Trastuzumab deruxtecan in previously treated HER2-positive metastatic or unresectable breast cancer: Real-life data from the temporary use authorization program in France.

BACKGROUND: Early access program (formerly cohort Temporary Authorization for Use) was granted for trastuzumab deruxtecan (T-DXd) in France based on DESTINY-Breast01 trial which demonstrated its efficacy and safety in HER2-positive metastatic/unresectable breast cancer after ≥2 anti-HER2-based regimens received at metastatic stage. METHODS: This multicenter real-world early access program included HER2-positive metastatic/unresectable breast patients pretreated with at least two lines of anti-HER2 regimens who received T-DXd 5.4 mg/kg intravenously in monotherapy every 3 weeks. RESULTS: Four hundred and fifty-nine patients (median age, 58 years; hormone receptor-positive, 67%; brain metastases, 28.1%) received T-DXd. Before inclusion, 81.7% of patients had radiation therapy and 76.5% had undergone surgery. Median number of prior metastatic treatment lines was four (range, 2-22); 99.8% patients had received trastuzumab, 94.8% trastuzumab emtansine and 79.3% pertuzumab. Follow-up was performed from September 30, 2020 to March 30, 2021; when the early access program stopped, the median duration of T-DXd treatment was 3.4 (range, 0-7.8) months. In 160 patients with available tumor assessment, objective response rate was 56.7% and 12.1% had progression. In 57 patients with available brain tumor assessment, complete or partial intracranial response was reported for 35.7% patients and 5.4% had progression. A total of 17 (3.7%) patients with interstitial lung disease (ILD) was reported with no cases of ILD-related death. CONCLUSIONS: In this early access program in patients with heavily pretreated HER2-positive metastatic/unresectable breast cancer, T-DXd had antitumor activity with a similar response to that reported in previous clinical studies. T-DXd was well tolerated and no new safety signals were observed.

Decision of adjuvant chemotherapy in intermediate risk luminal breast cancer patients: A prospective multicenter trial assessing the clinical and psychological impact of EndoPredict® (EpClin) use (UCBG 2-14).

PURPOSE: Genomic tests can identify ER-positive HER2-negative localized breast cancer patients who may not benefit from adjuvant chemotherapy. Such tests seem especially interesting in "intermediate" clinico-pathological risk categories. The psychological impact of the decision uncertainty in these women remains largely unexplored. We assessed the clinical and psychological impact of EndoPredict® (EpClin), a clinico-genomic test, in these patients. METHODS: This multicenter, single arm prospective study (NCT02773004) enrolled patients for which adjuvant chemotherapy was uncertain, based on predefined criteria. The primary endpoint was the proportion of change between initial adjuvant decision and final administration of chemotherapy. Secondary endpoints included post-test (Day 17) and 1-year patient reported outcomes. RESULTS: One third of 200 evaluable patients had a high EpClin score (≥3.32867; 10 years cumulative risk of distance failure ≥10%). The overall change rate of chemotherapy decision was 72/200 (35.8%, 95% CI 29.2-42.4). Chemotherapy was withdrawn in 57 cases (28.4% [22.2-34.8]) and added in 15 (7.5% [3.8-11.2]. 6 changes (8%) were based on patients' decisions. Anxiety and distress levels increased at Day 17 when adding chemotherapy after the test result (p < 10-7 and 0.00022 respectively), while stable in other situations. At 1-year, all patients had returned to the baseline anxiety and distress levels (mean anxiety 51.5, +/- SD = 2.5 [max. 80], mean distress 3±1 [max. 10]). CONCLUSIONS: EndoPredict ® (EpClin) is clinically useful in deciding whether or not to administer adjuvant chemotherapy in patients with intermediate risk. A single-step decision is preferable since adding chemotherapy at a later stage increases anxiety and distress.

Pharmacogenetics of capecitabine in advanced breast cancer patients.

