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  • American Association for Cancer Research (AACR)  (5)
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  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 24_Supplement ( 2013-12-15), p. P1-08-23-P1-08-23
    Abstract: Purpose: In 2009 we started a prospective, randomized Phase II trial to evaluate HER2-targeting without chemotherapy (CT) in HER2-positive (HER2+) metastatic breast cancer (MBC) patients (pts). Although the study was prematurely closed because of slow accrual, we decided to analyze the primary tumors in order to identify possible biomarkers that could identify, among the enrolled pts, those deriving the longest lasting benefit from HER2-targeting without CT. Experimental Design: In the HERLAP study (NCT00842998), pts with HER2+ MBC were randomized to trastuzumab or lapatinib as first-line therapy. Patients showing radiological signs of tumor regression after 8 weeks of treatment were allowed to continue on single agent anti-HER2 therapy until disease progression. CT was added to anti-HER-2 therapy in pts failing to achieve tumor regression at the 8-week evaluation and in those progressing at any time. Expression analysis of 105 selected genes was performed from formalin-fixed paraffin-embedded primary tumor samples. The research-based PAM50 intrinsic subtypes (Luminal A, Luminal B, HER2-enriched and Basal-like) and the normal breast-like group were also identified. Additionally, quantitative HER2 (H2T) and p95HER2 (p95) protein expression were evaluated using the HERmark® assay and the p95 VeraTag® assay, respectively. Potential predictors of persistence on protocol (PP, time from randomization to addition of chemotherapy to anti HER2-therapy or death from any cause) were studied by univariate and multivariate analysis. Results: Nineteen patients were enrolled. Median overall survival was 43 months and median PP was 3.8 months (0.8-38.8+) with 4 pts (21.1%) persisting on single agent T or L for longer than 12 months (14.9-38.8+ months). Seventeen pts were evaluable for PP. Gene expression analysis revealed that high expression of the 17q12-21 amplicon genes HER2 and GRB7, and the PAM50 HER2-enriched intrinsic profile, were significantly associated with longer PP. Conversely, high expression of luminal-related genes such as PGR, MDM2 and PIK3CA, or the PAM50 luminal intrinsic profile, were found associated with reduced PP. Quantitative H2T and p95 expression revealed that, increasing H2T/p95 ratio significantly associated with longer PP (HR 0.969, p = 0.010). When analyzed as a multivariable model, PAM50 intrinsic subtype and H2T/p95 ratio dichotomized around the median value independently predicted for longer PP (PAM50 non-luminal vs. Luminal A+B, HR 0.164, p = 0.078 and H2T/p95 ratio higher vs. lower/equal, HR 0.294, p = 0.062 respectively). Conclusions: Our data suggest that tumors belonging to the PAM50 “HER2-enriched” subtype tumors and/or with high H2T/p95 protein expression ratio are exquisitely sensitive to anti HER2-agents. MBC pts with these tumors may be candidates for studies aimed at establishing chemotherapy-free approaches. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-23.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 24_Supplement ( 2010-12-15), p. PD10-07-PD10-07
    Abstract: Background: Hormone receptors (HR) and the human epidermal growth factor receptor 2 (HER2) are key biological factors in breast cancer. Gene expression profile studies indicate that HER2-positive/HR-positive and HER2-positive/HR-negative tumors fall into two distinct subtypes. These two subtypes carry a different prognosis in the absence of HER2-targeting. Furthermore, a relationship has been documented between increasing HR expression and reduced chemoresponsiveness. Despite these differences, HER2-positive abvanced breast cancer patients are usually treated with a unified approach of combining chemotherapy with an HER2-targeting agent, regardless of HR status. We studied the association between hormone receptor (HR) expression and the clinical outcome of women with HER2-positive advanced breast cancer receiving chemotherapy plus trastuzumab. Methods: The effect of HR expression on overall response rate (ORR) and progression-free survival (PFS) to trastuzumab-based treatment was studied by univariate and multivariate analysis. HR positivity was defined as 1% or more tumor cells positive for the estrogen (ER) and/or for the progesterone (PgR) receptor by immunohistochemistry. For both ER and PgR, we studied different thresholds to identify levels of expression associated with the clinical outcomes of interest. Results: 227 consecutive advanced breast cancer patients receiving trastuzumab plus chemotherapy between June 1999 and November 2008 at two Institutions were retrospectively analyzed. One hundred eleven patients (49%) had HR-positive tumors. Compared with low or no expression, high expression of ER (30% or more) predicted reduced probability of