Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Recurrence in Breast Noninvasive Neoplasia: A 10-Year Follow-Up of TAM-01 Study.

PURPOSE: Five-year data of the phase III trial TAM-01 showed that low-dose tamoxifen at 5 mg once daily administered for 3 years in women with intraepithelial neoplasia (IEN) reduced by 52% the recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), without additional adverse events over placebo. Here, we present the 10-year results. METHODS: We randomly assigned 500 women with breast IEN (atypical ductal hyperplasia, lobular carcinoma in situ [LCIS], or hormone-sensitive or unknown DCIS) to low-dose tamoxifen or placebo after surgery with or without irradiation. The primary end point was the incidence of invasive breast cancer or DCIS. RESULTS: The TAM-01 population included 500 women (20% atypical ductal hyperplasia, 11% LCIS, and 69% DCIS). The mean (±SD) age at the start of treatment was 54 ± 9 years, and 58% of participants were postmenopausal. After a median follow-up of 9.7 years (IQR, 8.3-10.9 years), 66 breast cancers (15 in situ; 51 invasive) were diagnosed: 25 in the tamoxifen group and 41 in the placebo group (annual rate per 1,000 person-years, 11.3 with tamoxifen v 19.5 with placebo; hazard ratio [HR], 0.58; 95% CI, 0.35 to 0.95; log-rank P = .03). Most recurrences were invasive (77%) and ipsilateral (59%). Regarding contralateral breast cancer incidence, there were six events in the tamoxifen arm and 16 in the placebo arm (HR, 0.36; 95% CI, 0.14 to 0.92; P = .025). The number needed to be treated to prevent one case of breast event with tamoxifen therapy was 22 in 5 years and 14 in 10 years. The benefit was seen across all patient subgroups. There was a significant 50% reduction of recurrence with tamoxifen in the DCIS cohort, which represents 70% of the overall population (HR, 0.50; 95% CI, 0.28 to 0.91; P = .02). No between-group difference in the incidence of serious adverse events was reported during the prolonged follow-up period. CONCLUSION: Tamoxifen 5 mg once daily for 3 years significantly prevents recurrence from noninvasive breast cancer after 7 years from treatment cessation without long-term adverse events.

Perceptions of Death Among Patients with Advanced Cancer Receiving Early Palliative Care and Their Caregivers: Results from a Mixed-Method Analysis.

BACKGROUND: Oncologists are often concerned that talking about death with patients may hinder their relationship. However, the views of death held by patients have not been thoroughly investigated. This study aimed to describe the perception of death among patients with advanced cancer receiving early palliative care (EPC) and their caregivers. MATERIAL AND METHODS: Qualitative and quantitative analyses were performed on 2 databases: (a) transcripts of open-ended questionnaires administered to 130 cancer patients receiving EPC with a mean age of 68.4 years and to 115 primary caregivers of patients on EPC with a mean age of 56.8; (b) texts collected from an Italian forum, containing instances of web-mediated interactions between patients and their caregivers. RESULTS: Quantitative analysis shows that: (a) patients and caregivers are not afraid of speaking about death; (b) patients and caregivers on EPC use the word "death" significantly more than patients on standard oncology care (SOC) and their caregivers (P < .0001). For both participants on EPC and SOC, the adjectives and verbs associated with the word "death" have positive connotations; however, these associations are significantly more frequent for participants on EPC (verbs, Ps < .0001; adjectives, Ps < .003). Qualitative analysis reveals that these positive connotations refer to an actual, positive experience of the end of life in the EPC group and a wish or a negated event in the SOC group. CONCLUSIONS: EPC interventions, along with proper physician-patient communication, may be associated with an increased acceptance of death in patients with advanced cancer and their caregivers.

Changes in Cancer Patients' and Caregivers' Disease Perceptions While Receiving Early Palliative Care: A Qualitative and Quantitative Analysis.

