Samanta Sarti

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.

Trastuzumab-induced cardiotoxicity in early breast cancer patients: a retrospective study of possible risk and protective factors

Objective Although adjuvant trastuzumab improves survival in patients with HER2-positive early breast cancer, there is growing concern about the long-term effect of trastuzumab-induced cardiotoxicity (TIC). We retrospectively assessed the incidence of TIC and heart failure (HF) to identify possible risk and protective factors. Design Retrospective study. Setting Institute for Cancer Research and Treatment, Medical Oncology Department. Patients Consecutive patients who started adjuvant trastuzumab between 2007 and 2010. Main outcome Measures TIC was defined as an absolute left ventricular ejection fraction (LVEF) decrease ≥15 points from baseline or a LVEF<50%. Logistic regression was used to estimate OR and their 95% CI in order to evaluate the risk of TIC, considering potential cardiac risk factors (hypertension, hypercholesterolaemia, diabetes mellitus, smoke, cardiac ischaemia and previous chest radiotherapy) and protective factors (β-blockers, ACE inhibitors and/or angiotensin receptor blockers). Results Among 179 patients, 78 cases of TIC (44%, 95% CI 37% to 51%) and four cases of HF (2%, 95% CI 0% to 4%) were reported. 14 patients stopped trastuzumab as a result of TIC. None of the cardiac risk factors or concomitant cardiovascular medications altered the risk of TIC. A previous cumulative dose >240 mg/m2 of doxorubicin or >500 mg/m2 of epirubicin increased the risk of TIC compared with lower doses (OR 3.07; 95% CI 1.29 to 7.27, p=0.0011). Conclusions TIC is a frequent, albeit generally mild, adverse event in clinical practice. Further studies are warranted to better define the risk of and protective factors for TIC.

Androgen receptor signaling pathways as a target for breast cancer treatment

The androgen receptor (AR) is a ligand-dependent transcription factor, and its effects on breast range from physiological pubertal development and age-related modifications to cancer onset and proliferation. The prevalence of AR in early breast cancer is around 60%, and AR is more frequently expressed in ER-positive than in ER-negative tumors. We offer an overview of AR signaling pathways in different breast cancer subtypes, providing evidence that its oncogenic role is likely to be different in distinct biological and clinical scenarios. In particular, in ER-positive breast cancer, AR signaling often antagonizes the growth stimulatory effect of ER signaling; in triple-negative breast cancer (TNBC), AR seems to drive tumor progression (at least in luminal AR subtype of TNBC with a gene expression profile mimicking luminal subtypes despite being negative to ER and enriched in AR expression); in HER2-positive breast cancer, in the absence of ER expression, AR signaling has a proliferative role. These data represent the rationale for AR-targeting treatment as a potentially new target therapy in breast cancer subset using androgen agonists in some AR-positive/ER-positive tumors, AR antagonists in triple-negative/AR-positive tumors and in combination with anti-HER2 agents or with other signaling pathways inhibitors (including PI3K/MYC/ERK) in HER2-positive/AR-positive tumors. Only the ongoing and future prospective clinical trials will allow us to establish which agents are the best option in every specific condition, keeping in mind that there is evidence of opposite androgens and AR agonist/antagonist drug effects on cell proliferation particularly in AR-positive/ER-positive tumors.

Abstract PD1-1: Tumor infiltrating lymphocytes and correlation with outcome in the Cher-LOB study

