Hatem A. Azim

Dissecting the Heterogeneity of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers. It is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. TNBC is associated with a significantly higher probability of relapse and poorer overall survival in the first few years after diagnosis when compared with other breast cancer subtypes. This is observed despite its usual high sensitivity to chemotherapy. In the advanced setting, responses observed with chemotherapy lack durability. Early-stage clinical studies suggested impressive potential when a poly (ADP-ribose) polymerase (PARP) inhibitor is given for the treatment of advanced TNBC with BRCA gene dysfunction. The molecular complexity of TNBC has led to proposed subclassifications, which will be of great value for the development of targeted therapies. In this review, we discuss the biology of TNBC at the pathologic and the molecular levels. We also elaborate on the role of systemic therapies and the results of the first phase III clinical trial evaluating the addition of iniparib, a novel investigational anticancer agent that does not possess characteristics typical of the PARP inhibitor class, in combination with chemotherapy in advanced TNBC.

Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

F. A. Peccatori1, H. A. Azim Jr2, R. Orecchia3, H. J. Hoekstra4, N. Pavlidis5, V. Kesic6 & G. Pentheroudakis5, on behalf of the ESMO Guidelines Working Group* Fertility and Procreation Unit, Division of Gynaecologic Oncology, European Institute of Oncology, Milan, Italy; Department of Medicine, BrEAST Data Centre, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Department of Radiotherapy, European Institute of Oncology, Milan, Italy; Department of Surgical Oncology, University Medical Centre Groningen, Groningen, The Netherlands; Department of Medical Oncology, University of Ioannina, Ioannina, Greece; Department of Obstetrics and Gynaecology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia;

Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response

BACKGROUND Findings from the randomised phase 3 NeoALTTO trial in women with HER2-positive early breast cancer showed that the combination of lapatinib and trastuzumab significantly improved rates of pathological complete response compared with either drug alone. Here, we report data for the prespecified secondary endpoints of event-free and overall survival, and assess the association between these outcomes and pathological complete response. METHODS We enrolled women with HER2-positive early breast cancer and randomly assigned them to receive oral lapatinib (1500 mg), intravenous trastuzumab (4 mg/kg loading dose followed by 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab (same dose as for single agent) in combination for 6 weeks, followed by an additional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel (80 mg/m(2)). Definitive surgery was done 4 weeks after the last dose of paclitaxel. After surgery, women received three cycles of FEC (fluorouracil 500 mg/m(2) plus epirubicin 100 mg/m(2) plus cyclophosphamide 500 mg/m(2)) given intravenously every 3 weeks, followed by 34 weeks of the same assigned neoadjuvant anti-HER2 therapy. The primary endpoint was pathological complete response. Secondary endpoints included event-free and overall survival (intention-to-treat analysis), and the association between pathological complete response and event-free or overall survival (analysed by landmark analysis at 30 weeks after randomisation). Follow-up is ongoing, and the trial is registered with ClinicalTrials.gov, number NCT00553358. FINDINGS 455 patients were enrolled: 154 (34%) were assigned to the lapatinib group, 149 (33%) to the trastuzumab group, and 152 (33%) to the lapatinib plus trastuzumab group. At an event follow-up of 3·77 years (IQR 3·50-4·22), 3-year event-free survival was 78% (95% CI 70-84) in the lapatinib group, 76% (68-82) in the trastuzumab group, and 84% (77-89) in the combination group. Event-free survival did not differ between the lapatinib and trastuzumab groups (HR 1·06, 95% CI 0·66-1·69, p=0·81), nor between the combination and trastuzumab groups (0·78, 0·47-1·28, p=0·33). Median survival follow-up was 3·84 years (IQR 3·60-4·24), and 3-year overall survival was 93% (95% CI 87-96) for lapatinib, 90% (84-94) for trastuzumab, and 95% (90-98) for combination therapy. Overall survival did not significantly differ between the lapatinib and trastuzumab groups (HR 0·86, 95% CI 0·45-1·63, p=0·65), nor between the combination and trastuzumab groups (0·62, 0·30-1·25, p=0·19). Landmark analyses showed that 3-year event-free survival was significantly improved for women who achieved pathological complete response compared with those who did not (HR 0·38, 95% CI 0·22-0·63, p=0·0003), as was 3-year overall survival (0·35, 0·15-0·70, p=0·005). Adverse events occurred in 149 (99%) patients receiving lapatinib, 142 (96%) patients receiving trastuzumab, and 147 (99%) patients receiving combination therapy. The most common adverse events were diarrhoea, rash or erythema, hepatic adverse events, and neutropenia (not related to FEC administration), and were consistent with known safety profiles of lapatinib and trastuzumab. Three primary and eight secondary cardiac events occurred, with no significant difference in incidence between treatment groups for primary or any cardiac events. INTERPRETATION Although event-free survival or overall survival did not differ between treatment groups, findings from our study confirm that patients who achieve pathological complete response after neoadjuvant anti-HER2 therapy have longer event-free and overall survival than do patients without pathological complete response. FUNDING GlaxoSmithKline.