BACKGROUND: Little is known about the underlying mechanisms through which early palliative care (EPC) improves multiple outcomes in patients with cancer and their caregivers. The aim of this study was to qualitatively and quantitatively analyze patients' and caregivers' thoughts and emotional and cognitive perceptions about the disease prior to and during the EPC intervention, and in the end of life, following the exposure to EPC. MATERIALS AND METHODS: Seventy-seven patients with advanced cancer and 48 caregivers from two cancer centers participated in semistructured interviews. Their reports were qualitatively and quantitatively analyzed by the means of the grounded theory and a text-analysis program. RESULTS: Participants reported their past as overwhelmed by unmanaged symptoms, with detrimental physical and psychosocial consequences. The EPC intervention allowed a prompt resolution of symptoms and of their consequences and empowerment, an appreciation of its multidimensional approach, its focus on the person and its environment, and the need for EPC for oncologic populations. Patients reported that conversations with the EPC team increased their acceptance of end of life and their expectation of a painless future. Quantitative analysis revealed higher use of Negative Affects (p < .001) and Biological Processes words (p < .001) when discussing the past; Agency words when discussing the present (p < .001); Positive Affects (p < .001), Optimism (p = .002), and Insight Thinking words (p < .001) when discussing the present and the future; and Anxiety (p = .002) and Sadness words (p = .003) when discussing the future. CONCLUSION: Overall, participants perceived EPC to be beneficial. Our findings suggest that emotional and cognitive processes centered on communication underlie the benefits experienced by participants on EPC. IMPLICATIONS FOR PRACTICE: By qualitative and quantitative analyses of the emotional and cognitive perceptions of cancer patients and their caregivers about their experiences before and during EPC interventions, this study may help physicians/nurses to focus on the disease perception by patients/caregivers and the benefits of EPC, as a standard practice. The analysis of words used by patients/caregivers provides a proxy for their psychological condition and support in tailoring an EPC intervention, based on individual needs. This study highlights that the relationship of the triad EPC team/patients/caregivers may rise as a therapeutic tool, allowing increasing awareness and progressive acceptance of the idea of death.

Trastuzumab-lapatinib as neoadjuvant therapy for HER2-positive early breast cancer: Survival analyses of the CHER-Lob trial.

AIM: The Cher-LOB randomised phase II study showed that the combination of lapatinib-trastuzumab plus chemotherapy increases pathologic complete response (pCR) rate compared with chemotherapy plus either trastuzumab or lapatinib. Here, we report the post hoc survival analysis as per treatment arm, pCR and biomarkers. METHODS: The Cher-LOB study randomised 121 patients with human epidermal growth factor receptor 2-positive, stage II-IIIA breast cancer. A specific protocol to collect recurrence-free survival (RFS) and overall survival (OS) data was designed. Tumour-infiltrating lymphocytes (TILs) and PAM50-intrinsic subtyping were evaluated at baseline. RESULTS: At 9-year median follow-up, a trend towards RFS improvement with lapatinib-trastuzumab over trastuzumab was observed (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.18-1.05). Combining treatment arms, pCR was significantly associated with both RFS (HR 0.12, 95% CI 0.03-0.49) and OS (HR 0.12, 95% CI 0.03-0.49). TILs were significantly associated with RFS (HR = 0.978 for each 1% increment). Luminal-A subtype was a significant and independent predictor of improved RFS as compared with other PAM50-based intrinsic subtypes at the multivariate analysis including the most relevant clinicopathologic variables (HR 0.29, 95% CI 0.09-0.94, p = 0.040). CONCLUSIONS: Cher-LOB trial survival analysis confirmed the prognostic role of pCR and TILs and showed a signal for a better outcome with lapatinib-trastuzumab over trastuzumab. TRIAL REGISTRATION: NCT00429299.

Different semantic and affective meaning of the words associated to physical and social pain in cancer patients on early palliative/supportive care and in healthy, pain-free individuals.

