Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer.

BACKGROUND: Prospective data on the risk of recurrence among women with hormone receptor-positive early breast cancer who temporarily discontinue endocrine therapy to attempt pregnancy are lacking. METHODS: We conducted a single-group trial in which we evaluated the temporary interruption of adjuvant endocrine therapy to attempt pregnancy in young women with previous breast cancer. Eligible women were 42 years of age or younger; had had stage I, II, or III disease; had received adjuvant endocrine therapy for 18 to 30 months; and desired pregnancy. The primary end point was the number of breast cancer events (defined as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer) during follow-up. The primary analysis was planned to be performed after 1600 patient-years of follow-up. The prespecified safety threshold was the occurrence of 46 breast cancer events during this period. Breast cancer outcomes in this treatment-interruption group were compared with those in an external control cohort consisting of women who would have met the entry criteria for the current trial. RESULTS: Among 516 women, the median age was 37 years, the median time from breast cancer diagnosis to enrollment was 29 months, and 93.4% had stage I or II disease. Among 497 women who were followed for pregnancy status, 368 (74.0%) had at least one pregnancy and 317 (63.8%) had at least one live birth. In total, 365 babies were born. At 1638 patient-years of follow-up (median follow-up, 41 months), 44 patients had a breast cancer event, a result that did not exceed the safety threshold. The 3-year incidence of breast cancer events was 8.9% (95% confidence interval [CI], 6.3 to 11.6) in the treatment-interruption group and 9.2% (95% CI, 7.6 to 10.8) in the control cohort. CONCLUSIONS: Among select women with previous hormone receptor-positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort. Further follow-up is critical to inform longer-term safety. (Funded by ETOP IBCSG Partners Foundation and others; POSITIVE ClinicalTrials.gov number, NCT02308085.).

Obstetric and neonatal outcomes following taxane use during pregnancy: a systematic review.

BACKGROUND: The use of taxanes following the first trimester of pregnancy is endorsed by current clinical guidelines. However, evidence regarding their safety in terms of obstetric and neonatal outcomes is limited. METHODS: A comprehensive literature search was performed using the MEDLINE, CENTRAL and Web of Sciences databases from their inception up to 12/16/2022. Eligibility criteria included gestational taxane use, presentation of original findings, and individual case data presented. A descriptive statistical analysis was undertaken. RESULTS: A total of 159 patients treated with taxane-containing regimens during pregnancy were identified, resulting in 162 fetuses exposed in utero. The majority of patients had breast cancer (n = 88; 55.3%) or cervical cancer (n = 45; 28.3%). The most commonly employed taxane was paclitaxel (n = 131; 82.4%). A total of 111 (69.8%) patients were also treated with other cytotoxic drugs during pregnancy, including platinum salts (n = 70; 63.0%) and doxorubicin/cyclophosphamide (n = 20; 18.0%). While most patients received taxanes during the second trimester of pregnancy (n = 79; 70.0%), two were exposed to taxanes in the first trimester. Obstetric outcomes were reported in 105 (66.0%) cases, with the most frequent adverse events being preterm contractions or premature rupture of membranes (n = 12; 11.4%), pre-eclampsia/HELLP syndrome (n = 6; 5.7%), and oligohydramnios/anhydramnios (n = 6; 5.7%). All cases with pregnancy outcome available resulted in live births (n = 132). Overall, 72 (54.5%) neonates were delivered preterm, 40 (30.3%) were classified as small for gestational age (SGA), and 2 (1.5%) had an Apgar score of < 7 at 5 min. Perinatal complications included acute respiratory distress syndrome (n = 14; 10.6%), hyperbilirubinemia (n = 5; 3.8%), and hypoglycemia (n = 2; 1.5%). In addition, 7 (5.3%) cases of congenital malformations were reported. At a median follow-up of 16 months, offspring health status was available for 86 (65.2%), of which 13 (15.1%) had a documented complication, including delayed speech development, recurrent otitis media, and acute myeloid leukemia. CONCLUSIONS: Taxanes appear to be safe following the first trimester of pregnancy, with obstetric and fetal outcomes being similar to those observed in the general obstetric population. Future studies should aim to determine the most effective taxane regimen and dosage for use during gestation, with a specific focus on treatment safety.

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

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.

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

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.

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.

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.

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.

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.

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

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.

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

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.

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.

RANK-ligand (RANKL) expression in young breast cancer patients and during pregnancy.

