Gabriel Rinnerthaler

Neoadjuvant Chemotherapy and Targeted Therapy in Breast Cancer: Past, Present, and Future

Traditionally, neoadjuvant treatment for breast cancer was preserved for locally advanced and inflammatory disease, converting an inoperable to a surgical resectable cancer. In recent years, neoadjuvant therapy has become an accepted treatment option also for lower tumor stages in order to increase the rate of breast conserving therapy and to reduce the extent of surgery. Furthermore, treatment response can be monitored, and therefore, patient compliance may be increased. Neoadjuvant trials, additionally, offer the opportunity to evaluate new treatment options in a faster way and with fewer patients than large adjuvant trials. Compared to the metastatic setting, the issue of acquired resistance and pretreatments, which may distort treatment efficacy, can be avoided. New trial designs like window-of-opportunity trials or postneoadjuvant trials provide the chance to identify tumor sensitivity or to overcome tumor resistance in early tumor stages. In particular, in HER2-positive breast cancer, the neoadjuvant approach yielded great successes. The dual HER2 blockade with trastuzumab and pertuzumab recently showed the highest pCR rates ever reported. Many new drugs are in clinical testing with the aim to further increase pCR rates. Whether this endpoint really represents a surrogate for long-term outcome is not answered yet and will be discussed in this review.

Female gender may predict response to FOLFIRINOX in patients with unresectable pancreatic cancer: A single institution retrospective review

FOLFIRINOX is a highly active regimen for the treatment of patients with unresectable pancreatic cancer. However, treatment with FOLFIRINOX is associated with relevant toxicity and predictors for response to therapy are warranted. We retrospectively analyzed 49 patients with unresectable pancreatic cancer treated with FOLFIRINOX in order to evaluate a possible predictive role of clinical parameters and tumor characteristics for response to chemotherapy. Tumor samples were characterized histopathologically before treatment and expression of p53 and Ki67 was analyzed using automated immunohistochemistry. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. The overall objective response rate was 55.1%, the disease control rate was 70.6%. Female gender was associated with a significantly higher disease control rate of 91.7 compared to 48.0% in male patients (p=0.001) which reached 100% in female patients when primarily treated compared to treatment after surgical resection and relapse (77.8%, p=0.057). For all patients median PFS was 3.5 months (95% CI, 2.7-4.3 months) and median OS was 13 months (95% CI, 9.4-16.6 months). Female patients showed a tendency towards a longer median PFS (5.0 months, 95% CI, 3.6-6.4 months) compared to males (3.0 months, 95% CI, 2.4-3.6 months) (p=0.099). Serum levels of CA19.9 and CEA were significantly higher in female patients compared to male patients (p=0.037, p=0.05). Tumors of patients with response to FOLFIRINOX showed a higher expression level of p53 and Ki67 as well as higher serum levels of CA19.9 compared to non-responders, which was statistically not significant. Our study indicates that female gender is a positive predictor for therapy response to FOLFIRINOX in patients with unresectable pancreatic cancer. Female gender in turn was associated with increased levels of tumor markers CEA and CA19.9 and patients with higher serum levels of CA19.9 were more responsive to FOLFIRINOX.

miR-16-5p Is a Stably-Expressed Housekeeping MicroRNA in Breast Cancer Tissues from Primary Tumors and from Metastatic Sites