Early palliative/supportive care (ePSC) is a medical intervention focused on patient's needs, that integrates standard oncological treatment, shortly after a diagnosis of advanced/metastatic cancer. ePSC improves the appropriate management of cancer pain. Understanding the semantic and emotional impact of the words used by patients to describe their pain may further improve its assessment in the ePSC setting. Psycholinguistics assumes that the semantic and affective properties of words affect the ease by which they are processed and comprehended. Therefore, in this cross-sectional survey study we collected normative data about the semantic and affective properties of words associated to physical and social pain, in order to investigate how patients with cancer pain on ePSC process them compared to healthy, pain-free individuals. One hundred ninety patients and 124 matched controls rated the Familiarity, Valence, Arousal, Pain-relatedness, Intensity, and Unpleasantness of 94 words expressing physical and social pain. Descriptive and inferential statistics were performed on ratings in order to unveil patients' semantic and affective representation of pain and compare it with those from controls. Possible effects of variables associated to the illness experience were also tested. Both groups perceived the words conveying social pain as more negative and pain-related than those expressing physical pain, confirming previous evidence of social pain described as worse than physical pain. Patients rated pain words as less negative, less pain-related, and conveying a lower intense and unpleasant pain than controls, suggesting either an adaptation to the pain experience or the role played by ePSC in improving patients' ability to cope with it. This exploratory study suggests that a chronic pain experience as the one experienced by cancer patients on ePSC affects the semantic and affective representation of pain words.

Effect Modifiers of Low-Dose Tamoxifen in a Randomized Trial in Breast Noninvasive Disease.

PURPOSE: Low-dose tamoxifen halved recurrence after surgery in a phase III trial in breast noninvasive disease without increasing adverse events. We explored the effect of low-dose tamoxifen in clinically relevant subgroups, including menopausal status, estradiol levels, smoking, body mass index, and proliferation of baseline lesion. PATIENTS AND METHODS: Incidence of invasive breast cancer or ductal carcinoma in situ was the primary endpoint. HRs and interaction terms were estimated using Cox models. RESULTS: A favorable HR and 95% confidence interval (CI) could be demonstrated for postmenopausal status (HR = 0.30; 95% CI, 0.11-0.82 vs. HR = 0.73; 95% CI, 0.30-1.76 in premenopausal women; P interaction = 0.13), women with estradiol less than 15.8 pg/mL, presence of menopausal symptoms at baseline, and never smoking (P interaction = 0.07), although the interaction P value was >0.05 for all characteristics. Efficacy was similar in all body mass index categories. Tumors with Ki-67 above the median level of 10% had a greater benefit (HR = 0.27; 95% CI, 0.09-0.81) than those with Ki-67 ≤10% (HR = 1.58; 95% CI, 0.45-5.60; P interaction = 0.04). CONCLUSIONS: The efficacy of low-dose tamoxifen seems to be greater in postmenopausal women and in women with lower estradiol levels. Benefits appear to be larger also in women with menopausal symptoms, never smokers, and tumors with Ki-67 >10%. Our results by menopausal status provide important insight into low-dose tamoxifen personalized treatment, although caution is necessary given their exploratory nature. Observation of an improved response in tumors with Ki-67 >10% is consistent but the use of the marker in this setting is investigational.See related commentary by Fabian, p. 3510.

Immune microenvironment and intrinsic subtyping in hormone receptor-positive/HER2-negative breast cancer.

Little is known regarding the interaction between immune microenvironment and tumor biology in hormone receptor (HR)+/HER2- breast cancer (BC). We here assess pretreatment gene-expression data from 66 HR+/HER2- early BCs from the LETLOB trial and show that non-luminal tumors (HER2-enriched, Basal-like) present higher tumor-infiltrating lymphocyte levels than luminal tumors. Moreover, significant differences in immune infiltrate composition, assessed by CIBERSORT, were observed: non-luminal tumors showed a more proinflammatory antitumor immune infiltrate composition than luminal ones.

PIK3CA Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2+ Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype.