tumor response to trastuzumab plus chemotherapy (multivariate odds ratio 0.422, 95% confidence interval-C.I. 0.222-0.803, p = 0.009). In patients with HR-positive tumors the addition of maintenance endocrine therapy to trastuzumab after the completion of chemotherapy was associated with a significant increase in progression-free survival (hazard ratio-HR 0.521, 95% C.I. 0.3325-0.836, p = 0.007). Patients with HR-positive tumors not receiving maintenance endocrine therapy had similar PFS than patients with HR-negative tumors (HR 0.914, 95% C.I. 0.654-1.279, p = 0.601). In patients not receiving maintenance endocrine therapy, high ER expression (30% or more cells) was associated with non-significant trend towards reduced risk of progression, compared with patients with low or absent ER expression (HR 0.747, 95% C.I. 0.516-1.081, p = 0.122). Conclusions: Our results suggest a predictive role of HR expression in HER2-positive tumors. Further investigation in this patient subset is warranted to optimize the use of HER2-targeting agents, chemotherapy and endocrine therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD10-07.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 24_Supplement ( 2011-12-15), p. P3-07-04-P3-07-04
    Abstract: Introduction: Based on the recently published ACSOG Z0011 study (JAMA 2011;305:569), axillary dissection (AD) may be avoided in breast cancer (BC) patients with a clinically negative axilla and a positive sentinel lymph node (SLN) biopsy receiving breast conserving surgery (BCS). Because the number of positive axillary lymph nodes (ALN) is a widely accepted prognostic marker, we evaluated the potential impact of omission of AD on indication to adjuvant chemotherapy (ACT). Patients and methods: Among 1497 patients operated at our Institution over 10 years, we identified 321 patients fulfilling the inclusion criteria of the ACSOG Z0011 study (BCS plus SLNB, cT1-2, cN0 breast cancer and 1 to 2 positive SLN). All patients underwent AD. Each case, which was anonymized, was reviewed by our breast team in two rounds. In the first round, patient age, histopathology, linfovascular invasion, tumor grade, hormone receptor, HER2, and ki67 status and number of positive SN nodes (micro and/or macrometastatic) were available. In the second round, the information on ALN was added. At each round, the panel chose between three indications: 1) Recommend ACT; 2) Discuss ACT; 3) No ACT. Results: SN was micrometastatic in 145 (45%) and macrometastatic in 176 patients (55%). ALD revealed non-SNs metastases in 96 patients (30%). Forty-four of these patients had & gt;3 positive ALN (range 4–24). Indications at round 1 and 2 are summarized below. As a result of the disclosure of the total number of involved ALN, a change in the indication occurred in 51 patients (16%). The most frequent change was a recommendation to ACT (35 patients, 69% of the changes). Among these patients, 9 changed from No-ACT to recommend ACT. All except one change in the indication to ACT occurred in patients with immunohistochemically defined Luminal A and Luminal B/HER2 negative tumors and were mostly towards ACT. Conclusions: Omission of AD in patients with a positive SLN receiving BCS would have altered the indication to ACT in 16% of the patients at our Institution. Changes occurred almost exclusively in patients with hormone receptor positive/HER2−negative tumors. The implications of omission of AD must be taken into account before its widespread acceptance, including the possibility of a biologically tailored surgical approach. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-04.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 24_Supplement ( 2011-12-15), p. P1-18-02-P1-18-02
    Abstract: Background: a small percentage of breast cancer (BC) patients (pts) will develop oligo-metastatic disease (OMD), often with a solitary lesion (SL). Growing evidences suggest a survival benefit for pts who undergo local treatment for SL. However, 18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan might improve the detection of truly SL, an important prerequisite for local treatments. We describe pattern of presentation and management of pts with SL diagnosed by FDG-PET/CT. Patients and Methods: From a bi-institutional database we retrospectively identified 137 pts who underwent a PET/CT because of rising tumor markers (95, 69%) or clinical/radiological suspect of disease recurrence (42, 31%). Median time from surgery of primary tumor to metastatic progression was 48 months (range 6–216 months). Comparisons of categorical and continuous variables were analyzed by the Chi-Square test and Mann-Whitney U test. Significance was set at p & lt;0.05. Results: PET/CT was positive in 78/137 pts. In 35 pts (26%) abnormal PET/CT findings consisted of a single area of increased metabolic activity, whereas in the other 43 (31%) multiple hyper-metabolic lesions were found. Twenty/35 pts with single hyper-metabolic spots had confirmed malignant SL: 17 (49%) were