For quantitative microRNA analyses in formalin-fixed paraffin-embedded (FFPE) tissue, expression levels have to be normalized to endogenous controls. To investigate the most stably-expressed microRNAs in breast cancer and its surrounding tissue, we used tumor samples from primary tumors and from metastatic sites. MiRNA profiling using TaqMan® Array Human MicroRNA Cards, enabling quantification of 754 unique human miRNAs, was performed in FFPE specimens from 58 patients with metastatic breast cancer. Forty-two (72%) samples were collected from primary tumors and 16 (28%) from metastases. In a cross-platform analysis of a validation cohort of 32 FFPE samples from patients with early breast cancer genome-wide microRNA expression analysis using SurePrintG3 miRNA (8 × 60 K)® microarrays from Agilent® was performed. Eleven microRNAs could be detected in all samples analyzed. Based on NormFinder and geNorm stability values and the high correlation (rho ≥ 0.8) with the median of all measured microRNAs, miR-16-5p, miR-29a-3p, miR-126-3p, and miR-222-3p are suitable single gene housekeeper candidates. In the cross-platform validation, 29 human microRNAs were strongly expressed (mean log2-intensity > 10) and 21 of these microRNAs including miR-16-5p and miR-29a-3p were also stably expressed (CV < 5%). Thus, miR-16-5p and miR-29a-3p are both strong housekeeper candidates. Their Normfinder stability values calculated across the primary tumor and metastases subgroup indicate that miR-29a-3p can be considered as the strongest housekeeper in a cohort with mainly samples from primary tumors, whereas miR-16-5p might perform better in a metastatic sample enriched cohort.

Clonal evolution in relapsed and refractory diffuse large B-cell lymphoma is characterized by high dynamics of subclones

Little information is available about the role of certain mutations for clonal evolution and the clinical outcome during relapse in diffuse large B-cell lymphoma (DLBCL). Therefore, we analyzed formalin-fixed-paraffin-embedded tumor samples from first diagnosis, relapsed or refractory disease from 28 patients using next-generation sequencing of the exons of 104 coding genes. Non-synonymous mutations were present in 74 of the 104 genes tested. Primary tumor samples showed a median of 8 non-synonymous mutations (range: 0-24) with the used gene set. Lower numbers of non-synonymous mutations in the primary tumor were associated with a better median OS compared with higher numbers (28 versus 15 months, p=0.031). We observed three patterns of clonal evolution during relapse of disease: large global change, subclonal selection and no or minimal change possibly suggesting preprogrammed resistance. We conclude that targeted re-sequencing is a feasible and informative approach to characterize the molecular pattern of relapse and it creates novel insights into the role of dynamics of individual genes.

Bone-Targeted Therapy in Metastatic Breast Cancer - All Well-Established Knowledge?

Bone-targeted therapies like bisphosphonates (zoledronic acid or pamidronate) or denosumab are recommended in all patients with metastatic breast cancer and bone metastases, whether they are symptomatic or not. The choice between these 2 different agents, however, remains open. In this review, we critically discuss the emerging evidence for direct anti-tumor activity of bone-targeting agents, the utility of bone turnover markers for treatment decision and efficacy prediction, as well as the safety and financial aspects of bisphosphonates and denosumab. Furthermore, we provide a possible therapeutic algorithm, and present new pharmacologic agents which are being investigated for the treatment of meta-static bone disease.

SABCS 2016: systemic therapy for metastatic breast cancer

SummaryAt the 2016 San Antonio Breast Cancer Symposium, several interesting phasexa0II and phasexa0III studies investigating systemic therapies for metastatic breast cancer were presented. The PrEGOC 0102 trial demonstrated that the combination of fulvestrant plus everolimus is safe and effective and could be an alternative to exemestane plus everolimus for selected patients with hormone-receptor positive, HER2-negative disease. The pan-PI3K inhibitor buparlisib showed some activity in combination with fulvestrant after failure of everolimus in the BELLE-3 trial. PIK3CA mutation detected in circulating tumor DNA (ctDNA) was predictive for axa0buparlisib efficacy. Unfortunately, the unfavorable toxicity profile precludes further development of this drug. Nonetheless, PI3K seems to be axa0valid target in tumors resistant to mTOR inhibition. The BROCADE phasexa0II trial failed to show axa0statistically significant benefit by the addition of the PARP inhibitor veliparib to carboplatin and paclitaxel in patients with BRCA1/2 germline mutation. The overall response rate, however, was statistically significant higher in the veliparib arm compared to the placebo arm. Data from the phasexa0IIIxa0trial BROCADE-3 are awaited. Finally, the TNT trial did not identify further biomarkers, in addition to BRCA1/2 germline mutation, for carboplatin benefit in patients with metastatic triple-negative breast cancer.