PURPOSE: We explored the prognostic effect of PIK3CA mutation in HER2+ patients enrolled in the ShortHER trial. PATIENTS AND METHODS: The ShortHER trial randomized 1,253 patients with HER2+ breast cancer to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. PIK3CA hotspot mutations in exon 9 and 20 were analyzed by pyrosequencing. Expression of 60 genes, including PAM50 genes was measured using the nCounter platform. RESULTS: A mutation of the PIK3CA gene was detected in 21.7% of the 803 genotyped tumors. At a median follow-up of 7.7 years, 5-year disease-free survival (DFS) rates were 90.6% for PIK3CA mutated and 86.2% for PIK3CA wild-type tumors [HR, 0.84; 95% confidence interval (CI), 0.56-1.27; P = 0.417]. PIK3CA mutation showed a favorable prognostic impact in the PAM50 HER2-enriched subtype (n = 232): 5-year DFS 91.8% versus 76.1% (log-rank P = 0.049; HR, 0.46; 95% CI, 0.21-1.02). HER2-enriched/PIK3CA mutated versus wild-type tumors showed numerically higher tumor-infiltrating lymphocytes (TIL) and significant upregulation of immune-related genes (including CD8A, CD274, PDCD1, and MYBL2, a proliferation gene involved in immune processes). High TILs as well as the upregulation of PDCD1 and MYBL2 were associated with a significant DFS improvement within the HER2-enriched subtype (HR, 0.82; 95% CI, 0.68-0.99; P = 0.039 for 10% TILs increment; HR, 0.81; 95% CI, 0.65-0.99; P = 0.049 for PDCD1 expression; HR, 0.72; 95% CI, 0.53-0.99; P = 0.042 for MYBL2 expression). CONCLUSIONS: PIK3CA mutation showed no prognostic impact in the ShortHER trial. Within the HER2-enriched molecular subtype, patients with PIK3CA mutated tumors showed better DFS versus PIK3CA wild-type, which may be partly explained by upregulation of immune-related genes.

Validation of the AJCC prognostic stage for HER2-positive breast cancer in the ShortHER trial.

BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging has introduced prognostic stage based on anatomic stage combined with biologic factors. We aimed to validate the prognostic stage in HER2-positive breast cancer patients enrolled in the ShortHER trial. METHODS: The ShortHER trial randomized 1253 HER2-positive patients to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Patients were classified according to the anatomic and the prognostic stage. Distant disease-free survival (DDFS) was calculated from randomization to distant relapse or death. RESULTS: A total of 1244 patients were included. Compared to anatomic stage, the prognostic stage downstaged 41.6% (n = 517) of patients to a more favorable stage category. Five-year DDFS based on anatomic stage was as follows: IA 96.6%, IB 94.1%, IIA 92.4%, IIB 87.3%, IIIA 81.3%, IIIC 70.5% (P < 0.001). Five-year DDFS according to prognostic stage was as follows: IA 95.7%, IB 91.4%, IIA 86.9%, IIB 85.0%, IIIA 77.6%, IIIC 67.7% (P < 0.001). The C index was similar (0.69209 and 0.69249, P = 0.975). Within anatomic stage I, the outcome was similar for patients treated with 9 weeks or 1 year trastuzumab (5-year DDFS 96.2% and 96.6%, P = 0.856). Within prognostic stage I, the outcome was numerically worse for patients treated with 9 weeks trastuzumab (5-year DDFS 93.7% and 96.3%, P = 0.080). CONCLUSIONS: The prognostic stage downstaged 41.6% of patients, while maintaining a similar prognostic performance as the anatomic stage. The prognostic stage is valuable in counseling patients and may serve as reference for a clinical trial design. Our data do not support prognostic stage as guidance to de-escalate treatment. TRIAL REGISTRATION: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

Scalp Cooling in Daily Clinical Practice for Breast Cancer Patients Undergoing Curative Chemotherapy: A Multicenter Interventional Study.

OBJECTIVE: Chemotherapy-induced alopecia is a common and distressful side effect, especially among breast cancer patients. Scalp cooling (SC) can reduce hair loss during anthracycline- and taxane-based chemotherapy. This study assessed the effectiveness of SC in daily clinical practice in three Italian oncology units. METHODS: From 2014 to 2016, we prospectively included 220 female early-stage breast cancer patients undergoing curative chemotherapy in combination with SC using the Paxman device. Effectiveness was defined as the severity of hair loss according to the Common Terminology Criteria for Adverse Events Version 4.0 as follows: Grade 0, no hair loss; Grade 1, <50% hair loss not requiring a wig; and Grade 2, ≥50% hair loss at each cycle and at completion of chemotherapy. The tolerability and safety were also evaluated. RESULTS: The overall success rate of SC (hair loss Grade 0-1) was 68%. Severe hair loss was avoided in 89% of women receiving taxane-based chemotherapy and in 78% of women receiving both anthracyclines and taxanes. Among women undergoing anthracycline-based chemotherapy, 47% experienced hair preservation. SC was well tolerated, as only 20 patients discontinued SC for reasons other than hair loss. CONCLUSIONS: Our study confirmed that SC provides a reliable chance for breast cancer patients to keep their hair during taxane- and/or anthracycline-based chemotherapy.

Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Local and Contralateral Recurrence in Breast Intraepithelial Neoplasia.

PURPOSE: Tamoxifen administered for 5 years at 20 mg/d is effective in breast cancer treatment and prevention, but toxicity has limited its broad use. Biomarker trials showed that 5 mg/d is not inferior to 20 mg/d in decreasing breast cancer proliferation. We hypothesized that a lower dose given for a shorter period could be as effective in preventing recurrence from breast intraepithelial neoplasia but have a lower toxicity than the standard dose. PATIENTS AND METHODS: We conducted a multicenter randomized trial of tamoxifen, 5 mg/d or placebo administered for 3 years after surgery in women with hormone-sensitive or unknown breast intraepithelial neoplasia, including atypical ductal hyperplasia and lobular or ductal carcinoma in situ. The primary end point was the incidence of invasive breast cancer or ductal carcinoma in situ. RESULTS: Five hundred women 75 years of age or younger were included. After a median follow-up of 5.1 years (interquartile range, 3.9-6.3 years), there were 14 neoplastic events with tamoxifen and 28 with placebo (11.6 v 23.9 per 1,000 person-years; hazard ratio, 0.48; 95% CI, 0.26 to 0.92; P = .02), which resulted in a 5-year number needed to treat of 22 (95% CI, 20 to 27). Tamoxifen decreased contralateral breast events by 75% (three v 12 events; hazard ratio, 0.25; 95% CI, 0.07 to 0.88; P = .02). Patient-reported outcomes were not different between arms except for a slight increase in frequency of daily hot flashes with tamoxifen (P = .02). There were 12 serious adverse events with tamoxifen and 16 with placebo, including one deep vein thrombosis and one stage I endometrial cancer with tamoxifen and one pulmonary embolism with placebo. CONCLUSION: Tamoxifen at 5 mg/d for 3 years can halve the recurrence of breast intraepithelial neoplasia with a limited toxicity, which provides a new treatment option in these disorders.

Safety profile of subcutaneous trastuzumab for the treatment of patients with HER2-positive early or locally advanced breast cancer: primary analysis of the SCHEARLY study.

BACKGROUND: Subcutaneous trastuzumab (H SC) is a valuable alternative to the intravenous formulation. This study assessed H SC safety and tolerability in human epidermal growth factor receptor 2 (HER2)+ early/locally advanced breast cancer (EBC/LABC). METHODS: SCHEARLY is a prospective, two-cohort, non-randomised, multicentre Italian trial included in the umbrella study UmbHER1, planning a 1-year treatment with H SC 600 mg in HER2+ EBC/LABC. Patients were sequentially assigned to cohort A (N = 121) and B (N = 119) to receive H SC via a handheld syringe and a single-use injection device, respectively. Adjuvant or neoadjuvant treatment included anthracycline-containing regimens followed by H SC plus taxanes and then alone for 18 cycles totally. RESULTS: Two hundred forty patients were enrolled (adjuvant therapy: 81.7%; neoadjuvant therapy: 18.3%), and 201 completed the treatment (early discontinuation was mainly due to intercurrent adverse events [AEs], 7.5%). Overall, the two cohorts displayed similar safety profiles. From H SC start, the rate of treatment-related AEs in the safety population (N = 228) was 3.9% for grade ≥3 AEs; 0.9% for serious AEs (one pleuropericarditis and one anaphylactic shock, both resolved) and 14.5% for cardiac AEs, the most common being the decreased left ventricular ejection fraction (7.9%; mean reduction from the screening to the follow-up visit was 2.9%). No cases of congestive heart failure occurred. The rate of systemic administration-related reactions and local injection site reactions was 68.0% and 21.9%, respectively, mostly of grade 1-2. CONCLUSIONS: H SC 600 mg confirmed to be a safe and tolerable option as adjuvant/neoadjuvant therapy in patients with HER2+ EBC and LABC. CLINICALTRIALS. GOV IDENTIFIER: NCT01940497.