Background: Tumor infiltrating lymphocytes (TIL) are emerging as a strong prognostic and predictive factor for breast cancer, especially for the HER2-positive and triple negative subtypes (Loi S, Ann Oncol 2014; Dieci MV, Ann Oncol 2014). Here we report the results of the TIL biomarker analysis performed in the CherLOB study. Methods: The phase II neoadjuvant CherLOB study (Guarneri, J Clin Oncol 2012) randomized 121 HER2-positive, stage II-IIIA breast cancer patients to anthracyclines/taxane-based chemotherapy plus trastuzumab (arm A), lapatinib (arm B), or both (arm C). Primary endpoint was pathological complete response (pCR). Hematoxylin and eosin-stained slides from both pre-treatment biopsies and post-treatment surgical samples were centralized and evaluated for the % of intratumoral (It) and stromal (Str) TIL as previously described (Denkert C, J Clin Oncol 2010). Samples were classified as lymphocyte-predominant (LP) if ItTIL and/or StrTIL >=60% and as non-LP if ItTIL and StrTIL Results: Pre-treatment TIL evaluation was available for 105 of the 118 CherLOB patients who were assessable for pathological response. Both ItTIL and StrTIL as continuous variables (per 10% increase) were associated with a higher probability of achieving a pCR (adjusted OR: 2.64, 95%CI 1.46-4.79, p=0.001 and 1.32 95%CI 1.08-1.6, p=0.006 for ItTIL and StrTIL, respectively). pCR rates were significantly higher in LP compared to non-LP cases (59% vs 27%, p=0.011). According to treatment, TIL effect was more evident in patients treated with HER2 double-blockade (arm C). According to estrogen receptor (ER) status, no difference in pCR rates between LP and non-LP cases was observed in the ER-positive population, whereas pCR rate was more than doubled for ER-negative LP compared to ER-negative non-LP patients (Table 1). Overall, 71 of the 121 CherLOB patients had residual disease at surgery: for 54 of them, paired pre-treatment and post-treatment TIL were available. No significant changes in ItTIL and StrTIL levels were observed before and after treatment. However, six cases presented a LP phenotype on the residual disease; all but one of them started from a non-LP pre-treatment phenotype and received lapatinib as part of the neoadjuvant treatment (4 arm B, 1 arm C). Conclusions: In this analysis, TIL predicted the achievement of pCR for early HER2-positive patients undergoing neoadjuvant chemotherapy plus anti-HER2 agents. TIL predictive effect seems limited to ER-negative patients. Combinations of chemotherapy plus anti-HER2 agents containing lapatinib may be able to convert a non-LP into a LP tumor. Updating of follow-up is ongoing, correlations between TIL and survival will be presented at the meeting. Citation Format: Maria Vittoria Dieci, Giancarlo Bisagni, Katia Cagossi, Alberto Bottini, Samanta Sarti, Federico Piacentini, Pierfranco Conte, Valentina Guarneri. Tumor infiltrating lymphocytes and correlation with outcome in the Cher-LOB study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD1-1.

Pharmacokinetics, pharmacodynamics and clinical efficacy of pertuzumab in breast cancer therapy

Introduction: Pertuzumab is a recombinant, humanized monoclonal antibody that binds to the dimerization domain of human epidermal growth factor receptor 2 (HER2), inhibiting the heterodimerization of HER2 with other HER receptors. It has shown synergy with trastuzumab in preclinical studies, and has led to a significant prolongation of progression-free and overall survival compared with placebo when added to trastuzumab and docetaxel for the first-line treatment of HER2-positive metastatic breast cancer (BC). Areas covered: The HER family of receptors and their pathways, pertuzumab pharmacodynamics and preclinical activity, results from the main clinical trials, new drug combinations being developed, and predictors of response are discussed. Expert opinion: Pertuzumab represents an important anti-HER2 agent that differs from, but is synergistic with, trastuzumab. It is already a standard of care in the first-line treatment of HER2-positive metastatic BC, and studies are ongoing to define its role in the adjuvant setting. It is now imperative to identify which tumors need dual HER2 targeting and to study the activity of pertuzumab in combination with other HER-targeted agents, including anti-HER1, -HER3 or -HER4, which could also prove useful in HER2-normal cancers. Potential competitors are anti-HER3 antibodies and bi- or tri-specific antibodies. Development in combination with phosphoinositide 3-kinase inhibitors or with anti PD-L1 is warranted.

Long-term complete response in a patient with liver metastases from breast cancer treated with metronomic chemotherapy.

Background Preclinical studies have shown that several chemotherapeutic agents at low doses may affect the vascular system. Here we report the case of a patient with long-term cancer control by metronomic chemotherapy. Case Presentation A 62-year-old woman with breast cancer underwent a left mastectomy in July 2007. For a liver metastasis she was given first-line chemotherapy with doxorubicin plus paclitaxel every 21 days. A CT scan after the sixth cycle showed a partial response. It was decided to stop the treatment with doxorubicin and paclitaxel, and start metronomic therapy with cyclophosphamide 50 mg daily orally and methotrexate 2.5 mg twice daily, 2 days a week. After 6 months of this maintenance treatment, CT scan showed a complete response. We examined the expression of vascular endothelial growth factor receptor 2 (VEGFR2) in histological sections of the primary tumor of our patient, finding evidence of overexpression of the receptor. The metronomic treatment is still ongoing, and after 60 months the patient maintains a complete response. Conclusion This clinical case highlights how suitable metronomic chemotherapy can be used as maintenance therapy, allowing long-term treatment with no significant toxicity. This case suggests that the level of VEGFR2 is predictive of best response to antiangiogenic therapy.