INTRODUCTION: RANKL is important in mammary gland development during pregnancy and mediates the initiation and progression of progesterone-induced breast cancer. No clinical data are available on the effect of pregnancy on RANK/RANKL expression in young breast cancer patients. METHODS: We used our previously published dataset of 65 pregnant and 130 matched young breast cancer patients with full clinical, pathological, and survival information. 85% of patients had available transcriptomic data as well. RANK/RANKL expression by immunohistochemistry using H-score on the primary tumor and adjacent normal tissue was performed. We examined the difference in expression of RANK/RANKL between pregnant and non-pregnant patients and their association with clinicopathological features and prognosis. We also evaluated genes and pathways associated with RANK/RANKL expression on primary tumors. RESULTS: RANKL but not RANK expression was more prevalent in the pregnant group, both on the tumor and adjacent normal tissue, independent of other clinicopathological factors (both P <0.001). 18.7% of pregnant and 5.3% of non-pregnant patients had tumors showing ≥10% of cells with 3+ RANKL expression. RANKL expression was significantly higher in progesterone receptor-positive, and luminal A-like tumors, with negative correlation with Ki-67 (all P <0.001). On the contrary, RANK expression was higher in triple negative tumors (P <0.001). Using false discovery rate <0.05, 151 and 1,207 genes were significantly correlated with tumor-expressed RANKL and RANK expression by immunohistochemistry, respectively. High RANKL expression within primary tumor was associated with pathways related to mammary gland development, bone resorption, T-cell proliferation and regulation of chemotaxis, while RANK expression was associated with immune response and proliferation pathways. At a median follow-up of 65 months, neither RANK nor RANKL expression within tumor was associated with disease free survival in pregnant or non-pregnant group. CONCLUSIONS: Pregnancy increases RANKL expression both in normal breast and primary tumors. These results could guide further development of RANKL-targeted therapy.

Aromatase inhibitors in male breast cancer: a pooled analysis.

Although several studies have shown the efficacy of third-generation aromatase inhibitors (AIs) in women with breast cancer, the role of such molecules remains elusive in male breast cancer patients. It is also unknown whether the addition of gonadotropin-releasing hormone (GnRH) analogues to AIs would be a superior strategy or not. This pooled analysis was conducted in accordance with the PRISMA guidelines. All studies that examined the efficacy of AIs in metastatic male breast cancer were considered eligible. Overall, 15 studies (105 cases) were eligible for this pooled analysis. The mean age of the study sample was 62.8 years. ER status was positive in all eligible cases. AI was given as first line in 61.5 % of cases. GnRH analogue was co-administered with AI in 37.1 % of cases (n = 39). CR, PR, SD and PD were achieved in 5.7, 23.8, 37.2 and 33.3 % of cases, respectively. The median PFS and OS were equal to 10.0 and 39.0 months, respectively. Co-administration of GnRH analogues was associated with more than threefold increase in rates of clinical benefit (OR = 3.37, 95 % CI 1.30-8.73) but did not seem to correlate with better PFS or OS. No statistically significant associations between the examined outcomes and the other parameters were noted. Available data suggest that AIs may potentially play a promising role in the optimal therapeutic strategy for metastatic male breast cancer patients. Especially, co-administration of AI with a GnRH analogue seems to increase the rate of clinical benefit and could be more effective, warranting further consideration.

Genomic aberrations in young and elderly breast cancer patients.

BACKGROUND: Age at breast cancer diagnosis is a known prognostic factor. Previously, several groups including ours have shown that young age at diagnosis is associated with higher prevalence of basal-like tumors and aggressive tumor phenotypes. Yet the impact of age at diagnosis on the genomic landscape of breast cancer remains unclear. In this study, we examined the pattern of somatic mutations, chromosomal copy number variations (CNVs) and transcriptomic profiles in young and elderly breast cancer patients. METHODS: Analyses were performed on The Cancer Genome Atlas (TCGA) dataset. Patients with metastatic disease at diagnosis, classified as normal-like by PAM50 or had missing clinical information were excluded. Young patients were defined as ≤45 years of age, while elderly patients were those ≥70 years of age at breast cancer diagnosis. The remaining patients were classified as "intermediate". We evaluated the association between age at diagnosis and somatic mutations, CNV and gene expression in a logistic regression model adjusting for tumor size, nodal status, histology and breast cancer subtype. All analyses were corrected for multiple testing using the Benjamini-Hochberg approach. RESULTS: In this study, 125, 486 and 169 patients were ≤45, 46-69 and ≥70 years of age, respectively. Older patients had more somatic mutations (n = 44 versus 35 versus 31; P = 0.0009) and more CNVs, especially in ductal tumors (P = 0.02). Eleven mutations were independently associated with age at diagnosis, of which only GATA3 was associated with young age (15.2% versus 8.2% versus 9%; P = 0.003). Only two CNV events were independently associated with age, with more chr18p losses in older patients and more chr6q27 deletions in younger ones. Younger age at diagnosis was associated with higher expression of gene signatures related to proliferation, stem cell features and endocrine resistance. CONCLUSIONS: Age adds a layer of biological complexity beyond breast cancer molecular subtypes, classic pathological and clinical variables, worthy of further consideration in future drug development as we seek to refine therapeutic strategies in the era of personalized medicine.