Low-Dose Oral Cyclophosphamide and Methotrexate Maintenance for Hormone Receptor-Negative Early Breast Cancer: International Breast Cancer Study Group Trial 22-00.

PURPOSE: To evaluate the benefit of low-dose cyclophosphamide and methotrexate (CM) maintenance, which previously demonstrated antitumor activity and few adverse effects in advanced breast cancer, in early breast cancer. PATIENTS AND METHODS: International Breast Cancer Study Group (IBCSG) Trial 22-00, a randomized phase III clinical trial, enrolled 1,086 women (1,081 intent-to-treat) from November 2000 to December 2012. Women with estrogen receptor- and progesterone receptor-negative (< 10% positive cells by immunohistochemistry) early breast cancer any nodal and human epidermal growth factor receptor 2 status, were randomly assigned anytime between primary surgery and 56 days after the first day of last course of adjuvant chemotherapy to CM maintenance (cyclophosphamide 50 mg/day orally continuously and methotrexate 2.5 mg twice/day orally on days 1 and 2 of every week for 1 year) or to no CM. The primary end point was disease-free survival (DFS), which included invasive recurrences, second (breast and nonbreast) malignancies, and deaths. RESULTS: After a median of 6.9 years of follow-up, DFS was not significantly better for patients assigned to CM maintenance compared with patients assigned to no CM, both overall (hazard ratio [HR], 0.84; 95% CI, 0.66 to 1.06;P = .14) and in triple-negative (TN) disease (n = 814; HR, 0.80; 95% CI, 0.60 to 1.06). Patients with TN, node-positive disease had a nonstatistically significant reduced HR (n = 340; HR, 0.72; 95% CI, 0.49 to 1.05). Seventy-one (13%) of 542 patients assigned to CM maintenance did not start CM. Of 473 patients who received at least one CM maintenance dose (including two patients assigned to no CM), 64 (14%) experienced a grade 3 or 4 treatment-related adverse event; elevated serum transaminases was the most frequently reported (7%), followed by leukopenia (2%). CONCLUSION: CM maintenance did not produce a significant reduction in DFS events in hormone receptor-negative early breast cancer. The trend toward benefit observed in the TN, node-positive subgroup supports additional exploration of this strategy in the TN, higher-risk population.

Prospective Biomarker Analysis of the Randomized CHER-LOB Study Evaluating the Dual Anti-HER2 Treatment With Trastuzumab and Lapatinib Plus Chemotherapy as Neoadjuvant Therapy for HER2-Positive Breast Cancer.

BACKGROUND: The CHER-LOB randomized phase II study showed that the combination of lapatinib and trastuzumab plus chemotherapy increases the pathologic complete remission (pCR) rate compared with chemotherapy plus either trastuzumab or lapatinib. A biomarker program was prospectively planned to identify potential predictors of sensitivity to different treatments and to evaluate treatment effect on tumor biomarkers. MATERIALS AND METHODS: Overall, 121 breast cancer patients positive for human epidermal growth factor 2 (HER2) were randomly assigned to neoadjuvant chemotherapy plus trastuzumab, lapatinib, or both trastuzumab and lapatinib. Pre- and post-treatment samples were centrally evaluated for HER2, p95-HER2, phosphorylated AKT (pAKT), phosphatase and tensin homolog, Ki67, apoptosis, and PIK3CA mutations. Fresh-frozen tissue samples were collected for genomic analyses. RESULTS: A mutation in PIK3CA exon 20 or 9 was documented in 20% of cases. Overall, the pCR rates were similar in PIK3CA wild-type and PIK3CA-mutated patients (33.3% vs. 22.7%; p = .323). For patients receiving trastuzumab plus lapatinib, the probability of pCR was higher in PIK3CA wild-type tumors (48.4% vs. 12.5%; p = .06). Ki67, pAKT, and apoptosis measured on the residual disease were significantly reduced from baseline. The degree of Ki67 inhibition was significantly higher in patients receiving the dual anti-HER2 blockade. The integrated analysis of gene expression and copy number data demonstrated that a 50-gene signature specifically predicted the lapatinib-induced pCR. CONCLUSION: PIK3CA mutations seem to identify patients who are less likely to benefit from dual anti-HER2 inhibition. p95-HER2 and markers of phosphoinositide 3-kinase pathway deregulation are not confirmed as markers of different sensitivity to trastuzumab or lapatinib. IMPLICATIONS FOR PRACTICE: HER2 is currently the only validated marker to select breast cancer patients for anti-HER2 treatment; however, it is becoming evident that HER2-positive breast cancer is a heterogeneous disease. In addition, more and more new anti-HER2 treatments are becoming available. There is a need to identify markers of sensitivity to different treatments to move in the direction of treatment personalization. This study identified PIK3CA mutations as a potential predictive marker of resistance to dual anti-HER2 treatment that should be further studied in breast cancer.

