Publications by authors named "Hatem A Azim"

115 Publications

Knowledge, Practice, and Attitudes of Physicians in Low- and Middle-Income Countries on Fertility and Pregnancy-Related Issues in Young Women With Breast Cancer.

JCO Glob Oncol 2022 Jan;8:e2100153

Department of Medical Oncology, U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy.

Purpose: Fertility and pregnancy-related issues are highly relevant for young (≤ 40 years) patients with breast cancer. Limited evidence exists on knowledge, practice, and attitudes of physicians from low- and middle-income countries (LMICs) regarding these issues.

Methods: A 19-item questionnaire adapted from an international survey exploring issues about fertility preservation and pregnancy after breast cancer was sent by e-mail between November 2019 and January 2020 to physicians from LMICs involved in breast cancer care. Descriptive analyses were performed.

Results: A total of 288 physicians from Asia, Africa, America, and Europe completed the survey. Median age was 38 years. Responders were mainly medical oncologists (44.4%) working in an academic setting (46.9%). Among responders, 40.2% and 53.8% reported having never consulted the available international guidelines on fertility preservation and pregnancy after breast cancer, respectively. 25.0%, 19.1%, and 24.3% of responders answered to be not at all knowledgeable about embryo, oocyte, or ovarian tissue cryopreservation, respectively; 29.2%, 23.6%, and 31.3% declared that embryo, oocyte, and ovarian tissue cryopreservation were not available in their countries, respectively. 57.6% of responders disagreed or were neutral on the statement that controlled ovarian stimulation can be considered safe in patients with breast cancer. 49.7% and 58.6% of responders agreed or were neutral on the statement that pregnancy in breast cancer survivors may increase the risk of recurrence overall or only in those with hormone receptor-positive disease, respectively.

Conclusion: This survey showed suboptimal knowledge, practice, and attitudes of physicians from LMICs on fertility preservation and pregnancy after treatment completion in young women with breast cancer. Increasing awareness and education on these aspects are needed to improve adherence to available guidelines and to promote patients' oncofertility counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/GO.21.00153DOI Listing
January 2022

Who are the women who enrolled in the POSITIVE trial: A global study to support young hormone receptor positive breast cancer survivors desiring pregnancy.

Breast 2021 Oct 3;59:327-338. Epub 2021 Aug 3.

Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA. Electronic address:

Background: Premenopausal women with early hormone-receptor positive (HR+) breast cancer receive 5-10 years of adjuvant endocrine therapy (ET) during which pregnancy is contraindicated and fertility may wane. The POSITIVE study investigates the impact of temporary ET interruption to allow pregnancy.

Methods: POSITIVE enrolled women with stage I-III HR + early breast cancer, ≤42 years, who had received 18-30 months of adjuvant ET and wished to interrupt ET for pregnancy. Treatment interruption for up to 2 years was permitted to allow pregnancy, delivery and breastfeeding, followed by ET resumption to complete the planned duration.

Findings: From 12/2014 to 12/2019, 518 women were enrolled at 116 institutions/20 countries/4 continents. At enrolment, the median age was 37 years and 74.9 % were nulliparous. Fertility preservation was used by 51.5 % of women. 93.2 % of patients had stage I/II disease, 66.0 % were node-negative, 54.7 % had breast conserving surgery, 61.9 % had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed ET (41.8 %), followed by tamoxifen + ovarian function suppression (OFS) (35.4 %). A greater proportion of North American women were <35 years at enrolment (42.7 %), had mastectomy (59.0 %) and received tamoxifen alone (59.8 %). More Asian women were nulliparous (81.0 %), had node-negative disease (76.2%) and received tamoxifen + OFS (56.0 %). More European women had received chemotherapy (69.3 %).

Interpretation: The characteristics of participants in the POSITIVE study provide insights to which patients and doctors considered it acceptable to interrupt ET to pursue pregnancy. Similarities and variations from a regional, sociodemographic, disease and treatment standpoint suggest specific sociocultural attitudes across the world.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.breast.2021.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365381PMC
October 2021

Pregnancy After Breast Cancer: A Systematic Review and Meta-Analysis.

J Clin Oncol 2021 10 1;39(29):3293-3305. Epub 2021 Jul 1.

Fertility and Procreation Unit, Gynecologic Oncology Department, European Institute of Oncology IRCCS, Milan, Italy.

Purpose: Many patients and physicians remain concerned about the potential detrimental effects of pregnancy after breast cancer (BC) in terms of reproductive outcomes and maternal safety. This systematic review and meta-analysis aimed at providing updated evidence on these topics.

Methods: A systematic literature review was conducted to identify studies including patients with a pregnancy after BC (PROSPERO number CRD42020158324). Likelihood of pregnancy after BC, their reproductive outcomes, and maternal safety were assessed. Pooled relative risks, odds ratios (ORs), and hazard ratios (HRs) with 95% CIs were calculated using random effects models.

Results: Of 6,462 identified records, 39 were included involving 8,093,401 women from the general population and 112,840 patients with BC of whom 7,505 had a pregnancy after diagnosis. BC survivors were significantly less likely to have a subsequent pregnancy compared with the general population (relative risk, 0.40; 95% CI, 0.32 to 0.49). Risks of caesarean section (OR, 1.14; 95% CI, 1.04 to 1.25), low birth weight (OR, 1.50; 95% CI, 1.31 to 1.73), preterm birth (OR, 1.45; 95% CI, 1.11 to 1.88), and small for gestational age (OR, 1.16; 95% CI, 1.01 to 1.33) were significantly higher in BC survivors, particularly in those with previous chemotherapy exposure, compared with the general population. No significantly increased risk of congenital abnormalities or other reproductive complications were observed. Compared to patients with BC without subsequent pregnancy, those with a pregnancy had better disease-free survival (HR, 0.66; 95% CI, 0.49 to 0.89) and overall survival (HR, 0.56; 95% CI, 0.45 to 0.68). Similar results were observed after correcting for potential confounders and irrespective of patient, tumor, and treatment characteristics, pregnancy outcome, and timing of pregnancy.

Conclusion: These results provide reassuring evidence on the safety of conceiving in BC survivors. Patients' pregnancy desire should be considered a crucial component of their survivorship care plan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.21.00535DOI Listing
October 2021

Prognosis of breast cancer diagnosed during pregnancy and early postpartum according to immunohistochemical subtype: A matched case-control study.

Breast Cancer Res Treat 2021 Jul 16;188(2):489-500. Epub 2021 Jun 16.

Breast Cancer Center, Hospital Zambrano Hellion, Tecnologico de Monterrey, Av. Batallon de San Patricio 112, 66278, Real San Agustin, San Pedro Garza Garcia, NL, Mexico.

Purpose: Pregnancy-associated breast cancer (PABC) poses a clinical challenge and its prognosis remains controversial. During the pregnancy and postpartum periods, the breast undergoes biological events that may uniquely influence disease behavior and treatment response. This study aimed to assess if a PABC diagnosis influences survival compared to non-PABC.