Abstract P3-11-06: Bevacizumab in combination with docetaxel+trastuzumab +/- non-pegylated liposomal doxorubicin: Final results of ABCSG-32, a prospective, randomized phase II-study

BACKGROUND Pathological complete response (pCR) after neoadjuvant systemic therapy is correlated with better prognosis in HER2-positive, early breast cancer. Bevacizumab (B) was shown to add efficacy to neoadjuvant systemic treatment in HER2-negative, early breast cancer in terms of pCR-rate but failed in the adjuvant setting of both, HER2-negative and HER2-positive disease. The role of B in the neoadjuvant treatment of HER2-positive, early breast cancer is not defined. Thus, ABCSG-32 was designed as a randomized phase II trial to evaluate the efficacy, the non-cardiac safety, and the cardiac toxicity of B when added to docetaxel + trastuzumab (DT) +/- non-pegylated liposomal doxorubicin (N) in the neoadjuvant setting of early, HER2-positive breast cancer. METHODS 100 patients with biopsy-proven, invasive, early, HER2-positive breast cancer were stratified according to major risk factors including estrogen receptor (ER)-status, histology, tumor grade, and center and were randomized to receive 6 cycles (q 21 days) of either D100 mg/m2+T8/6mg/kg (DT, n=25), DT+B15mg/kg (DTB, n=25), D75T+N50 mg/m2 (DTN, n=26), or D75TN+B15 mg/m2 (DTNB, n=24). All patients received pegfilgrastim 6 mg sc on day 2. pCR was defined as the absence of invasive tumor cells in the breast and total pCR (tpCR) was defined as the absence of invasive tumor cells in the breast and axillary nodes after NST. Left ventricular (LV) ejection fraction (EF) was measured at baseline, before each treatment cycle, and before sugery. A cardiac toxicity event (CTE) was defined as the occurrence of either symptomatic LV dysfunction NYHA II-III, or an asymptomatic drop of EF (adEF) of >15% from baseline, or an adEF RESULTS The overall rate of pCR in all patients was 52% (DT: 36%, DTB: 51%, DTN: 63%, DTNB: 62%). In the ER-negative subgroup (n=43) the overall pCR rate was 63% (DT: 31%, DTB: 70%, DTN: 75%, DTNB: 88%) and the overall tpCR rate was 60% (DT: 31%, DTB: 60%, DTN: 75%, DTNB: 88%). Cardiac toxicity was low with a CTE in only3 patients (DT:0, DHB:1, DTN:1, DTNB:1). Non-cardiac toxicity/patient as evaluated by the incidence of serious adverse events (SAE,n=50) and significant safety events (SSE, n=114) was acceptable (SAE: DT:8, DTB:12, DTN:14, DTNB: 16; SSE: DT: 23, DTB: 31, DTN: 29, DTNB: 31). No differences in the incidence of non-serious AE and no new safety signals for B and N were detected. In 8 patients the treatment was terminated early (DT: 0, DTB: 3, DTN: 2, DTNB: 3). CONCLUSIONS Our data show that all regimens tested are effective in inducing pCR in HER2-positive early breast cancer. The addition of B and/or N to DT may lead to pCR/tpCR-rates of 51-88% with the highest activity seen in the ER-negative subgroup. 6 cycles of these regimens can safely be administered to patients with HER2-positive early breast cancer and further phase III-evaluation appear to be warranted. Citation Format: Guenther G Steger, Richard Greil, Michael Hubalek, Michael A Fridrik, Christian F Singer, Rupert Bartsch, Marija Balic, Peter Dubsky, Daniel Egle, Simon P Gampenrieder, Georg Pfeiler, David Mayr, Theresa Czech, Gabriel Rinnerthaler, Ruth Exner, Andreas L Petzer, Paul Sevelda, Alois Lang, Margaretha Rudas, Barbara Krause, Michael Seifert, Sophie Frantal, Christoph C Zielinski, Michael Gnant. Bevacizumab in combination with docetaxel+trastuzumab +/- non-pegylated liposomal doxorubicin: Final results of ABCSG-32, a prospective, randomized phase II-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 P3-11-06.