Preoperative carboplatin-paclitaxel-bevacizumab in triple-negative breast cancer: final results of the phase II Ca.Pa.Be study.

PURPOSE: The phase II Ca.Pa.Be trial evaluated preoperative carboplatin-paclitaxel in combination with bevacizumab in triple-negative breast cancer patients with previously untreated stage II-III disease. The primary aim was the assessment of the rate of pathologic complete response (pCR). Secondary aims included safety, breast-conserving surgery rate, and early response assessment with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). METHODS: Patients with hormone receptor-negative, HER-2-negative stage II-III breast cancer were eligible. Treatment included paclitaxel 80 mg/mq + carboplatin area under the curve (AUC) 2 on days 1, 8, and 15, combined with bevacizumab 10 mg/kg on days 1 and 15 each 28 days, for 5 courses. At baseline, patients underwent breast DCE-MRI, followed by a single dose of bevacizumab 5 mg/kg (day -6). DCE-MRI was repeated before the initiation of chemotherapy. RESULTS: Forty-four patients were enrolled. Forty-three patients underwent surgery, and 22 (50 %) received breast-conserving surgery (conversion rate from mastectomy indication at baseline, 34.4 %). A pCR in breast and axillary lymph nodes occurred in 22 patients (50 %). Bevacizumab-associated adverse events (AEs) were mild: G1-2 hypertension and bleeding occurred in 6 (13.6 %) and 12 (27 %) patients, respectively. No G4 nonhematologic AEs were recorded. More frequent G3 AEs were liver function test abnormalities (6.8 %), and diarrhea and fatigue (4.5 % each). The only G3-4 hematologic toxicity was neutropenia (G3, 25 %; G4, 9 %). Early assessed DCE-MRI response parameters failed to predict pCR. CONCLUSIONS: The neoadjuvant anthracycline-free combination of weekly paclitaxel and carboplatin plus bevacizumab is active and safe in triple-negative breast cancer, and the rate of pCR is comparable to that observed with more intensive carboplatin- and bevacizumab-containing regimens. Further investigation is warranted.

Double-blind, placebo-controlled, multicenter, randomized, phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative, operable breast cancer.

PURPOSE: This is a randomized, double-blind, placebo-controlled study aimed to evaluate the clinical and biologic effects of letrozole plus lapatinib or placebo as neoadjuvant therapy in hormone receptor (HR) -positive/human epidermal growth factor receptor 2 (HER2) -negative operable breast cancer. METHODS: Ninety-two postmenopausal women with stage II to IIIA primary breast cancer were randomly assigned to preoperative therapy consisting of 6 months of letrozole 2.5 mg orally daily plus lapatinib 1,500 mg orally daily or placebo. Surgery was performed within 2 weeks from the last study medication. Clinical response was assessed by ultrasonography. Pre- and post-treatment samples were evaluated for selected biomarkers. Fresh-frozen tissue samples were collected for genomic analyses. RESULTS: Numerically similar clinical response rates (partial + complete response) were observed (70% for letrozole-lapatinib and 63% for letrozole-placebo). Toxicities were generally mild and manageable. A significant decrease in Ki-67 and pAKT expression from baseline to surgery was observed in both arms. Overall, 34 patients (37%) had a mutation in PIK3CA exon 9 or 20. In the letrozole-lapatinib arm, the probability of achieving a clinical response was significantly higher in the presence of PIK3CA mutation (objective response rate, 93% v 63% in PIK3CA wild type; P = .040). CONCLUSION: The combination of letrozole-lapatinib in early breast cancer was feasible, with expected and manageable toxicities. In unselected estrogen receptor-positive/HER2-negative patients, letrozole-lapatinib and letrozole-placebo resulted in a similar overall clinical response rate and similar effect on Ki-67 and pAKT. Our secondary end point findings of a significant correlation between PIK3CA mutation and response to letrozole-lapatinib in HR-positive/HER2-negative early breast cancer must now be independently confirmed.

Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study.

PURPOSE: This is a noncomparative, randomized, phase II trial of preoperative taxane-anthracycline in combination with trastuzumab, lapatinib, or combined trastuzumab plus lapatinib in patients with human epidermal growth factor receptor 2 (HER2) -positive, stage II to IIIA operable breast cancer. The primary aim was to estimate the percentage of pathologic complete response (pCR; no invasive tumor in breast and axillary nodes). PATIENTS AND METHODS: In the three arms, chemotherapy consisted of weekly paclitaxel (80 mg/m(2)) for 12 weeks followed by fluorouracil, epirubicin, and cyclophosphamide for four courses every 3 weeks. The patients randomly assigned to arm A received a 4-mg loading dose of trastuzumab followed by 2 mg weekly; in arm B patients received lapatinib 1,500 mg orally (PO) daily; and in arm C, patients received trastuzumab and lapatinib 1,000 mg PO daily. RESULTS: A total of 121 patients were randomly assigned. Diarrhea and dermatologic and hepatic toxicities were observed more frequently in patients receiving lapatinib. No episodes of congestive heart failure were observed. The rates of breast-conserving surgery were 66.7%, 57.9%, and 68.9% in arms A, B and C, respectively. The pCR rates were 25% (90% CI, 13.1% to 36.9%) in arm A, 26.3% (90% CI, 14.5% to 38.1%) in arm B, and 46.7% (90% CI, 34.4% to 58.9%) in arm C (exploratory P = .019). CONCLUSION: The primary end point of the study was met, with a relative increase of 80% in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib. These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer.

Rare case of male breast cancer and axillary lymphoma in the same patient: an unique case report.

Breast cancer in men is uncommon, and even more rare is the simultaneous presentation of two different malignancies. A 39-year-old man was diagnosed with both breast cancer and axillary lymphoma. Familiar history revealed that his mother died because of breast cancer. The patient underwent fine needle aspiration leading to the diagnosis of malignant lesion. Modified radical mastectomy was performed. Histology revealed an infiltrating ductal carcinoma 2.8 cm wide, grade 2, with vascular and lymphatic invasion. Surprisingly, one of the second level nodes was confirmed as a high-grade large B cell non-Hodgkin's lymphoma. No family inheritance or gene mutations (BRCA 1 and 2) were found. The patient underwent local radiotherapy, followed by 6 chemotherapy courses (RCHOP) and treatment with tamoxifen 20 mg/daily. To our knowledge, this is the first case reported in literature of male breast cancer and axillary lymphoma simultaneously confirmed in the same patient.

Incidence of breast cancer in Italy: mastectomies and quadrantectomies performed between 2000 and 2005.

OBJECTIVES: We aimed to determine the incidence of women's breast cancer in Italy without using statistical approximations. METHODS: We analyzed the national hospitalizations database at the Ministry of Health to calculate the number of major surgeries in Italian women (mastectomies and quadrantectomies) due to breast cancer between 2000 and 2005, overall and by age groups (<44, 45-64, 65-74 and >or= 75 years old). RESULTS: Over the six years examined, an overall number of 100,745 mastectomies and 168,147 quadrantectomies were performed. A total of 41,608 major surgeries due to breast cancer were performed in the year 2000 and this number rose to 47,200 in 2005, with a 13.4% increase over six years. CONCLUSION: by analyzing the hospitalizations database concerning major breast surgery, incidence of breast cancer in Italy was found to be 26.5% higher than the official estimations which have been computed using statistical models (namely 47,200 vs. 37,300 cases in year 2005).