Methods: A single-center record review was performed to identify PABC patients diagnosed from January 2007 through June 2018. Two controls were matched to each PABC case by stage, immunohistochemical (IHC) subtype, age (± 3) and year of diagnosis (± 2). Disease-free survival (DFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared with the log-rank test. Multivariate analysis was used to assess the impact of PABC on outcomes.

Results: 125 PABC patients (pregnant: 62; postpartum: 63) and 250 controls were included. Median follow-up was 67.7 and 73.4 months, respectively. 4-year DFS was 62% in pregnant vs 78% in controls (p = 0.010), and 63% in postpartum vs 83% in controls (p = 0.034). Subanalysis by IHC subtype revealed a significantly inferior DFS in PABC with hormone receptor-positive/HER2-negative (p = 0.032) and HER2-positive disease (p = 0.005) compared to corresponding non-PABC patients. 4-year OS was similar between case groups and controls. Multivariate analysis supported the independent impact of pregnant and postpartum status on DFS (p < 0.05).

Conclusion: Patients diagnosed during pregnancy and early postpartum are at high risk of recurrence. Further research is warranted to better characterize PABC tumor biology and enable the identification of novel therapeutic interventions to improve treatment outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-021-06225-4DOI Listing
July 2021

Clinical behavior and outcomes of breast cancer in young women with germline BRCA pathogenic variants.

NPJ Breast Cancer 2021 Feb 12;7(1):16. Epub 2021 Feb 12.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Young breast cancer (BC) patients carrying a germline BRCA pathogenic variant (mBRCA) have similar outcomes as non-carriers. However, the impact of the type of gene (BRCA1 vs. BRCA2) and hormone receptor status (positive [HR+] vs. negative [HR-]) on clinical behavior and outcomes of mBRCA BC remains largely unknown. This is an international, multicenter, hospital-based, retrospective cohort study that included mBRCA patients diagnosed, between January 2000 and December 2012, with stage I-III invasive early BC at age ≤40 years. From 30 centers worldwide, 1236 young mBRCA BC patients were included. Among 808 and 428 patients with mBRCA1 or mBRCA2, 191 (23.6%) and 356 (83.2%) had HR+tumors, respectively (P < 0.001). Median follow-up was 7.9 years. Second primary BC (P = 0.009) and non-BC malignancies (P = 0.02) were more frequent among mBRCA1 patients while distant recurrences were less frequent (P = 0.02). Irrespective of hormone receptor status, mBRCA1 patients had worse disease-free survival (DFS; adjusted HR = 0.76, 95% CI = 0.60-0.96), with no difference in distant recurrence-free interval (DRFI) and overall survival (OS). Patients with HR+ disease had more frequent distant recurrences (P < 0.001) and less frequent second primary malignancies (BC: P = 0.005; non-BC: P = 0.18). No differences in DFS and OS were observed according to hormone receptor status, with a tendency for worse DRFI (adjusted HR = 1.39, 95% CI = 0.94-2.05) in patients with HR+ BC. Type of mBRCA gene and hormone receptor status strongly impact BC clinical behavior and outcomes in mBRCA young patients. These results provide important information for patients' counseling on treatment, prevention, and surveillance strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41523-021-00224-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880991PMC
February 2021

Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells.

Nat Commun 2020 12 10;11(1):6335. Epub 2020 Dec 10.

Division of Hematology/Oncology, Department of Medicine, American University of Beirut, Beirut, Lebanon.

Most breast cancers exhibit low immune infiltration and are unresponsive to immunotherapy. We hypothesized that inhibition of the receptor activator of nuclear factor-κB (RANK) signaling pathway may enhance immune activation. Here we report that loss of RANK signaling in mouse tumor cells increases leukocytes, lymphocytes, and CD8 T cells, and reduces macrophage and neutrophil infiltration. CD8 T cells mediate the attenuated tumor phenotype observed upon RANK loss, whereas neutrophils, supported by RANK-expressing tumor cells, induce immunosuppression. RANKL inhibition increases the anti-tumor effect of immunotherapies in breast cancer through a tumor cell mediated effect. Comparably, pre-operative single-agent denosumab in premenopausal early-stage breast cancer patients from the Phase-II D-BEYOND clinical trial (NCT01864798) is well tolerated, inhibits RANK pathway and increases tumor infiltrating lymphocytes and CD8 T cells. Higher RANK signaling activation in tumors and serum RANKL levels at baseline predict these immune-modulatory effects. No changes in tumor cell proliferation (primary endpoint) or other secondary endpoints are observed. Overall, our preclinical and clinical findings reveal that tumor cells exploit RANK pathway as a mechanism to evade immune surveillance and support the use of RANK pathway inhibitors to prime luminal breast cancer for immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-20138-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728758PMC
December 2020

Reply to S. A. Narod et al.

J Clin Oncol 2020 12 30;38(36):4352-4354. Epub 2020 Oct 30.

Hatem A. Azim Jr, MD, PhD, Tecnologico de Monterrey, Centro de Cancer de Mama del Hospital Zambrano Hellion, Monterrey, Nuevo Leon, Mexico; Lieveke Ameye, MSc, PhD and Marianne Paesmans, MSc, Data Centre, Institut Jules Bordet and Université Libre de Bruxelles, Brussels, Belgium; and Matteo Lambertini, MD, PhD, Department of Internal Medicine and Medical Specialties, School of Medicine, University of Genova, Genova; and Department of Medical Oncology, U.O.C Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.02850DOI Listing
December 2020

Clinical utility of genomic signatures in young breast cancer patients: a systematic review.

NPJ Breast Cancer 2020 25;6:46. Epub 2020 Sep 25.

Breast Cancer Center, Hospital Zambrano Hellion, Tecnologico de Monterrey, San Pedro Garza Garcia, Mexico.

Risk stratification by genomic signatures has been shown to improve prognostication and guide treatment decisions among patients with hormone-sensitive breast cancer. However, their role in young women has not been fully elucidated. In this review, a systematic search was conducted for published articles and abstracts from major congresses that evaluated the use of genomic signatures in young breast cancer patients. A total of 71 studies were analyzed, including 561,188 patients of whom 27,748 (4.9%) were young. Women aged ≤40 years were subjected to genomic testing at a similar rate to older women but had a higher proportion of intermediate- to high-risk tumors when classified by EndoPredict ( = 0.04), MammaPrint ( < 0.01), and Oncotype DX ( < 0.01). In young women with low genomic risk, 6-year distant recurrence-free survival was 94%, while 5-year overall survival was nearly 100%. Nonetheless, young patients classified as low-risk had a higher tendency to receive chemotherapy compared to their older counterparts. In conclusion, genomic tests are useful tools for identifying young patients in whom chemotherapy omission is appropriate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41523-020-00188-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519162PMC
September 2020

Pregnancy After Breast Cancer in Patients With Germline Mutations.

