DFS) and overall survival (OS).Results: Five-year DFS and OS for the whole group were 29% and 49% respectively. On the univariate analysis, patients without axillary nodal involvement at the time of mastectomy had significantly greater 5-year DFS and OS than patients with nodal involvement (51% vs. 14% and 70% vs. 34% respectively, p< 0.05). DFS was also significantly better for patients receiving systemic therapy after local treatment (31% vs. 19%). On the multivariate analysis, absence of nodal involvement and systemic therapy were associated with longer DFS (p = 0.044 and p = 0.008, respectively) and OS (p = 0.009 and p = 0.011, respectively). None of the other factors analyzed including menopausal status, T-stage, number of involved nodes, receptor status, adjuvant therapy, sites of first recurrence, or time from mastectomy to first recurrence had a predictive value for DFS and OS.Conclusion: Patients with stage IV-NED have poor prognosis due to early development of metastatic disease. Absence of axillary nodal involvement at the time of mastectomy and systemic therapy following local management is associated with improved DFS and OS. These results suggest that systemic therapy after local treatment in stage IV-NED is indicated. Poor prognosis in patients with previous nodal involvement warrants new approaches.

Bcl-6 mutation status provides clinically valuable information in early-stage B-cell chronic lymphocytic leukemia

In B-cell chronic lymphocytic leukemia (B-CLL), somatic mutation of IgVH genes defines a subgroup with favorable prognosis, whereas the absence of IgVH mutations is correlated with a worse outcome. Mutations of the BCL-6 gene are also observed in a subset of B-CLL, but the clinical significance of this molecular alteration remains uncertain. We examined the distribution of IgVH and BCL-6 gene mutations in 95 well-characterized patients with Binet stage A B-CLL, and correlated them with clinical, laboratory, cytogenetic findings and disease progression. Mutations of the BCL-6 gene were observed only in cases harboring mutated IgVH. Unexpectedly, coexistence of IgVH and BCL-6 mutations was correlated with shorter treatment-free interval (TFI) compared to cases harboring only IgVH mutation (median, 55 months vs not reached; P=0.01), resembling the clinical course of unmutated IgVH cases (median TFI, 44 months). As expected, deletions of 17p13 (P53 locus) and 11q22 (ATM locus) were observed in cases with unmutated IgVH, except one patient who showed mutations of both IgVH and BCL-6. No other statistically significant differences were observed among the genetic subgroups. Our data indicate that BCL-6 mutations identify a subgroup of Binet stage A B-CLL patients with a high risk of progression despite the presence of mutated IgVH gene.

Myelodysplastic syndromes: an update on molecular pathology

The myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid disorders characterised by impaired peripheral blood cell production due to bone marrow dysplasia affecting one or more of the major myeloid cell lines. MDS are one of five major categories of myeloid neoplasms according to the World Health Organization (WHO) classification system for haematological cancers. Given their cytological and cytogenetic heterogeneity, these diseases probably constitute a group of molecularly distinct entities with variable degrees of ineffective haematopoiesis and susceptibility to leukaemic transformation. Recent studies provide some insights into the physiopathology of MDS. In the early stages, one mechanism contributing to hypercellular marrow and peripheral blood cytopenia is a significant increase in programmed cell death (apoptosis) in haematopoietic cells. Furthermore, altered responses in relation to cytokines, the immune system and bone marrow stroma also contribute to the disease phenotype. Deletions of chromosome 5q31–q32 are the most common recurring cytogenetic abnormalities detected in MDS. The 5q- syndrome is a new entity recognised in the WHO classification since 2001 and is associated with a good prognosis. Haploinsufficiency of multiple genes mapping to the common deleted region at 5q31–32 may contribute to the pathogenesis of 5q- syndrome and other MDS with 5q- deletion. Many studies have demonstrated that altered DNA methylation and histone acetylation can alter gene transcription. Abnormal methylation of transcription promoter sites is universal in patients with MDS, and the number of involved loci is increased in high-risk disease and secondary leukaemias. A better understanding of the pathogenesis of MDS can contribute to the development of new treatments such as hypomethylating drugs, immunomodulatory agents such as lenalidomide, and immunosuppressive drugs aimed at reversing the specific alteration that results in improvement in patients with MDS.

Genomic abnormalities acquired in the blastic transformation of splenic marginal zone B-cell lymphoma.

Among 20 cases of typical splenic marginal zone lymphoma (SMZL), two cases had blastic transformation. The genetic mechanisms underlying the morphologic transformation were investigated by comparing genetic changes in initial and blastic phases. A complex karyotype including trisomy of 3q and genomic gain of 17q22-q24 was seen in both cases at diagnosis. However, the extra copy of 3q was lost during the transformation process in both tumors. Additionally, the Karpas 1718 cell line, which was derived from a patient with transformed SMZL and carried a trisomy of 3q, also evidenced the spontaneous loss of the extra 3q during the culturing process. Other acquired abnormalities observed exclusively in the transformation phase included amplification and/or translocation of bands 7p22-q22 and 19p13. These findings suggest that the loss of +3q and the acquisition of other genomic imbalances may represent unique markers for the transformation process of SMZL. We hypothesize that the trisomy of 3q may correlate with the indolent nature of SMZL, and that the loss of this acquired abnormality leads to or accompanies the development of blastic tumors.

A high proportion of cells carrying trisomy 12 is associated with a worse outcome in patients with chronic lymphocytic leukemia

The prognosis of chronic lymphocytic leukemia (CLL) patients displaying trisomy 12 (+12) remains unclear. In this study, we analyzed the influence of the proportion of cells with +12, and other clinical and biologic factors, in time to first therapy (TTFT) and overall survival (OS), in 289 patients diagnosed with CLL carrying +12. Median OS was 129 months. One hundred seventy‐four patients (60.2%) presented +12 in <60% of cells. TTFT and OS for this subgroup were longer than for the subgroup with +12 in ≥60% of cells, with a median TTFT of 49 months (CI95%, 39–58) vs 30 months (CI95%, 22–38) (P = 0.001); and a median OS of 159 months (CI95%, 119–182), vs 96 months (CI95%, 58–134) (P = 0.015). Other factors associated with a shorter TTFT were: Binet stage, B symptoms, lymphadenopathy, splenomegaly, high lymphocyte count, 11q‐, high β2microglobulin, and high LDH. In the multivariate analysis, clinical stage, +12 in ≥60% of cells, high lymphocyte count, B symptoms, and 11q‐ in addition, resulted of significance in predicting shorter TTFT. Significant variables for OS were: Binet stage, lymphadenopathy, splenomegaly, high LDH, high β2microglobulin, 11q‐, and CD38. In the multivariate analysis, only Binet stage, 11q‐, and high β2microglobulin significantly predicted shorter OS. CLL with +12 entails a heterogeneous group with intermediate prognosis. However, a high proportion of cells carrying +12 separates a subgroup of patients with poor outcome. Copyright