Androgen Receptor Expression in Breast Cancer: What Differences Between Primary Tumor and Metastases?

Genomic studies have shown that the androgen receptor (AR) pathway plays an important role in some breast cancer subtypes. However few data are present on the concordance between AR expression in primary tumors and metastases. We investigated AR expression by using immunohistochemistry (IHC) in 164 primary tumors and 83 metastases, to explore its distribution in the different tumor subtypes and its concordance between the two sample types and according to sampling time. AR was more highly expressed in luminal A and B than HER2-positive and triple negative primary tumors. A similar distribution was found in metastases, and the concordance of AR expression between primary tumors and metastases was greater than 60%. No association between sampling time and AR expression was observed. We found a good concordance of AR expression between primary tumor and metastasis, but the variability remains high between the two types of specimens, regardless of the variation in sampling time. For this reason, if used for treatment decisions, AR evaluation should be repeated in each patient whenever a new biopsy is performed, as commonly done for the other breast cancer biomarkers.

Androgen receptor in advanced breast cancer: is it useful to predict the efficacy of anti-estrogen therapy?

BackgroundAndrogen receptor (AR) is widely expressed in breast cancer (BC) but its role in estrogen receptor (ER)-positive tumors is still controversial. The AR/ER ratio has been reported to impact prognosis and response to antiestrogen endocrine therapy (ET).MethodsWe assessed whether AR in primary tumors and/or matched metastases is a predictor of efficacy of first-line ET in advanced BC. Patients who had received first-line ET (2002–2011) were recruited, while those given concomitant chemotherapy or trastuzumab or pretreated with > 2 lines of chemotherapy were excluded. ER, progesterone receptor (PgR), Ki67 and AR expression were assessed by immunohistochemistry, and HER2 mainly by fluorescent in-situ hybridization. Cut-offs of 1 and 10% immunostained cells were used to categorize AR expression.ResultsAmong 102 evaluable patients, biomarkers were assessed in primary tumors in 70 cases and in metastases in 49, with 17 patients having both determinations. The overall concordance rate between primary tumors and metastases was 64.7% (95% CI 42%-87.4%) for AR status. AR status did not affect TTP significantly, whereas PgR and Ki67 status did. AR/PgR ≥0.96 was associated with a significantly shorter TTP (HR = 1.65, 95% CI 1.05-2.61, p = 0.028). AR status in primary tumors or metastases was not associated with progressive disease (PD) as best response. In contrast, Ki67 ≥ 20% and PgR < 10% showed a statistically significant association with PD as best response.ConclusionsAR expression does not appear to be useful to predict the efficacy of ET in advanced BC, whereas Ki67 and PgR exert a greater impact on its efficacy.

Abstract P2-08-03: Survival analysis of the prospective randomized Cher-Lob study: Correlation with tumor infiltrating lymphocytes