CDK4/6 inhibition in luminal breast cancer

SummaryEndocrine therapy represents the basis for the treatment of estrogen receptor-positive breast cancer, but several tumors harbor intrinsic resistance and acquired resistance to endocrine therapy is inevitable in metastatic disease. Combination strategies of endocrine therapy with targeted agents are aimed to overcome endocrine resistance. The selective CDK4/6 inhibitor palbociclib has shown promising results in metastatic luminal breast cancer when used in combination with endocrine therapy both in the first-line setting as in pretreated women. The drug showed axa0manageable safety profile with uncomplicated neutropenia as the most frequent side effect. Approval was already granted in the US and is also awaited during 2016 for Europe.

Poly-ligand profiling differentiates trastuzumab-treated breast cancer patients according to their outcomes

Assessing the phenotypic diversity underlying tumour progression requires the identification of variations in the respective molecular interaction networks. Here we report proof-of-concept for a platform called poly-ligand profiling (PLP) that surveys these system states and distinguishes breast cancer patients who did or did not derive benefit from trastuzumab. We perform tissue-SELEX on breast cancer specimens to enrich single-stranded DNA (ssDNA) libraries that preferentially interact with molecular components associated with the two clinical phenotypes. Testing of independent sample sets verifies the ability of PLP to classify trastuzumab-treated patients according to their clinical outcomes with ROC-AUC of 0.78. Standard HER2 testing of the same patients gives a ROC-AUC of 0.47. Kaplan–Meier analysis reveals a median increase in benefit from trastuzumab-containing treatments of 300 days for PLP-positive compared to PLP-negative patients. If prospectively validated, PLP may increase success rates in precision oncology and clinical trials, thus improving both patient care and drug development.Patients’ selection is particularly important in cancer treatment. Here the authors present a proof-of-principle methodology that could be potentially important in assisting therapeutic decisions in the treatment of breast cancer patients.

SABCS 2017: lifestyle factors, hormone receptor-positive advanced disease, liquid biopsies, and prognosis

SummaryThis article reviews the clinically most relevant presentations at the San Antonio Breast Cancer Symposium (SABCS) 2017 on the topics lifestyle factors, hormone receptor-positive advanced disease, liquid biopsies, and prognosis.In axa0retrospective analysis of the Women’s Health Initiative Observational Study, axa0reduction in the body mass index (BMI) of at least 5% within 3xa0years significantly reduced the risk of breast cancer compared to women with axa0stable weight (HR 0.77; 95% CI 0.78–0.98). In the MONALEESA-7 trial investigating ribociclib or placebo in combination with endocrine therapy as first-line treatment in pre- and perimenopausal women with hormone receptor-positive, human epidermal growthxa0factorxa02 (HER2)-negative metastatic breast cancer, axa0significantly longer progression-free survival was shown for patients treated with ribociclib compared to the placebo group (23.8 vs. 13.0xa0months; HR 0.55; 95% CI 0.43–0.72; Pu202f<u20090.001). In axa0pooled toxicity and efficacy analysis of elderly women treated with axa0cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in combination with an aromatase inhibitor in first-line, toxicities of higher grade were more common in elderly compared to younger patients, despite comparable efficacy. And the Clinical Treatment Score post-5xa0years (CTS5), accurately estimated the risk of late recurrence after 5xa0years of adjuvant endocrine treatment using routinely available clinical parameters.