J Clin Oncol 2020 09 16;38(26):3012-3023. Epub 2020 Jul 16.

Department of Medical Oncology, Institut Jules Bordet and Université Libre de, Brussels, Belgium.

Purpose: Young women with germline mutations have unique reproductive challenges. Pregnancy after breast cancer does not increase the risk of recurrence; however, very limited data are available in patients with mutations. This study investigated the impact of pregnancy on breast cancer outcomes in patients with germline mutations.

Patients And Methods: This is an international, multicenter, hospital-based, retrospective cohort study. Eligible patients were diagnosed between January 2000 and December 2012 with invasive early breast cancer at age ≤ 40 years and harbored deleterious germline mutations. Primary end points were pregnancy rate, and disease-free survival (DFS) between patients with and without a pregnancy after breast cancer. Pregnancy outcomes and overall survival (OS) were secondary end points. Survival analyses were adjusted for guarantee-time bias controlling for known prognostic factors.

Results: Of 1,252 patients with germline mutations (, 811 patients; , 430 patients; , 11 patients) included, 195 had at least 1 pregnancy after breast cancer (pregnancy rate at 10 years, 19%; 95% CI, 17% to 22%). Induced abortions and miscarriages occurred in 16 (8.2%) and 20 (10.3%) patients, respectively. Among the 150 patients who gave birth (76.9%; 170 babies), pregnancy complications and congenital anomalies occurred in 13 (11.6%) and 2 (1.8%) cases, respectively. Median follow-up from breast cancer diagnosis was 8.3 years. No differences in DFS (adjusted hazard ratio [HR], 0.87; 95% CI, 0.61 to 1.23; = .41) or OS (adjusted HR, 0.88; 95% CI, 0.50 to 1.56; = .66) were observed between the pregnancy and nonpregnancy cohorts.

Conclusion: Pregnancy after breast cancer in patients with germline mutations is safe without apparent worsening of maternal prognosis and is associated with favorable fetal outcomes. These results provide reassurance to patients with -mutated breast cancer interested in future fertility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.02399DOI Listing
September 2020

Estimation of historical control rate for a single arm de-escalation study - Application to the POSITIVE trial.

Breast 2020 Oct 2;53:1-7. Epub 2020 Jun 2.

International Breast Cancer Study Group Statistical Center, Department of Data Sciences, Division of Biostatistics, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02215, USA. Electronic address:

Background: Although randomized controlled clinical trials are optimal to evaluate the effect of an experimental therapy, single-arm trials are required whenever randomization is unethical or not feasible, such as de-escalation studies. We propose using prospectively identified historical controls to place results of single-arm, de-escalation trials into context.

Methods: POSITIVE is a prospective, single-arm study in young women with hormone-receptor-positive early breast cancer to determine if temporarily interrupting adjuvant endocrine therapy in order to become pregnant increases the risk of a breast cancer event. After 272 women enrolled in POSITIVE, we identified a cohort of 1499 SOFT/TEXT patients potentially eligible to enroll in POSITIVE who did not interrupt endocrine therapy. Method I used the SOFT/TEXT cohort to calculate annualized hazard rates by a piecewise exponential model. Method II used the SOFT/TEXT cohort to group-match SOFT/TEXT patients to POSITIVE patients; sample sets of SOFT/TEXT patients were randomly drawn 5000 times to obtain sets having patient, disease, and treatment characteristics more balanced with POSITIVE participants.

Results: Compared with SOFT/TEXT, POSITIVE participants were younger, less likely to be overweight/obese, had fewer positive nodes, and fewer received aromatase inhibitor or chemotherapy. The estimated 3-year breast cancer free interval event rates were 9.5% (95% CI: 7.9%,11.1%) for Method I and 9.4% (95% CI: 7.8%,10.9%) for Method II, compared with 5.8% initially assumed when POSITIVE was designed.

Conclusion: External control datasets should be identified before launching single-arm, de-escalation trials and methods applied during their conduct to provide context for interim monitoring and interpretation of the final analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.breast.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375555PMC
October 2020

Adjuvant ovarian function suppression and tamoxifen in premenopausal breast cancer patients: A meta-analysis.

Curr Probl Cancer 2020 12 26;44(6):100592. Epub 2020 May 26.

School of Medicine, Monterrey Institute of Technology, Monterrey, MX.

Background: The benefit of adding ovarian function suppression (OFS) to tamoxifen in the adjuvant treatment of premenopausal women with breast cancer is uncertain. We conducted a meta-analysis of randomized controlled trials that addressed this question.

Methods: Systematic search of PubMed, the web of science, and the meeting library of ASCO, ESMO, and SABCS was conducted using the following keywords: tamoxifen, ovarian suppression, and breast cancer. Eligible studies were those recruiting patients with breast cancer randomized to receive adjuvant tamoxifen and OFS versus tamoxifen alone. Pooled hazard ratio [HR]) for disease-free (DFS) and overall survival (OS) with 95% confidence interval (CI) were calculated using the fixed effect model.

Results: We searched a total of 845 records, of which 5 clinical trials, including 7557 patients, were eligible for our analysis. Adding OFS to tamoxifen improved DFS with pooled HR: 0.88 (95% CI: 0.80-0.96, P= 0.004) and OS (pooled HR: 0.87 {95% CI: 0.77-0.98, P= 0.02}) compared to tamoxifen alone. The benefit of the addition of OFS to tamoxifen was mostly observed in patients younger than 40 years where the pooled HRs of DFS was 0.76 (95% CI: 0.63-0.91; P= 0.004), and in those who received adjuvant chemotherapy with pooled HRs of DFS 0.80 (95% CI: 0.65-0.99, P= 0.042). There was an increase in the incidence of all grade musculoskeletal symptoms and high-grade hot flushes with the addition of OFS with risk ratios of 1.12 (95% CI: 1.07-1.17, P< 0.001) and 2.14 (95% CI: 1.01-4.51, P= 0.047) respectively.

Conclusion: Our analysis indicates that the addition of OFS to tamoxifen improves DFS and OS. This strategy could be considered in patients in which tamoxifen alone is not deemed sufficient or in case of poor tolerance to OFS with aromatase inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.currproblcancer.2020.100592DOI Listing
December 2020

Fertility preservation in patients with mutation.

Ecancermedicalscience 2020 6;14:1033. Epub 2020 May 6.

Breast Cancer Centre, Hospital Zambrano Hellion, Tecnologico de Monterrey, San Pedro Garza Garcia, Mexico.