Elucidating Prognosis and Biology of Breast Cancer Arising in Young Women Using Gene Expression Profiling

Purpose: Breast cancer in young women is associated with poor prognosis. We aimed to define the role of gene expression signatures in predicting prognosis in young women and to understand biological differences according to age. Experimental Design: Patients were assigned to molecular subtypes [estrogen receptor (ER)+/HER2−; HER2+, ER−/HER2−)] using a three-gene classifier. We evaluated whether previously published proliferation, stroma, and immune-related gene signatures added prognostic information to Adjuvant! online and tested their interaction with age in a Cox model for relapse-free survival (RFS). Furthermore, we evaluated the association between candidate age-related genes or gene sets with age in an adjusted linear regression model. Results: A total of 3,522 patients (20 data sets) were eligible. Patients aged 40 years or less had a higher proportion of ER−/HER2− tumors (P < 0.0001) and were associated with poorer RFS after adjustment for breast cancer subtype, tumor size, nodal status, and histologic grade and stratification for data set and treatment modality (HR = 1.34, 95% CI = 1.10–1.63, P = 0.004). The proliferation gene signatures showed no significant interaction with age in ER+/HER2− tumors after adjustment for Adjuvant! online. Further analyses suggested that breast cancer in the young is enriched with processes related to immature mammary epithelial cells (luminal progenitors, mammary stem, c-kit, RANKL) and growth factor signaling in two independent cohorts (n = 1,188 and 2,334). Conclusions: Proliferation-related prognostic gene signatures can aid treatment decision-making for young women. However, breast cancer arising at a young age seems to be biologically distinct beyond subtype distribution. Separate therapeutic approaches such as targeting RANKL or mammary stem cells could therefore be needed. Clin Cancer Res; 18(5); 1341–51. ©2012 AACR.

Cancer and fertility preservation: International recommendations from an expert meeting

In the last years, thanks to the improvement in the prognosis of cancer patients, a growing attention has been given to the fertility issues. International guidelines on fertility preservation in cancer patients recommend that physicians discuss, as early as possible, with all patients of reproductive age their risk of infertility from the disease and/or treatment and their interest in having children after cancer, and help with informed fertility preservation decisions. As recommended by the American Society of Clinical Oncology and the European Society for Medical Oncology, sperm cryopreservation and embryo/oocyte cryopreservation are standard strategies for fertility preservations in male and female patients, respectively; other strategies (e.g. pharmacological protection of the gonads and gonadal tissue cryopreservation) are considered experimental techniques. However, since then, new data have become available, and several issues in this field are still controversial and should be addressed by both patients and their treating physicians.In April 2015, physicians with expertise in the field of fertility preservation in cancer patients from several European countries were invited in Genova (Italy) to participate in a workshop on the topic of “cancer and fertility preservation”. A total of ten controversial issues were discussed at the conference. Experts were asked to present an up-to-date review of the literature published on these topics and the presentation of own unpublished data was encouraged. On the basis of the data presented, as well as the expertise of the invited speakers, a total of ten recommendations were discussed and prepared with the aim to help physicians in counseling their young patients interested in fertility preservation.Although there is a great interest in this field, due to the lack of large prospective cohort studies and randomized trials on these topics, the level of evidence is not higher than 3 for most of the recommendations highlighting the need of further research efforts in many areas of this field. The participation to the ongoing registries and prospective studies is crucial to acquire more robust information in order to provide evidence-based recommendations.