PURPOSE: Germinal gene polymorphisms can explain a part of the interpatient pharmacodynamic variability of anticancer drugs, particularly fluoropyrimidines. Genes for which polymorphisms may potentially influence pharmacodynamics of fluoropyrimidines, including capecitabine, are thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and dihydropyrimidine dehydrogenase (DPD). EXPERIMENTAL DESIGN: The aim of this prospective pilot study was to analyze the effect of TS, MTHFR, and DPD gene polymorphisms on toxicity and efficacy in advanced breast cancer patients receiving capecitabine as monotherapy. Germinal polymorphisms of TS (6 bp deletion in the 3' region and 28 bp repeats, including G>C mutation in the 5' region), MTHFR (677C>T and 1298A>C), and DPD (IVS14+1G>A) were determined in 105 consecutive patients. RESULTS: A trend toward a higher global toxicity grade 3 and 4 was observed in patients homozygous for the TS 3RG allele compared with patients heterozygous for the 3RG allele or patients not carrying the 3RG allele (50% versus 19% versus 13% respectively, P=0.064). The sole patient bearing the DPD IVS14+1G>A mutation (heterozygous) deceased from hematologic toxicity. The median response duration was 5.8 months (95% confidence interval, 4.3-7.2). Duration of response was significantly shortened in patients homozygous for the 3RG allele compared with others (P=0.037). CONCLUSIONS: The present data suggest that 3RG3RG breast cancer patients are not good candidates for capecitabine therapy. In addition, attention should be paid to DPD deficiency in breast cancer patients receiving capecitabine. These preliminary data require further confirmation on a larger number of patients.

Prospective, multicenter French study evaluating the clinical impact of the Breast Cancer Intrinsic Subtype-Prosigna® Test in the management of early-stage breast cancers.

PURPOSE: The Prosigna® breast cancer prognostic gene signature assay identifies a gene-expression profile that permits the classification of tumors into subtypes and gives a score for the risk of recurrence (ROR) at 10 years. The primary objective of this multicenter study was to evaluate the impact of Prosigna's assay information on physicians' adjuvant treatment decisions in patients with early-stage breast cancer. Secondary objectives were to assess confidence of practitioners in their therapeutic recommendations before and after the added information provided by the Prosigna assay; and to evaluate the emotional state of patients before and after the Prosigna test results. METHODS: Consecutive patients with invasive early-stage breast cancer were enrolled in a prospective, observational, multicenter study carried out in 8 hospitals in France. The Prosigna test was carried out on surgical specimens using the nCounter® Analysis System located at the Institut Curie. Both before and after receiving the Prosigna test results, physicians completed treatment confidence questionnaires and patients completed questionnaires concerning their state of anxiety, the difficulties felt in face of the therapy and quality of life. Information was also collected at 6 months regarding the physicians' opinion on the test results and the patients' degree of anxiety, difficulties with therapy and quality of life. RESULTS: Between March 2015 and January 2016, 8 study centers in France consecutively enrolled 210 postmenopausal women with estrogen receptor (ER) positive, human epidermal growth hormone-2 (HER-2) negative, and node negative tumors, either stage 1 or stage 2. Intrinsic tumor subtypes as assessed by the Prosigna test were 114 (58.2%) Luminal A, 79 (40.3%) Luminal B, 1 (0.5%) HER-2 enriched (HER-2E), and 2 (1.0%) basal-like. Before receiving the Prosigna test results, physicians categorized tumor subtypes based on immunohistochemistry (IHC) as Luminal A in 126 (64%) patients and Luminal B in 70 (36%) patients, an overall discordance rate of 25%. The availability of Prosigna assay results was significantly associated with the likelihood of change in treatment recommendations, with 34 patients (18%) having their treatment plan changed from Adjuvant Chemotherapy to No Adjuvant Chemotherapy or vice versa (p<0.001, Fisher's exact test). Prosigna test results also decreased patients' anxiety about the chosen adjuvant therapy, and improved emotional well-being and measures of personal perceptions of uncertainty. CONCLUSIONS: The results of this prospective decision impact study are consistent with 2 previous, identically designed studies carried out in Spain and Germany. The availability of Prosigna test results increased the confidence of treating physicians in their adjuvant treatment decisions, and led to an 18% change in chemotherapy treatment plan (from Adjuvant Chemotherapy to No Adjuvant Chemotherapy or vice versa). Prosigna testing decreased anxiety and improved measures of health-related quality of life in patients facing adjuvant therapy. The 25% discordance between Prosigna test and IHC subtyping underlines the importance of molecular testing for optimal systemic therapy indications in early breast cancer.