Evidence suggests a likely negative impact of deleterious mutations on female fertility. Hence, different studies have aimed to address the reproductive potential and performance of fertility preservation strategies in -mutated breast cancer patients with a prime focus on their safety and efficacy. However, several uncertainties exist in many domains of this field. The aim of the current paper is to overview the reproductive potential and fertility preservation options in breast and ovarian cancer patients harbouring a mutation. We also discuss pre-implantation genetic testing in an attempt to help physicians during oncofertility counselling of these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3332/ecancer.2020.1033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221131PMC
May 2020

Understanding the benefits and challenges of first-line cyclin-dependent kinases 4 and 6 inhibitors in advanced breast cancer among postmenopausal women.

Breast J 2020 04 10;26(4):630-642. Epub 2019 Nov 10.

American University of Beirut Medical Center, Beirut, Lebanon.

Endocrine therapy (ET) has been regarded for many years as the standard treatment for patients with hormone receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer (ABC) without visceral crisis. However, the efficacy of single-agent ET is constrained by the development of resistance, attributed to alterations in several intracellular signaling pathways, including those related to cell cycle dysregulation. The cyclin-dependent kinases 4 and 6 (CDK4/6) are principal regulators of cell cycle progression from the G1-phase into the DNA synthesis (S)-phase. In vitro inhibition of CDK4/6 activity has potent antiproliferative properties against luminal breast cancer cell lines, which are enhanced when combined with traditional ET. This has led to a substantial interest in targeting this pathway to overcome endocrine resistance in the clinic. Three selective CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) have been approved as first-line therapy in combination with an aromatase inhibitor, or fulvestrant in the case of ribociclib in patients with ER+/HER2- ABC. To date, there is no clue as to which subgroup of patients might benefit most from these combinations. Here, we outline some of the established approaches to overcome endocrine resistance, with special emphasis on the unique mechanism of action of CDK4/6 inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tbj.13637DOI Listing
April 2020

Lucitanib for the Treatment of HR/HER2 Metastatic Breast Cancer: Results from the Multicohort Phase II FINESSE Study.

Clin Cancer Res 2020 01 16;26(2):354-363. Epub 2019 Oct 16.

European Institute of Oncology, IRCCS, and University of Milan, Milan, Italy.

Purpose: The gene is amplified in 14% of patients with HR /HER2 breast cancer. Efficacy and safety of lucitanib, an inhibitor of VEGFR1-3, FGFR1-3, and PDGFRα/β, were assessed.

Patients And Methods: Patients with HR /HER2 metastatic breast cancer (MBC) received oral lucitanib in three centrally confirmed cohorts: (i) amplified, (ii) nonamplified, 11q13 amplified, and (iii) and 11q13 nonamplified. Key inclusion criteria included Eastern Cooperative Oncology Group Performance Status ≤2, ≥1 line of anticancer therapy, but ≤2 lines of chemotherapy. Primary endpoint was overall response rates (ORR) by RECIST1.1. Simon's two-stage design was used: If ≥2 patients responded among 21 patients, 20 additional patients could be enrolled in each cohort. copy-number variation (CNV) was determined by FISH and droplet digital PCR, whereas FGFR1 expression was determined by IHC.

Results: Seventy-six patients (32/18/26 in cohorts 1/2/3) from nine countries were enrolled. The prespecified primary endpoint was met in cohort 1 with ORR of 19% [95% confidence interval (CI), 9%-35%], but not in cohorts 2 and 3 with ORR of 0% (95% CI, 0%-18%) and 15% (95% CI, 6%-34%), respectively. Frequent adverse events included hypertension (87%), hypothyroidism (45%), nausea (33%), and proteinuria (32%). Exploratory biomarker analyses suggested higher ORR in patients with high amplification (≥4 CNV) than those without high amplification (22% vs. 9%). ORR in patients with FGFR1-high tumors (IHC, H-score ≥50) was 25% versus 8% in FGFR1-low cancers.

Conclusions: Lucitanib had modest antitumor activity and significant hypertension-related toxicity in patients with HR /HER2 MBC. Although based on small sample sizes, exploratory biomarker analyses suggested that patients with high amplification or expression might derive greater benefit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-1164DOI Listing
January 2020

Dose-Ranging and Cohort-Expansion Study of Monalizumab (IPH2201) in Patients with Advanced Gynecologic Malignancies: A Trial of the Canadian Cancer Trials Group (CCTG): IND221.

Clin Cancer Res 2019 10 15;25(20):6052-6060. Epub 2019 Jul 15.

Canadian Cancer Trials Group, Kingston, Ontario, Canada.

Purpose: Monalizumab binds CD94/NKG2A, preventing HLA-E inhibition of tumor lymphocytes. A dose-ranging/cohort expansion trial of monalizumab for recurrent gynecologic malignancies was conducted to determine the recommended phase II dose (RP2D) and to explore clinical activity, pharmacokinetics, pharmacodynamics, safety, and immunogenicity.

Patients And Methods: Participants (and part 2 expansion cohorts) included (i) platinum-sensitive ovarian, (ii) platinum-resistant ovarian, (iii) squamous cervical (CX), and (iv) epithelial endometrial (END) carcinomas. Part 1 assessed monalizumab at 1, 4, or 10 mg/kg every 2 weeks. In part 2, ≥4 patients/cohort underwent pre- and on-treatment tumor biopsies. Preset criteria determined cohort expansion.

Results: A total of 58 participants were evaluable. The RP2D was 10 mg/kg i.v. every 2 weeks. Dose proportionality and 100% NKG2A saturation were observed. Related adverse events were mild: headache, abdominal pain, fatigue, nausea, and vomiting. Grade 3 related adverse events were nausea (1), vomiting (1), dehydration (1), fatigue (2), anorexia (1), dyspnea (1), and proctitis (1). Dose-limiting toxicities were not observed. Hematologic and biochemical changes were mild and not dose related. Best response was SD: part 1, 7 of 18 (39%) [3.4 months (1.4-5.5)], and part 2, 7 of 39 (18%) [1.7 months (CX) to 14.8 months (END)]. Neither a predictive biomarker for SD nor evidence of pharmacodynamic effects was identified. There was a trend to significance between a reduction in lymphocyte HLA-E total score and pharmacodynamics.

Conclusions: Monalizumab 10 mg/kg i.v. every 2 week is well tolerated in patients with pretreated gynecologic cancers. Short-term disease stabilization was observed. Future studies should assess combinations with other agents, including immunotherapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-0298DOI Listing
October 2019

IPH4102, a first-in-class anti-KIR3DL2 monoclonal antibody, in patients with relapsed or refractory cutaneous T-cell lymphoma: an international, first-in-human, open-label, phase 1 trial.

Lancet Oncol 2019 08 25;20(8):1160-1170. Epub 2019 Jun 25.

Stanford Cancer Institute, Stanford, CA, USA.

Background: IPH4102 is a first-in-class monoclonal antibody targeting KIR3DL2, a cell surface protein that is expressed in cutaneous T-cell lymphoma, and predominantly in its leukaemic form, Sézary syndrome. We aimed to assess the safety and activity of IPH4102 in cutaneous T-cell lymphoma.