An update on PARP inhibitors—moving to the adjuvant setting

Inhibition of poly(ADP-ribose) polymerase (PARP) enzymes is a potential synthetic lethal therapeutic strategy in cancers harbouring specific DNA-repair defects, including those arising in carriers of BRCA1 or BRCA2 mutations. Since the development of first-generation PARP inhibitors more than a decade ago, numerous clinical trials have been performed to validate their safety and efficacy, bringing us to the stage at which adjuvant therapy with PARP inhibitors is now being considered as a viable treatment option for patients with breast cancer. Nevertheless, the available data do not provide clear proof that these drugs are efficacious in the setting of metastatic disease. Advancement of a therapy to the neoadjuvant and adjuvant settings without such evidence is exceptional, but seems reasonable in the case of PARP inhibitors because the target population that might benefit from this class of drugs is small and well defined. This Review describes the evolution of PARP inhibitors from bench to bedside, and provides an up-to-date description of the key published or otherwise reported clinical trials of these agents. The specific considerations and challenges that might be encountered when implementing these compounds in the adjuvant treatment of breast cancer in the clinic are also highlighted.

Prognostic Impact of Pregnancy After Breast Cancer According to Estrogen Receptor Status: A Multicenter Retrospective Study

PURPOSE We questioned the impact of pregnancy on disease-free survival (DFS) in women with history of breast cancer (BC) according to estrogen receptor (ER) status. PATIENTS AND METHODS A multicenter, retrospective cohort study in which patients who became pregnant any time after BC were matched (1:3) to patients with BC with similar ER, nodal status, adjuvant therapy, age, and year of diagnosis. To adjust for guaranteed time bias, each nonpregnant patient had to have a disease-free interval at least equal to the time elapsing between BC diagnosis and date of conception of the matched pregnant one. The primary objective was DFS in patients with ER-positive BC. DFS in the ER-negative cohort, whole population, and overall survival (OS) were secondary objectives. Subgroup analyses included DFS according to pregnancy outcome and BC-pregnancy interval. With a two-sided α = 5% and β = 20%, 645 ER-positive patients were required to detect a hazard ratio (HR) = 0.65. RESULTS A total of 333 pregnant patients and 874 matched nonpregnant patients were analyzed, of whom 686 patients had an ER-positive disease. No difference in DFS was observed between pregnant and nonpregnant patients in the ER-positive (HR = 0.91; 95% CI, 0.67 to 1.24, P = .55) or the ER-negative (HR = 0.75; 95% CI, 0.51 to 1.08, P = .12) cohorts. However, the pregnant group had better OS (HR = 0.72; 95% CI, 0.54 to 0.97, P = .03), with no interaction according to ER status (P = .11). Pregnancy outcome and BC-pregnancy interval did not seem to impact the risk of relapse. CONCLUSION Pregnancy after ER-positive BC does not seem to reduce the risk of BC recurrence.