Economic Impact of Gene Expression Profiling in Patients with Early-Stage Breast Cancer in France.

BACKGROUND AND AIMS: The heterogeneous nature of breast cancer can make decisions on adjuvant chemotherapy following surgical resection challenging. Oncotype DX is a validated gene expression profiling test that predicts the likelihood of adjuvant chemotherapy benefit in early-stage breast cancer. The aim of this study is to determine the costs of chemotherapy in private hospitals in France, and evaluate the cost-effectiveness of Oncotype DX from national insurance and societal perspectives. METHODS: A multicenter study was conducted in seven French private hospitals, capturing retrospective data from 106 patient files. Cost estimates were used in conjunction with a published Markov model to assess the cost-effectiveness of using Oncotype DX to inform chemotherapy decision making versus standard care. Sensitivity analyses were performed. RESULTS: The cost of adjuvant chemotherapy in private hospitals was estimated at EUR 8,218 per patient from a national insurance perspective and EUR 10,305 from a societal perspective. Cost-effectiveness analysis indicated that introducing Oncotype DX improved life expectancy (+0.18 years) and quality-adjusted life expectancy (+0.17 QALYs) versus standard care. Oncotype DX was found cost-effective from a national insurance perspective (EUR 2,134 per QALY gained) and cost saving from a societal perspective versus standard care. Inclusion of lost productivity costs in the modeling analysis meant that costs for eligible patients undergoing Oncotype DX testing were on average EUR 602 lower than costs for those receiving standard care. CONCLUSIONS: As Oncotype DX was found both cost and life-saving from a societal perspective, the test was considered to be dominant to standard care. However, the delay in coverage has the potential to erode the quality of the French healthcare system, thus depriving patients of technologies that could improve clinical outcomes and allow healthcare professionals to better allocate hospital resources to improve the standard of care for all patients.

Rearrangement involving chromosomes 1 and 8 in a retroperitoneal lipoma.

Superficial lipomas are very common benign adipose tissue tumors. In contrast, deep-seated lipomas such as retroperitoneal lipomas, are extremely rare and have to be carefully distinguished from well-differentiated liposarcomas for appropriate treatment and follow-up. We report to, our knowledge, the first cytogenetic analysis of a retroperitoneal lipoma occurring in an adult, which showed a complex rearrangement interpreted as t(1;8)(q32;q22-q23) followed by a pericentric inversion of der(8). There was no detectable rearrangement of chromosome 12, and in particular no 12q14-q15 amplification. Because rearrangements of the 8q11-q13 region involving the PLAG1 gene have been described in lipoblastoma-another kind of benign adipose tumor--we used fluorescence in situ hybridization analysis to determine in the present case the chromosomal breakpoint on 8q was located between the ETO (8q22) and COX6C (8q22-q23) genes at a great distance from PLAG1. Karyotypic analysis of additional cases of retroperitoneal lipomas will be required to assess the significance of chromosome 1 and 8 rearrangements in a continuous effort to attain a better classification of adipose tissue tumors. Of great importance is the determination of such genetic markers as additional tools for the differential diagnosis between benign and malignant forms of adipose tumors, and to avoid erroneous diagnoses.

[From cytogenetics to cytogenomics of adipose tissue tumors: 1. Benign adipose tissue tumors]. / De la cytogénétique à la cytogénétique à la cytogénomique des tumeurs adipocytaires: 1. Tumeurs adipocytaires bénignes.