Methods: We did an international, first-in-human, open-label, phase 1 clinical trial with dose-escalation and cohort-expansion parts in five academic hospitals in the USA, France, the UK, and the Netherlands. Eligible patients had histologically confirmed relapsed or refractory primary cutaneous T-cell lymphoma, an Eastern Cooperative Oncology group performance score of 2 or less, were aged 18 years or older, and had received at least two previous systemic therapies. Ten dose levels of IPH4102, administered as an intravenous infusion, ranging from 0·0001 mg/kg to 10 mg/kg, were assessed using an accelerated 3 + 3 design. The primary endpoint was the occurrence of dose-limiting toxicities during the first 2 weeks of treatment, defined as toxicity grade 3 or worse lasting for 8 or more days, except for lymphopenia. Global overall response by cutaneous T-cell lymphoma subtype was a secondary endpoint. Safety and activity analyses were done in the per-protocol population. The study is ongoing and recruitment is complete. This trial is registered with ClinicalTrials.gov, number NCT02593045.

Findings: Between Nov 4, 2015, and Nov 20, 2017, 44 patients were enrolled. 35 (80%) patients had Sézary syndrome, eight (18%) had mycosis fungoides, and one (2%) had primary cutaneous T-cell lymphoma, not otherwise specified. In the dose-escalation part, no dose limiting toxicity was reported and the trial's safety committee recommended a flat dose of 750 mg for the cohort-expansion, corresponding to the maximum administered dose. The most common adverse events were peripheral oedema (12 [27%] of 44 patients) and fatigue (nine [20%]), all of which were grade 1-2. Lymphopenia was the most common grade 3 or worse adverse event (three [7%]). One patient developed possibly treatment-related fulminant hepatitis 6 weeks after IPH4102 discontinuation and subsequently died. However, the patient had evidence of human herpes virus-6B infection. Median follow-up was 14·1 months (IQR 11·3-20·5). A confirmed global overall response was achieved in 16 (36·4% [95% CI 23·8-51·1]) of 44 patients, and of those, 15 responses were observed in 35 patients with Sézary syndrome (43% [28·0-59·1]).

Interpretation: IPH4102 is safe and shows encouraging clinical activity in patients with relapsed or refractory cutaneous T-cell lymphoma, particularly those with Sézary syndrome. If confirmed in future trials, IPH4102 could become a novel treatment option for these patients. A multi-cohort, phase 2 trial (TELLOMAK) is underway to confirm the activity in patients with Sézary syndrome and explore the role of IPH4102 in other subtypes of T-cell lymphomas that express KIR3DL2.

Funding: Innate Pharma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(19)30320-1DOI Listing
August 2019

Knowledge, attitudes and practice of physicians towards fertility and pregnancy-related issues in youngBRCA-mutated breast cancer patients.

Reprod Biomed Online 2019 May 10;38(5):835-844. Epub 2019 Jan 10.

Fertility Clinic, Research Laboratory on Human Reproduction, CUB-Erasme and Université Libre de Bruxelles, Brussels, Belgium.

Research Question: This study explored the knowledge, attitudes and practice of physicians towards fertility and pregnancy-related issues in young BRCA-mutated breast cancer patients.

Design: Physicians attending two international breast cancer conferences completed a 26-item questionnaire exploring fertility preservation, pregnancy during (BCP) or after breast cancer. A statistical comparison was carried out of the responses exploring the same issues in young breast cancer patients overall or specifically in those with BRCA mutations.

Results: The survey was completed by 273 physicians. Ovarian tissue cryopreservation (33% versus 40%; P = 0.009) and gonadotrophin-releasing hormone analogues during chemotherapy (74% versus 81%; P = 0.001) were less commonly suggested in BRCA-mutated patients than in the overall breast cancer population. 42% of respondents agreed or were neutral on the statement that ovarian stimulation should not be considered safe in BRCA-mutated breast cancer patients. 45% and 30% agreed or were neutral on the statement that pregnancy in breast cancer survivors may increase the risk of recurrence in BRCA-mutated patients or in the overall breast cancer population, respectively (P < 0.001). 15% and 3% disagreed that transplanting the cryopreserved ovarian tissue can be considered safe in BRCA-mutated patients or in the overall breast cancer population, respectively (P < 0.001). 33.3% were against the addition of platinum agents as neoadjuvant chemotherapy in BRCA-mutated patients with BCP.

Conclusions: Several misconceptions on fertility preservation and pregnancy-related issues in breast cancer patients persist even among physicians directly involved in breast cancer care. Focused research efforts to address these issues in BRCA-mutated breast cancer patients and education to improve physicians' knowledge and adherence to available guidelines are urgently needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rbmo.2018.11.031DOI Listing
May 2019

Pregnancies during and after trastuzumab and/or lapatinib in patients with human epidermal growth factor receptor 2-positive early breast cancer: Analysis from the NeoALTTO (BIG 1-06) and ALTTO (BIG 2-06) trials.

Cancer 2019 01 18;125(2):307-316. Epub 2018 Oct 18.

Department of Medicine, Institut Jules Bordet and Université Libre de Bruxelles (ULB), Brussels, Belgium.

Background: Limited data exist on the safety of using anti-human epidermal growth factor receptor 2 (HER2) targeted agents during pregnancy. To date, only retrospective studies have assessed the prognosis of patients with a pregnancy after prior early breast cancer, with no data in HER2-positive patients.

Methods: The Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) trial and the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial were randomized phase 3 trials for patients with HER2-positive early breast cancer. In both trials, pregnancy information was prospectively collected. Pregnancy outcomes were compared between patients unintentionally exposed to trastuzumab and/or lapatinib during gestation (the exposed group) and those who became pregnant after trastuzumab and/or lapatinib completion (the unexposed group). In the ALTTO trial, disease-free survival (DFS) was compared between pregnant patients and those aged 40 years or younger without a subsequent pregnancy via an extended Cox model with time-varying covariates to account for a guarantee-time bias.

Results: Ninety-two patients (12 in the exposed group and 80 in the unexposed group) had a pregnancy: 7 in the NeoALTTO trial and 85 in the ALTTO trial. Seven patients (58.3%) in the exposed group and 10 patients (12.5%) in the unexposed group opted for an induced abortion; in the unexposed group, 10 patients (12.5%) had a spontaneous abortion. No pregnancy/delivery complications were reported for the remaining cases, who successfully completed their pregnancy, with the exception of 1 fetus with trisomy 21 (Down syndrome). No significant difference in DFS (adjusted hazard ratio, 1.12; 95% confidence interval, 0.52-2.42) was observed between young patients with a pregnancy (n = 85) and young patients without a pregnancy (n = 1307).