Background: We previously reported the correlation between tumor infiltrating lymphocytes (TIL) at baseline and pathological complete response (pCR) after neoadjuvant chemotherapy plus anti-HER2 agents for HER2-positive patients included in the prospective randomized CherLOB study (Dieci , SABCS 2014). Here we report the survival analysis results. Methods: The phase II neoadjuvant CherLOB study (Guarneri, J Clin Oncol 2012) randomized 121 HER2-positive, stage II-IIIA breast cancer patients to anthracyclines/taxane-based chemotherapy plus trastuzumab, lapatinib, or both. A part from endocrine therapy for hormone receptor-positive patients, adjuvant treatment was left to physicians9 decision. This included trastuzumab for up to 1 year. Intratumoral (It) and stromal (Str) TIL were centrally evaluated on Hematoxylin and eosin-stained slides from pre-treatment biopsies and post-treatment surgical samples. For the present analysis, follow up was updated as of May 2015 (median follow up 68.3 months). Event-free survival (EFS) was calculated as the time interval from randomization to: recurrence, second primary cancer, death from any cause. Results: Among the 118 patients evaluable for pathological response, pCR (ypT0/is ypN0) was confirmed as a strong prognostic factor for EFS (HR 0.15, 95% CI 0.04-0.64, p=0.01). Both pre-treatment ItTIL and StrTIL evaluations were available for 105 patients, median values were 5% and 17% (interquartile range 0%-15% and 9%-40%, respectively). Table 1 summarizes the results of the survival analysis for the association of TIL with EFS. A non-significant trend for better EFS with increasing It-TIL (per 10%) was observed. Patients with ItTIL above the median value had a more prolonged EFS compared to patients with ItTIL below median (5-yrs EFS rate 89% vs 76%), with borderline statistical significance for the comparison between the two groups. No difference according to StrTIL above vs below median value was observed (5-yrs EFS rate 83% vs 82%, respectively). A comparison between lymphocyte predominant (LP) tumors, as defined by the generally accepted cut-off of ItTIL and/or StrTIL >=60%, vs non-LP cases was not performed due to low number of patients (n=17) and events (n=1) in the LP group. Among the 63 patients with residual disease, ItTIL and StrTIL evaluated on the surgical sample were not associated to EFS. Conclusions: In this low-powered analysis, TIL did not provide significant prognostic information for HER2-positive breast cancer patients treated in the CherLOB study. However, a non-significant trend suggests a positive correlation between increased levels of It-TIL and better EFS. The evaluation of immune gene expression signatures and their correlation with survival is ongoing, results will be available for the meeting. Citation Format: Dieci MV, Bisagni G, Cagossi K, Generali DG, Sarti S, Piacentini F, Conte P, Guarneri V. Survival analysis of the prospective randomized Cher-Lob study: Correlation with tumor infiltrating lymphocytes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-03.

Abstract P3-06-23: Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of preoperative chemotherapy plus trastuzumab and lapatinib in patients with HER2-positive operable breast cancer

Introduction: In vitro studies have shown that lapatinib enhances the immune-mediated cytotoxicity (ADCC) of trastuzumab. FcγR polymorphisms have been associated with both ADCC and clinical activity of trastuzumab in patients with HER2-positive metastatic breast cancer. There are no data on the relationship between these polymorphisms and the combination of trastuzumab plus lapatinib in the early stage setting. We performed a pharmacogenomics analysis of CHER-LOB, a randomized phase II trial of preoperative chemotherapy plus trastuzumab (arm A), lapatinib (arm B), or both (arm C) in HER2-positive operable breast cancer. Methods: FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Pathologic complete response (pCR) of genotyped cases was evaluated by FcγR polymorphism and treatment arm. Results: Genotyping was successfully performed in 73/121 (60%) patients. No deviation from the Hardy-Weinberg equilibrium was observed. Similarly to the overall results of the CHER-LOB study, in the subset of patients genotyped in this analysis, a significant improvement in pCR rate was observed in favor of the combination of lapatinib plus trastuzumab (arm C) compared to arm A (OR=3.66, P=0.037), and B (OR=3.03, P=0.049). Such improvement was restricted to carriers of FcγRIIIa V allele (C vs. A, OR=5.33, P=0.043; C vs. B, OR=6.50, P=0.012), while it was not observed in patients with FcγRIIIa F/F genotype (C vs. A, OR=2.14, P=0.642; C vs. B, OR=0.71, P=0.737). Disease free survival (DFS) was not different by treatment arm in all genotyped cases, but a trend toward significance for an interaction between FcγRIIIa V allele and better DFS with the combination of lapatinib plus trastuzumab was detected (P=0.058). No significant associations were observed by FcγRIIa polymorphism. Conclusions: Host-related immune signatures may mediate lapatinib enhanced trastuzumab-dependent ADCC. FcγRIIIa genotypes may help predict different outcomes to lapatinib plus trastuzumab in HER2-Positive Early Breast Cancer. Citation Format: Antonino Musolino, Valentina Guarneri, Nadia Naldi, Beatrice Bortesi, Daniela Boggiani, Paolo Sgargi, Daniele G Generali, Federico Piacentini, Maria V Dieci, Massimo Ambroggi, Katia Cagossi, Lorenzo Gianni, Samanta Sarti, Giancarlo Bisagni, Antonio Frassoldati, Pierfranco Conte, Andrea Ardizzoni. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of preoperative chemotherapy plus trastuzumab and lapatinib in patients with HER2-positive operable breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-23.