Benign lipomatous tumors are characterized at the genetic level by different types of chromosomal abnormalities. A rearrangement of the HMGIC (HMGA2) gene, localized in 12q15 and coding for an architectural non-histone DNA protein, is observed in a majority of solitary superficial lipomas. Alterations of HMGIC are often resulting from reciprocal translocations, such as t(3;12)(q27-28;q15) that fuses LPP with HMGIC, but a variety of chromosomal anomalies, such as deletions, inversions or insertions are also observed. Rearrangements of chromosomal regions 6p21-22, 13q, 11q13, 12q13 or others are described in approximately one third of superficial lipoma cases with abnormal karyotypes. The genes involved in these alterations remain to be determined. Lipoblastomas are pediatric neoplasms that are characterized by rearrangements of PLAG1, located in 8q11-12 whereas hibernomas, that resemble brown fat, are associated with 11q13 rearrangements together with often complex chromosomal alterations. Deletions of 13q and 16q have been identified in spindle cell lipomas. A t(11;16)(q13;p12-13) have been described in the two published karyotypes of chondroid lipomas. The chromosomal features of other rare benign lipomatous tumors, the differential diagnosis of which is occasionally difficult, such as infiltrating intra-muscular lipomas, organic deep-seated lipomas, or angiomyolipomas, myolipomas, myxolipomas are still poorly defined. Although the genetic characterization of benign lipomatous tumors has been dramatically in progress over the last ten years, many aspects remain obscure and warrant future investigations for a better comprehension of underlying molecular mechanisms.

[Cardiac tolerance of the combination paclitaxel-anthracyclines in the context of the management of cancer of the breast]. / Tolérance cardiaque des associations paclitaxel-anthracyclines dans le cadre de la prise en charge du cancer du sein.

Within the past decades there has been major interest in associating the paclitaxel into the management of breast cancer patients with a strong improvement of clinical results. Moreover, doxorubicin is historically one of the major chemotherapeutic agents in breast cancer treatment. So, investigations of the combination of the paclitaxel with doxorubicin have logically taken place in the strategy of breast cancer management. Also, this association became a standard of care neoadjuvantly in locally advanced breast cancer. The aim of this review of literature consists to make a special focus on cardiac toxicity occurring after doxorubicin and paclitaxel association and to give adequate directions for the next future in this promising combination.

Variability of origin for the neocentromeric sequences in analphoid supernumerary marker chromosomes of well-differentiated liposarcomas.

Well-differentiated liposarcomas (WDLPS) and dedifferentiated liposarcomas are cytogenetically characterized by the presence of supernumerary ring or giant chromosomes containing amplified material from the 12q14-15 region. These chromosomes contain neocentromeres, which are able to bind the kinetochore proteins and to ensure a stable mitotic transmission although they do not show detectable alpha-satellite sequences. WDLPS is the sole solid tumor for which the presence of a neocentromere is a consistent and specific feature. By immunostaining with anti-centromere antibodies in combination with FISH analysis (immunoFISH) in four cases of WDLPS, we have shown that sequences from the region 12q14-21 region were not located at the neocentromere site. In addition, we have microdissected the neocentromeric region from a giant supernumerary chromosome in the 94T778 WDLPS cell line. By using immunoFISH and positional cloning we have shown that the neocentromere of this cell line originated from a region at 4p16.1, rich in AT sequences and in long interspersed nucleotide element (LINE)1, that was co-amplified with 12q14-15. We have observed that this 4p sequence was not involved in the neocentromere of the supernumerary giant chromosome present in the 93T449 WDLPS cell line derived from a metachronous recurrence of the same primary WDLPS than 94T778. Altogether, these results indicate that the neocentromeres in WDLPS originate from amplified chromosomal regions other than 12q14-15 and do not involve a specific and recurrent DNA sequence. These sequences might be activated for centromeric function by epigenetic mechanisms.

Phase II trial evaluating a docetaxel-capecitabine combination as treatment for hormone-refractory prostate cancer.