Conclusions: For patients with HER2-positive early breast cancer, having a pregnancy after treatment completion appears to be safe without compromising fetal outcome or maternal prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.31784DOI Listing
January 2019

The BCY3/BCC 2017 survey on physicians' knowledge, attitudes and practice towards fertility and pregnancy-related issues in young breast cancer patients.

Breast 2018 Dec 22;42:41-49. Epub 2018 Aug 22.

Fertility and Procreation Unit, Gynecologic Oncology Department, IRCCS European Institute of Oncology, European School of Oncology (ESO), Milan, Italy.

Background: Fertility and pregnancy-related issues are major concerns for young breast cancer patients. Limited data are available on physicians' knowledge, attitudes and practice in these fields.

Methods: A 26-item questionnaire exploring 3 different topics (fertility preservation, pregnancy after breast cancer and breast cancer during pregnancy) was sent by email to physicians attending the 2016 3rd European School of Oncology (ESO) - European Society for Medical Oncology (ESMO) Breast Cancer in Young Women Conference (BCY3) and the 15th St. Gallen International Breast Cancer Conference 2017 (BCC 2017). Given the selected sample, survey respondents were expected to have a higher than average interest in the management of breast cancer patients. Descriptive analyses were performed.

Results: A total of 273 physicians (105 at BCY3 and 168 at BCC 2017) completed the survey; 37.0%, 46.9% and 34.8% reported never having consulted the available international guidelines on fertility preservation, pregnancy after breast cancer and management of breast cancer during pregnancy, respectively. Up to 18.3% of respondents did not know if the different fertility preservation options were available in their country; 22.3% suggested that controlled ovarian stimulation should not be considered safe in patients with hormone receptor-positive disease. A total of 30.4% of respondents agreed or were neutral on the statement that pregnancy in breast cancer survivors may increase the risk of recurrence. Regarding breast cancer during pregnancy, 23.8% and 38.1% disagreed or were neutral on the statements that endocrine therapy and anti-HER2 agents should be avoided during pregnancy, respectively.

Conclusions: Further educational initiatives are needed to improve physicians' knowledge and adherence to available guidelines when addressing fertility and pregnancy-related issues in young breast cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.breast.2018.08.099DOI Listing
December 2018

Breast cancer diagnosed during pregnancy is associated with enrichment of non-silent mutations, mismatch repair deficiency signature and mucin mutations.

NPJ Breast Cancer 2018 6;4:23. Epub 2018 Aug 6.

1Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.

Breast cancer diagnosed during pregnancy (BCP) is a rare and highly challenging disease. To investigate the impact of pregnancy on the biology of breast cancer, we conducted a comparative analysis of a cohort of BCP patients and non-pregnant control patients by integrating gene expression, copy number alterations and whole genome sequencing data. We showed that BCP exhibit unique molecular characteristics including an enrichment of non-silent mutations, a higher frequency of mutations in mucin gene family and an enrichment of mismatch repair deficiency mutational signature. This provides important insights into the biology of BCP and suggests that these features may be implicated in promoting tumor progression during pregnancy. In addition, it provides an unprecedented resource for further understanding the biology of breast cancer in young women and how pregnancy could modulate tumor biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41523-018-0077-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078984PMC
August 2018

Tumor PIK3CA Genotype and Prognosis in Early-Stage Breast Cancer: A Pooled Analysis of Individual Patient Data.

J Clin Oncol 2018 04 22;36(10):981-990. Epub 2018 Feb 22.

Dimitrios Zardavas and Debora Fumagalli, Breast International Group; Christos Sotiriou, Université Libre de Bruxelles, Brussels, Belgium; Luc te Marvelde and Roger L. Milne, Cancer Council; Roger L. Milne and Sherene Loi, University of Melbourne, Melbourne; Barry Iacopetta, University of Western Australia, Western Australia; Sandra O'Toole and Elena Lopez-Knowles, Garvan Institute of Medical Research, Darlinghurst, Australia; George Fountzilas and Vassiliki Kotoula, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki; Evangelia Razis, Hygeia Hospital; George Papaxoinis, Hippokration Hospital, Athens, Greece; Heikki Joensuu, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Mary Ellen Moynahan, Memorial Sloan Kettering Cancer Center, New York, NY; Bryan T. Hennessy, Beaumont Hospital and Royal College of Surgeons, Dublin, Ireland; Ivan Bieche, Curie Institut, Paris; Thomas Bachelot, Centre de Recherche en Cancérologie de Lyon, Lyon; Stefan Michiels, Gustave Roussy and Inserm, Univ. Paris-Sud, Univ. Paris-Saclay, Villejuif, France; Lao H. Saal, Lund University, Lund; Olle Stal, Qing Wang, and Gizeh Perez-Tenorio, Linköping University, Linköping, Sweden; Jeanette Dupont Jensen, University of Southern Denmark, on behalf of the Danish Breast Cancer Cooperative Group, Odense, Denmark; Elena Lopez-Knowles, Royal Marsden NHS Trust and Institute of Cancer Research, London; Daniel W. Rea, University of Birmingham, Birmingham, United Kingdom; Mattia Barbaraeschi, Santa Chiara Hospital, Trento, Italy; Shinzaburo Noguchi, Osaka University, Osaka Japan; Hatem A. Azim Jr, American University of Beirut (AUB), Beirut, Lebanon; Enrique Lerma, Universitat Autònoma de Barcelona, Barcelona, Spain; Cornelis J.H. can de Velde, Leiden University Medical Center, Leiden, the Netherlands; Vicky Sabine, University of Guelph, Guelph; John M.S. Bartlett, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

Purpose Phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA) mutations are frequently observed in primary breast cancer. We evaluated their prognostic relevance by performing a pooled analysis of individual patient data. Patients and Methods Associations between PIK3CA status and clinicopathologic characteristics were tested by applying Cox regression models adjusted for age, tumor size, nodes, grade, estrogen receptor (ER) status, human epidermal growth factor receptor 2 (HER2) status, treatment, and study. Invasive disease-free survival (IDFS) was the primary end point; distant disease-free survival (DDFS) and overall survival (OS) were also assessed, overall and by breast cancer subtypes. Results Data from 10,319 patients from 19 studies were included (median OS follow-up, 6.9 years); 1,787 patients (17%) received chemotherapy, 4,036 (39%) received endocrine monotherapy, 3,583 (35%) received both, and 913 (9%) received none or their treatment was unknown. PIK3CA mutations occurred in 32% of patients, with significant associations with ER positivity, increasing age, lower grade, and smaller size (all P < .001). Prevalence of PIK3CA mutations was 18%, 22%, and 37% in the ER-negative/HER2-negative, HER2-positive, and ER-positive/HER2-negative subtypes, respectively. In univariable analysis, PIK3CA mutations were associated with better IDFS (HR, 0.77; 95% CI, 0.71 to 0.84; P < .001), with evidence for a stronger effect in the first years of follow-up (0 to 5 years: HR, 0.73; 95% CI, 0.66 to 0.81; P < .001; 5 to 10 years: HR, 0.82; 95% CI, 0.68 to 0.99; P = .037); > 10 years: (HR, 1.15; 95% CI, 0.84 to 1.58; P = .38; P heterogeneity = .02). In multivariable analysis, PIK3CA genotype remained significant for improved IDFS ( P = .043), but not for the DDFS and OS end points. Conclusion In this large pooled analysis, PIK3CA mutations were significantly associated with a better IDFS, DDFS, and OS, but had a lesser prognostic effect after adjustment for other prognostic factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2017.74.8301DOI Listing
April 2018

Response.