Long-term toxic effects of adjuvant chemotherapy in breast cancer

Breast cancer is the most common malignant tumor affecting women. Adjuvant systemic therapies have been shown to have a significant impact on reducing the risk for breast cancer recurrence and overall mortality. Chemotherapy remains an important and frequently used treatment option in the adjuvant setting, and the associated short-term adverse events are very well described. However, there is insufficient information regarding the long-term sequelae of most chemotherapeutic agents. In this review, we describe different potential long-term adverse events associated with adjuvant chemotherapy in breast cancer, with a particular focus on long-term cardiac toxicity, secondary leukemia, cognitive function, and neurotoxicity. In addition, we discuss the effect of adjuvant chemotherapy on fertility and sexual function of young breast cancer patients. These adverse events are frequently overshadowed by the well-demonstrated clinical efficacy and/or reassuring short-term safety profiles of the different chemotherapy regimens commonly used today. We believe that a proper understanding and appreciation of these adverse events will enable us to refine our strategies for managing breast cancer. The fact that adjuvant chemotherapy is often given to patients who might not really need it urges us to consider the whole spectrum of chemotherapy risks versus benefits to maximize benefit without compromising quality of life.

Safety of pregnancy following breast cancer diagnosis: A meta-analysis of 14 studies

BACKGROUND Due to the rising trend of delaying pregnancy to later in life, more women are diagnosed with breast cancer before completing their families. Therefore, enquiry into the feasibility and safety of pregnancy following breast cancer diagnosis is on the rise. Available evidence suggests that women with a history of breast cancer are frequently advised against future conception for fear that pregnancy could adversely affect their breast cancer outcome. Hence, we conducted a meta-analysis to understand the effect of pregnancy on overall survival of women with a history of breast cancer. METHODS Two of the authors independently performed a literature search up to September 2009 with no language restrictions. Eligible studies were published retrospective control-matched, population-based and hospital-based studies that have addressed the impact of pregnancy on the overall survival of women with history of breast cancer. Pooling of data was done using the random effect model. Unpublished statistics from three studies were obtained to perform further subgroup and sensitivity analyses. This included examining the effect of pregnancy according to age at diagnosis, healthy mother effect, type of study, nodal status and other parameters. RESULTS Fourteen studies were included in this meta-analysis (1244 cases and 18,145 controls). Women who got pregnant following breast cancer diagnosis had a 41% reduced risk of death compared to women who did not get pregnant [PRR: 0.59 (90% confidence interval (CI): 0.50-0.70)]. This difference was seen irrespective of the type of the study and particularly in women with history of node-negative disease. In a subgroup analysis, we compared the outcome of women with history of breast cancer who became pregnant to breast cancer patients who did not get pregnant and were known to be free of relapse. In this analysis, we did not find significant differences in survival between either group [PRR: 0.85; 95% CI: 0.53-1.35]. CONCLUSIONS This study confirms that pregnancy in women with history of breast cancer is safe and does not compromise their overall survival. Hence, breast cancer survivors should not be denied the opportunity of future conception.

Treatment of the pregnant mother with cancer: a systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part I: Solid tumors.

The association of cancer and pregnancy is increasingly encountered nowadays in clinical practice. Due to the relative rarity of the situation, it lacks a systematized approach. Different systemic therapies are used in managing cancer with uncertainty regarding the potential hazards they could pose on the pregnancy and/or the fetus. We have performed a systematic review of literature to identify all reports addressing cancer patients who were exposed to any of the known systemic therapies during the course of the pregnancy. The results were discussed in two parts; part I addresses pregnant patients with solid tumors while part I for those with hematological malignancies. In part I, we identified different solid tumors diagnosed and treated during the course of pregnancy. Breast cancer was the most commonly treated followed by ovarian cancer. Other tumors were treated as well including lung cancer, cervical cancer, sarcoma and melanomas. It is important to acknowledge the intent of therapy (palliative vs. curative) and the patients has to be properly counseled to reach an informed decision. We aim to provide a more robust consensus on how to approach these cases and provide a higher degree of evidence to support the safety of applying certain management strategies over the other.