BC recurrences and 3 (9%) were new primary tumors other than BC. In the remaining 15 pts, hyper-metabolic SL were consistent with areas of inflammation, past trauma, thyroid struma and physiological ovarian functioning. Eight pts with SL (2: liver, 3: bone, 2: soft tissues, 1: lung) underwent local therapy, which consisted of surgical excision ± radiation therapy (4 pts), percutaneous cementoplasty and radiation therapy (2 pts), radiation therapy alone (1 pts) and percutaneous radiofrequency ablation (1 pts). After local treatment 7 pts also received systemic therapy: chemotherapy for 3 and endocrine therapy for 4 pts. Pts with solitary bone lesion also received zoledronic acid. Nine pts received only systemic therapy (4: soft tissues, 2: bone, 2: liver, 1: lung). Median age at the time of diagnosis of SL, histology of primary tumor, hormone receptor status, HER2 status, site of SL and prior exposure to adjuvant chemotherapy did not differ between pts treated with local or systemic therapy. At the time of this analysis, 11/17 pts with confirmed SL had progressed (5 had been treated with local and systemic therapy and 6 with systemic therapy alone), and all the pts were alive. Discussion: Our retrospective analysis suggests that FDG-PET/CT is a useful tool to identify BC pts with OMD susceptible of local and aggressive treatment, despite the impressive number of solitary non-neoplastic lesions. Our numbers are too small to point out any benefit from the addition of local over systemic treatment, and survival analyses were not significant. Nevertheless, due to growing evidences of a benefit of aggressive treatments for SL, treatment options for pts with OMD cannot leave aside local treatments. However, with the limitation due to small numbers and retrospective design, our data are hypothesis generating, and should be interpreted with caution. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-18-02.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 5
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 24_Supplement ( 2011-12-15), p. P2-12-31-P2-12-31
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 24_Supplement ( 2011-12-15), p. P2-12-31-P2-12-31
    Abstract: Purpose: We sought to evaluate whether moderate HER2 immunohistochemical (IHC) expression (2+ and no HER2/amplification) identifies early breast cancer (EBC) with a distinct prognostic profile. Methods: A total of 1295 women (median age 58, range 22–94) undergoing surgery for EBC from Jan 1995 to Sept 2009 were retrospectively reviewed. All patients had undergone HER2 testing by the HercepTest and, when needed, by fluorescence in-situ hybridization (FISH). All tests were carried on at our Institutional Surgical Pathology laboratory. The impact of HER2 status on disease-free survival (DFS) was corrected for other clinical and pathological potential covariates by Cox Proportional Regression Analysis. Results: A total of 494 (38%), 486 (38%), 119 (9%) and 196 (15%) of the patients had HER2 0+, 1+ 2+ and positive (3+ or FISH+) tumors, respectively. Sixty-one of 196 patients with HER2−positive EBC received adjuvant trastuzumab. A total of 298 DFS events occurred at median follow-up of 59 months (4-137 months). By using HER2 0+ status as reference, multivariate analysis revealed that HER2 2+ expression was associated with a significant increase in the risk of a DFS event (HR 2.303, 95% C.I. 1.501−3.533, p & lt;0.001), whereas HER2 1+ was not (HR 0.976, 95% C.I. 0.698−1.365, p=0.889). We performed exploratory two-group comparisons by further classifying tumors according to hormone-receptor status (cutoff for ER and PgR positivity ≥10% of stained cells). Results are summarized in the table. HER2 2+ expression was associated with worse prognosis in both ER and/or PgR positive and ER/PgR negative tumors. In the latter group, HER2 2+ expression was associated with a particularly high rate of DFS events, with a 60-month projected DFS of 20%. Furthermore, while DFS curves plateaued at 60 months for HER2−positive tumors (with and without adjuvant trastuzumab) and for ER/PgR negative tumors with HER2 0/1+ expression, hormone receptor positive/HER2 2+ tumors displayed a particularly high rate of late relapses (beyond 60 months). Results did not change using a 1% cutoff to define ER and PgR positivity. Conclusion: Moderate HER2 positivity (IHC 2+/FISH negative) identifies EBC patients at increased risk of a DFS event, regardless of hormone receptor status. Due to suggestions from large randomized trials that the benefits of trastuzumab may not be limited to HER2−positive tumors, patients with HER2 2+ EBC are ideal candidates for studies testing this hypothesis. Multivariate Hazard Ratios, corrected by age, lymph-node status, tumor diameter, tumor grade, proliferation (Ki 67 index) and receipt of adjuvant chemotherapy Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-31.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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