J Natl Cancer Inst 2018 08;110(8):919-920

Department of Internal Medicine, Division of Hematology-Oncology, American University of Beirut (AUB), Beirut, Lebanon.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djx292DOI Listing
August 2018

Response.

J Natl Cancer Inst 2018 05;110(5):541

Department of Internal Medicine, American University of Beirut (AUB), Beirut, Lebanon.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djx242DOI Listing
May 2018

Long-term Safety of Pregnancy Following Breast Cancer According to Estrogen Receptor Status.

J Natl Cancer Inst 2018 04;110(4):426-429

Department of Internal Medicine, American University of Beirut (AUB), Beirut, Lebanon.

Safety of pregnancy in women with history of estrogen receptor (ER)-positive breast cancer remains controversial. In this multicenter case-control study, 333 patients with pregnancy after breast cancer were matched (1:3) to 874 nonpregnant patients of similar characteristics, adjusting for guaranteed time bias. Survival estimates were calculated using the Kaplan-Meier analysis; groups were compared with the log-rank test. All reported P values were two-sided. At a median follow-up of 7.2 years after pregnancy, no difference in disease-free survival was observed between pregnant and nonpregnant patients with ER-positive (hazard ratio [HR] = 0.94, 95% confidence interval [CI] = 0.70 to 1.26, P = .68) or ER-negative (HR = 0.75, 95% CI = 0.53 to 1.06, P = .10) disease. No overall survival (OS) difference was observed in ER-positive patients (HR = 0.84, 95% CI = 0.60 to 1.18, P = .32); ER-negative patients in the pregnant cohort had better OS (HR = 0.57, 95% CI = 0.36 to 0.90, P = .01). Abortion, time to pregnancy, breastfeeding, and type of adjuvant therapy had no impact on patients' outcomes. This study provides reassuring evidence on the long-term safety of pregnancy in breast cancer survivors, including those with ER-positive disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djx206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658852PMC
April 2018

Fertility and pregnancy issues in BRCA-mutated breast cancer patients.

Cancer Treat Rev 2017 Sep 14;59:61-70. Epub 2017 Jul 14.

Fertility Clinic, Research Laboratory on Human Reproduction, CUB-Erasme, and Université Libre de Bruxelles (U.L.B.), Brussels, Belgium.

Fertility and pregnancy-related issues represent one of the main areas of concerns for young women with breast cancer. Carrying a germline deleterious BRCA mutation adds additional burden on this regard due to the specific issues that should be considered during the oncofertility counseling of this special patient group. Despite the availability of a growing amount of data in the general breast cancer population on the feasibility and safety of fertility preservation and pregnancy after diagnosis, numerous challenges remain for BRCA-mutated breast cancer patients in whom very limited studies have been performed so far. Therefore, studies aiming to address the specific issues of these patients, including the impact of the mutation on their fertility potential, the safety and efficacy of the different strategies for fertility preservation, and the feasibility of having a pregnancy after diagnosis, should be considered a research priority. The aim of the present manuscript is to perform an in depth overview on the role of BRCA mutations in breast cancer with a specific focus on their impact on reproductive potential, and to discuss the fertility and pregnancy issues faced by BRCA-mutated breast cancer patients. The final goal of this manuscript is to highlight current and upcoming knowledge in this field for trying to help physicians dealing with these patients during oncofertility counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ctrv.2017.07.001DOI Listing
September 2017

Regional Nodal Irradiation After Breast Conserving Surgery for Early HER2-Positive Breast Cancer: Results of a Subanalysis From the ALTTO Trial.

J Natl Cancer Inst 2017 08;109(8)

Breast Data Center, Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.

Background: Two randomized trials recently demonstrated that regional nodal irradiation (RNI) could reduce the risk of recurrence in early breast cancer; however, these trials were conducted in the pretrastuzumab era. Whether these results are applicable to human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients treated with anti-HER2-targeted therapy is unknown.

Methods: This retrospective analysis was performed on patients with node-positive breast cancer who were enrolled in the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization phase III adjuvant trial and subjected to BCS. The primary objective of the present study was to examine the effect of RNI on disease-free survival (DFS). A multivariable cox regression analysis adjusted for number of positive lymph nodes, tumor size, grade, age, hormone receptors status, presence of macrometastatis, treatment arm, and chemotherapy timing was carried out to investigate the relationship between RNI and DFS.

Results: One thousand six hundred sixty-four HER2-positive breast cancer patients were included, of whom 878 (52.8%) had received RNI to the axillary, supraclavicular, and/or internal mammary lymph nodes. Patients in the RNI group had higher nodal burden and more frequently had tumors larger than 2 cm. At a median follow-up of 4.5 years, DFS was 84.3% in the RNI group and 88.3% in the non-RNI group. No differences in regional recurrence (0.9 % vs 0.6 %) or in overall survival (93.6% vs 95.3%) were observed between the two groups. After adjustment in multivariable analysis, there was no statistically significant association between RNI and DFS (hazard ratio = 0.96, 95% confidence interval = 0.71 to 1.29).

Conclusions: Our analysis did not demonstrate a DFS benefit of RNI in HER2-positive, node-positive patients treated with adjuvant HER2-targeted therapy. The benefit of RNI in HER2-positive breast cancer needs further testing within randomized clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djw331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279283PMC
August 2017

Impact of Diabetes, Insulin, and Metformin Use on the Outcome of Patients With Human Epidermal Growth Factor Receptor 2-Positive Primary Breast Cancer: Analysis From the ALTTO Phase III Randomized Trial.

J Clin Oncol 2017 May 13;35(13):1421-1429. Epub 2017 Mar 13.

Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Université Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of Medicine, Baltimore, MD; Lyndsay Harris, Case Western Reserve University School of Medicine, Cleveland, OH; Julie Gralow, Seattle Cancer Care Alliance, Seattle, WA; Alvaro Moreno-Aspitia, Mayo Clinic, Jacksonville, FL; Michael Andersson, Rigshospitalet University Hospital Copenhagen, Denmark; Judith Kroep, Leiden University Medical Center, Leiden, the Netherlands; Tanja Cufer, University Clinic Golnik Medical Faculty, Ljubljana, Slovenia; Sergio D. Simon, Hospital Israelita Albert Einstein; Sergio D. Simon, Grupo Brasileiro de Estudos do Cancer de Mama, São Paulo, Brazil; Pamela Salman, Fundación Arturo López Pérez, Santiago, Chile; Masakazu Toi, Kyoto University, Kyoto, Japan; Maccon Keane, University Hospital Galway, Galway; and Maccon Keane, Cancer Trials Ireland, Dublin, Ireland.