Immunology and breast cancer: toward a new way of understanding breast cancer and developing novel therapeutic strategies.

Every cancer triggers an immune response that constitutes an important first-line protection against cancer progression. In breast cancer, there is an increasing awareness of the relationship between the immune system and tumor evolution. The tumor microenvironment is composed of a variety of immune cells that can control or arrest malignant progression. Chemotherapy and targeted therapy have been shown to modulate this immune microenvironment. Recently, tumor-infiltrating lymphocytes have emerged as a predictive and prognostic biomarker in early breast cancer. In addition, immune gene expression signatures have been shown to be associated with prognosis in triple-negative and human epidermal growth factor receptor 2-positive breast cancer. Such findings have increased interest in the development of immunotherapeutic agents for breast cancer, and multiple clinical trials of anticancer vaccines and immune checkpoint inhibitors are ongoing. In this review, we summarize what is known about the relationship between immunity and breast carcinoma, explore the relevance of this information to the clinical and research settings, and give a portrait of new therapeutic strategies using immunotherapy in breast cancer.

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.

Biology of breast cancer in young women.

Breast cancer arising at a young age is relatively uncommon, particularly in the developed world. Several studies have demonstrated that younger patients often experience a more aggressive disease course and have poorer outcome compared to older women. Expression of key biomarkers, including endocrine receptors, HER2 and proliferation markers, appears to be different in younger patients and young women are more likely to harbor a genetic predisposition. Despite these differences, little research to date has focused on the biology of these tumors to refine prognosis, and potentially direct treatment strategies, which remain similar to those offered to older patients. Accumulating evidence suggests the differences in breast stroma in younger patients and changes that occur with pregnancy and breastfeeding likely contribute to the different biology of these tumors. Reproductive behaviors appear to impact the biology of tumors developing later in life. In addition, tumors arising during or shortly following pregnancy appear to exhibit unique biological features. In this review, we discuss our emerging understanding of the biology of breast cancer arising at a young age at both the pathologic and the genomic level. We elucidate the potential role of genomic signatures, the impact of pregnancy and breastfeeding on breast cancer biology, and how even current knowledge might advance the clinical management of young breast cancer patients.

Treatment options for pregnant women with ovarian tumors.

Diagnosis of ovarian mass during pregnancy is a rare event. Treatment of ovarian malignancies during pregnancy depends on histology, grade, stage, and gestational weeks. When possible, surgical excision is indicated, and sometimes, fertility-sparing surgery is recommended. Administration of systemic treatment before or after surgery is indicated as in nonpregnant women. Preliminary data suggest that platinum salts and taxanes are safe during pregnancy. Management of ovarian tumors in pregnancy requires a multidisciplinary approach to guarantee an optimal treatment for the mother and the fetus.

Neurofibromatosis type I with breast cancer: not only for women!

The association of neurofibromatosis type I with invasive male breast cancer is a rare clinical entity with only one case in literature reported in 1953. Women with NF1 are at risk of developing breast cancer and men also may be at risk but there is scarce data on the risk and association of NF1 with male breast cancer due to its rarity. Established clinical trials in male breast cancer patients are lacking and the results are extrapolated from female breast cancer patients. The treatment of male breast cancer is followed as per the guidelines of premenopausal female breast cancer and tamoxifen is the hormone treatment in them. Mendes et al suggests that silencing of NF1 gene confers resistance to tamoxifen. Our conclusions are that since NF1 is mutated or deleted in one third of sporadic breast cancers, its role as a molecular driver for treatment has to be further explored.

Taxanes for the treatment of breast cancer during pregnancy: an international cohort study.