BACKGROUND: Docetaxel is a well-recognized drug in patients with hormone-refractory prostate cancer (HRPC), either alone or combined with estramustine. In this indication, a Phase II trial was conducted investigating a docetaxel-capecitabine combination. METHODS: Forty-six patients presenting with documented HRPC were enrolled in the study. The treatment regimen consisted of docetaxel (D) at a dose of 35 mg /m2/week (intravenously, 3 consecutive weeks) plus oral capecitabine (C) at a dose of 625 mg/m2 twice daily (Days 5-18) every 28 days for 4 cycles. The primary endpoint was the biological response defined as a reduction in prostate-specific antigen (PSA) level > or =50%. Secondary endpoints were overall survival, safety, and quality of life. RESULTS: Thirty of 44 assessable patients (68.2%) achieved a biological response, 14 of whom (31.8%) normalized their PSA value. The median overall survival time was 17.7 months (95% confidence interval, 15.8 to not reached). Four treatment cycles were completed by 87% of the patients. Hematologic toxicity was mild. The main Grade 3-4 toxicities were cutaneous toxicity (13.1%) and changes in nails (6.5%). Physical functioning and role scales were higher before treatment (P = .02 and P = .003, respectively), fatigue and diarrhea were more frequent during and after treatment (P = .0003 and P = .03, respectively), and pain was lower during and after treatment. CONCLUSIONS: The results of the current study demonstrated the high efficacy of the DC combination in patients with HRPC, and the associated good tolerability. This combination offers a new alternative to the docetaxel-estramustine combination. Further randomized trials are warranted.

Ceftriaxone monotherapy for the treatment of febrile neutropenia in patients with solid tumors: a prospective study of 100 episodes.

BACKGROUND: Broad-spectrum beta-lactam is the standard therapy for febrile neutropenia (FN) in cancer patients. The aim of our study was to evaluate the treatment of FN by a once-daily administration of ceftriaxone (CFX) alone. MATERIAL/METHODS: From Jan. 1, 1997 to Dec. 31, 2001 we prospectively analyzed 100 episodes of FN in 94 patients. Inclusion criteria were: fever > or = 38.5 degrees C, neutrophil count (NC) <500/microl, presumed short duration (<7 days), and no antimicrobial treatment within the preceding 72 h. Treatment consisted of 2 g daily intravenous CFX alone until NC>500. Success criteria were: afebrile within 48 hours under CFX alone and without secondary infection. RESULTS: Twenty-seven episodes occurred in patients with performance status (PS)>2. The median duration of neutropenia was 3.5 days (range 1-22). Etiology of fever was: 75 of unknown origin (FUO), 6 clinically defined (CDI), and 19 microbiologically documented (MDI). Median CFX treatment duration was 5 days. Successful response was obtained in 87% of cases; no deaths occurred. Treatment efficacy differed between FUO, CDI, and MDI with, respectively, 92.0, 83.3, and 68.4% success rates (p=0.042). Treatment failure was mostly observed in patients with PS > or = 2 (p=0.0001). Among the 13 failures, 4 resolved in less than 4 days with CFX alone and 9 required additional or modified antimicrobial treatment. CONCLUSIONS: Considering the marked practical advantages of CFX alone (well-tolerated treatment with minimum side effects, once-daily administration, low cost, and high response rates), this single-agent regimen appears to be a valuable option in treatment of FN in patients with solid tumors.

11q13 alterations in two cases of hibernoma: large heterozygous deletions and rearrangement breakpoints near GARP in 11q13.5.

Hibernomas are rare, benign tumors with a histological appearance resembling that of brown adipose tissue. The diagnosis of hibernomas may be difficult because some of them contain only a small number of the characteristic multivacuolated fat cells and can be mistakenly classified as well-differentiated liposarcomas. Cytogenetic information has been reported for 10 cases, showing that these tumors are characterized by structural rearrangements involving 11q13. Previous fluorescence in situ hybridization (FISH) studies revealed consistent and sometimes cryptic losses of the MEN1 region in 11q13.1. Here, we describe the molecular cytogenetic analysis of two new hibernoma cases. Both tumors showed complex rearrangements, simultaneously including translocations, inversions, and deletions affecting the pair of chromosomes 11. The translocation partners were chromosome 5 in one case and chromosomes 16 and 22 in the other case. The 11q13 region was concomitantly rearranged on both chromosomes 11. FISH studies revealed large heterozygous deletions within the 11q13 band, from 11q13.1 to 11q13.5. Genes such as PYGM, MEN1, CCND1, FGF3, ARIX, and GARP were deleted, showing that the size of the 11q13 altered region was larger than previously reported. Furthermore, both tumors had breakpoints in 11q13.5, one of them in the immediate proximity of the GARP gene. Our results suggest that rearrangements of GARP or a neighboring gene may be important for the pathogenesis of hibernomas.