Purpose Previous studies have suggested an association between metformin use and improved outcome in patients with diabetes and breast cancer. In the current study, we aimed to explore this association in human epidermal growth factor receptor 2 (HER2 ) -positive primary breast cancer in the context of a large, phase III adjuvant trial. Patients and Methods The ALTTO trial randomly assigned patients with HER2-positive breast cancer to receive 1 year of either trastuzumab alone, lapatinib alone, their sequence, or their combination. In this substudy, we evaluated whether patients with diabetes at study entry-with or without metformin treatment-were associated with different disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) compared with patients without diabetes. Results A total of 8,381 patients were included in the current analysis: 7,935 patients (94.7%) had no history of diabetes at diagnosis, 186 patients (2.2%) had diabetes with no metformin treatment, and 260 patients (3.1%) were diabetic and had been treated with metformin. Median follow-up was 4.5 years (0.16 to 6.31 years), at which 1,205 (14.38%), 929 (11.08%), and 528 (6.3%) patients experienced DFS, DDFS, and OS events, respectively. Patients with diabetes who had not been treated with metformin experienced worse DFS (multivariable hazard ratio [HR], 1.40; 95% CI, 1.01 to 1.94; P = .043), DDFS (multivariable HR, 1.56; 95% CI, 1.10 to 2.22; P = .013), and OS (multivariable HR, 1.87; 95% CI, 1.23 to 2.85; P = .004). This effect was limited to hormone receptor-positive patients. Whereas insulin treatment was associated with a detrimental effect, metformin had a salutary effect in patients with diabetes who had HER2-positive and hormone receptor-positive breast cancer. Conclusion Metformin may improve the worse prognosis that is associated with diabetes and insulin treatment, mainly in patients with primary HER2-positive and hormone receptor-positive breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2016.69.7722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455460PMC
May 2017

The prognostic performance of Adjuvant! Online and Nottingham Prognostic Index in young breast cancer patients.

Br J Cancer 2016 Dec 1;115(12):1471-1478. Epub 2016 Nov 1.

Department of Medicine, BrEAST Data Centre, Institut Jules Bordet, and l'Université Libre de Bruxelles (U.L.B.), Boulevard de Waterloo 121, 1000 Brussels, Belgium.

Background: Limited data are available on the prognostic performance of Adjuvant! Online (AOL) and Nottingham Prognostic Index (NPI) in young breast cancer patients.

Methods: This multicentre hospital-based retrospective cohort study included young (⩽40 years) and older (55-60 years) breast cancer patients treated from January 2000 to December 2004 at four large Belgian and Italian institutions. Predicted 10-year overall survival (OS) and disease-free survival (DFS) using AOL and 10-year OS using NPI were calculated for every patient. Tools ability to predict outcomes (i.e., calibration) and their discriminatory accuracy was assessed.

Results: The study included 1283 patients, 376 young and 907 older women. Adjuvant! Online accurately predicted 10-year OS (absolute difference: 0.7%; P=0.37) in young cohort, but overestimated 10-year DFS by 7.7% (P=0.003). In older cohort, AOL significantly underestimated both 10-year OS and DFS by 7.2% (P<0.001) and 3.2% (P=0.04), respectively. Nottingham Prognostic Index significantly underestimated 10-year OS in both young (8.5%; P<0.001) and older (4.0%; P<0.001) cohorts. Adjuvant! Online and NPI had comparable discriminatory accuracy.

Conclusions: In young breast cancer patients, AOL is a reliable tool in predicting OS at 10 years but not DFS, whereas the performance of NPI is sub-optimal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/bjc.2016.359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155359PMC
December 2016

RNA Sequencing to Predict Response to Neoadjuvant Anti-HER2 Therapy: A Secondary Analysis of the NeoALTTO Randomized Clinical Trial.

JAMA Oncol 2017 Feb;3(2):227-234

Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium15Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.

Importance: In neoadjuvant trials, treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancers with dual HER2 blockade resulted in increased pathologic complete response (pCR) rates compared with each targeted agent alone. Amplification and/or overexpression of HER2 currently remains the only biomarker for therapeutic decisions, but it is insufficient to explain the heterogeneous response to anti-HER2 agents.

Objective: To investigate the ability of clinically and biologically relevant genes and gene signatures (GSs) measured by RNA sequencing to predict the efficacy of anti-HER2 agents.

Design, Setting, And Participants: The neoadjuvant NeoALTTO trial randomized 455 women with HER2-positive early-stage breast cancer to trastuzumab, lapatinib, or the combination for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide after surgery. The present substudy, which was planned in the NeoALTTO main protocol, evaluated the association of pretreatment gene expression levels defined using RNA sequencing with pCR and event-free survival (EFS).

Main Outcomes And Measures: Gene expression-based biomarkers using RNA sequencing were examined for their association with response to anti-HER2 therapy and long-term outcome.

Results: Sequencing data were available for 254 (56%) of the NeoALTTO participants (mean [SD] age of substudy participants, 48.8 [11.2] years). The expression of ERBB2/HER2 was the most significant predictor of pCR, followed by HER2-enriched subtype, ESR1, treatment arm, ER immunohistochemical analysis scores, Genomic Grade Index, immune, proliferation, and AKT/mTOR GSs. Adjusting for clinicopathological variables and treatment arms, ERBB2/HER2, HER2-enriched subtype, ESR1, and Genomic Grade Index remained significant. Immune GSs were associated with higher pCR only in the combination arm (odds ratio, 2.1; 95% CI, 1.2-4.0; interaction test P = .01), while the stroma GSs were significantly associated with higher pCR in the single arms and with lower pCR in the combination arm (odds ratio, 0.46; 95% CI, 0.25-0.84; P = .009). None of the evaluated variables was associated with EFS after correction for multiple testing, but this analysis was underpowered.

Conclusions And Relevance: High levels of ERBB2/HER2 and low levels of ESR1 were associated with pCR in all treatment arms. In the combination arm, high expression of immune and stroma GSs were significantly associated with higher and lower pCR rates, respectively, and should be further explored as candidate predictive markers.

Trial Registration: clinicaltrials.gov Identifier: NCT00553358.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2016.3824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374044PMC
February 2017

What is the role of informed decision-making?

Expert Rev Anticancer Ther 2016 09 12;16(9):893. Epub 2016 Aug 12.

a BrEAST Data Centre, Department of Medicine, Institut Jules Bordet , Université Libre de Bruxelles , Brussels , Belgium.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14737140.2016.1218280DOI Listing
September 2016
-->