INTRODUCTION: The addition of taxanes to anthracycline-based chemotherapy is considered standard of care in the treatment of breast cancer. However, there are insufficient data regarding the safety of taxanes during pregnancy. The aim of this study was to describe the incidence of obstetric and neonatal adverse events associated with the use of taxane-containing chemotherapy regimens for the treatment of breast cancer during pregnancy. METHODS: This is a multicenter, international cohort study of breast cancer patients treated with taxanes during pregnancy. A descriptive analysis was undertaken to synthetize available data. RESULTS: A total of 103 patients were included, most of whom were treated with paclitaxel and anthracyclines given in sequence during gestation (90.1%). The median gestational age at taxane initiation was 28 weeks (range = 12-37 weeks). Grade 3-4 adverse events were reported in 7 of 103 (6.8%) patients. The most common reported obstetric complications were intrauterine growth restriction (n = 8 of 94, 8.5%) and preterm premature rupture of membranes (n = 5 of 94, 5.3%). The live birth rate was 92 of 94 (97.9%), and the median gestational age at delivery was 37 weeks (range = 32-40 weeks). Admission to an intensive care unit was reported in 14 of 88 (15.9%) neonates, and 17 of 70 (24.3%) live births resulted in small for gestational age neonates. Congenital malformations were reported in 2 of 93 (2.2%). CONCLUSION: Obstetric and neonatal outcomes after taxane exposure during pregnancy were generally favorable and did not seem to differ from those reported in the literature with standard anthracycline-based regimens. This study supports the use of taxanes during gestation when clinically indicated.

Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy.

PURPOSE: We investigated time to pregnancy, efficacy and safety of fertility preservation, and assisted reproductive technologies (ARTs) in women with early hormone receptor-positive breast cancer (BC) desiring future pregnancy. PATIENTS AND METHODS: POSITIVE is an international, single-arm, prospective trial, in which 518 women temporarily interrupted adjuvant endocrine therapy to attempt pregnancy. We evaluated menstruation recovery and factors associated with time to pregnancy and investigated if ART use was associated with achieving pregnancy. The cumulative incidence of BC-free interval (BCFI) events was estimated according to the use of ovarian stimulation at diagnosis. The median follow-up was 41 months. RESULTS: Two hundred seventy-three patients (53%) reported amenorrhea at enrollment, of whom 94% resumed menses within 12 months. Among 497 patients evaluable for pregnancy, 368 (74%) reported at least one pregnancy. Young age was the main factor associated with shorter time to pregnancy with cumulative incidences of pregnancy by 1 year of 63.5%, 54.3%, and 37.7% for patients age <35, 35-39, and 40-42 years, respectively. One hundred and seventy-nine patients (36%) had embryo/oocyte cryopreservation at diagnosis, of whom 68 reported embryo transfer after enrollment. Cryopreserved embryo transfer was the only ART associated with higher chance of pregnancy (odds ratio, 2.41 [95% CI, 1.75 to 4.95]). The cumulative incidence of BCFI events at 3 years was similar for women who underwent ovarian stimulation for cryopreservation at diagnosis, 9.7% (95% CI, 6.0 to 15.4), compared with those who did not, 8.7% (95% CI, 6.0 to 12.5). CONCLUSION: In POSITIVE, fertility preservation using ovarian stimulation was not associated with short-term detrimental impact on cancer prognosis. Pregnancy rates were highest among those who underwent embryo/oocyte cryopreservation followed by embryo transfer.

The Landscape of BRCA Mutations among Egyptian Women with Breast Cancer.

BACKGROUND: Deleterious germline mutations in BRCA1 and BRCA2 genes are associated with a high risk of breast and ovarian cancer. In many developing countries, including Egypt, the prevalence of BRCA1/2 mutations among women with breast cancer (BC) is unknown. AIM: We aimed to determine the prevalence of deleterious germline BRCA mutations in Egyptian patients with breast cancer. METHODS: We report the results of a cohort study of 81 Egyptian patients with breast cancer who were tested for germline BRCA1/2 mutations during routine clinical practice, mostly for their young age of presentation, BC subtype, or presence of family history. In addition, we searched five databases to retrieve studies that reported the prevalence of BRCA1/2 mutation status in Egyptian women with BC. A systematic review of the literature was performed, including prospective and retrospective studies. RESULTS: In our patient cohort study, 12 patients (14.8%) were positive for either BRCA1/2 deleterious mutations. Moreover, 13 (16.1%) patients had a variant of unknown significance (VUS) of BRCA1/2 genes. Twelve studies were eligible for the systematic review, including 610 patients. A total of 19 deleterious germline mutations in BRCA1/2 were identified. The pooled prevalence of BRCA1/2 mutations was 40% (95% confidence interval 1-80%). CONCLUSION: The reported prevalence was highly variable among the small-sized published studies that adopted adequate techniques. In our patient cohort, there was a high incidence of VUS in BRCA1/2 genes. Accordingly, there is an actual demand to conduct a prospective well-designed national study to accurately estimate the prevalence of BRCA1/2 mutations among patients with BC in Egypt.