Role of biologic therapy and chemotherapy in hormone receptor- and HER2-positive breast cancer

Background: To review the efficacy of chemotherapy and human epidermal growth factor receptor 2 (HER2)-targeted therapy when used in addition to hormonal therapy for the optimal management of estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-positive (HER2+) breast cancer.Design: Literature published from January 2003 to March 2008 was reviewed to assess the use of chemotherapy and biologic therapy in addition to hormonal agents.Results: Aromatase inhibitors (AIs) demonstrated greater effectiveness in the adjuvant setting than tamoxifen for the management of ER+ and HER2+ breast cancer. Evidence of cross talk between HER2- and ER-signaling pathways suggests that combined treatment with HER2 blockade and hormonal therapy may offer clinical advantages beyond those provided by hormonal therapy alone in ER+/HER2+ disease. Combined therapy with trastuzumab plus an aromatase AI significantly improves progression-free survival, response rates, and clinical benefits when compared with AI monotherapy in postmenopausal women. Several large studies demonstrated that trastuzumab significantly improves disease-free and overall survival when given in combination with, or following, chemotherapy, regardless of hormone receptor status.Conclusions: HER2-targeted therapy maybe combined with AIs for the treatment of ER+/HER2+ metastatic breast cancer in postmenopausal women. HER2-targeted therapy in combination with AIs for treatment of ER+/HER2+ early breast cancer needs to be prospectively evaluated.     

First‐Line Treatment Patterns and Clinical Outcomes in Patients With HER2‐Positive and Hormone Receptor‐Positive Metastatic Breast Cancer From registHER

Background.

Limited data are available describing the natural history of patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer (MBC). We examined first-line treatment patterns and clinical outcomes in patients with HER2-positive, HR-positive MBC in a real-world setting.

Methods.

registHER is a prospective, observational cohort of 1,023 patients with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up time: 27 months). Demographics, first-line treatment patterns, and clinical outcomes were examined for 530 HER2-positive, HR-positive patients. Progression-free survival (PFS) and overall survival (OS) times were examined. Multivariate analyses adjusted for baseline demographic and prognostic factors.

Results.

HER2-positive, HR-positive patients receiving first-line trastuzumab plus hormonal therapy had significantly longer PFS times than patients who received hormonal therapy only (13.8 vs. 4.8 months; adjusted hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.22–0.60); a nonsignificant reduction in OS time was observed (adjusted HR: 0.55, 95% CI: 0.27–1.14). Compared with patients who received first-line trastuzumab plus chemotherapy, patients who received first-line trastuzumab plus chemotherapy and hormonal therapy had longer median PFS times (20.4 months vs. 9.5 months; adjusted HR: 0.53, 95% CI: 0.42–0.68); a statistically significant reduction in risk of death was observed (adjusted HR: 0.50, 95% CI: 0.36–0.70). Sequential use of chemotherapy and hormonal therapy was associated with improved OS times when compared with concurrent use (adjusted PFS HR: 0.81, 95% CI: 0.54–1.21; adjusted OS HR: 0.48, 95% CI: 0.26–0.89).

Conclusions.

These real-world data in patients with HER2-positive/HR-positive MBC provide evidence that, with or without chemotherapy, dual targeting of HRs and HER2 receptors is associated with significantly prolonged PFS and OS times.     

Locally advanced breast cancer

Opinion statement Over the past 20 years, the prognosis for women diagnosed with locally advanced breast cancer (LABC; clinical stages IIB through IIIB) has improved significantly with recognition of the efficacy of multimodal therapy for reducing both local and distant recurrences, even in patients with inflammatory breast cancer (IBC). Most patients will respond to induction, or neoadjuvant, chemotherapy (NAC) with an anthracycline-based regimen, enabling many patients with large but operable tumors to undergo breast-conserving surgery (BCS) and enabling resection in most patients with inoperable disease. However, only a small percentage of patients achieve a pathologic complete response (CR) with this approach. Long-term disease-free survival (DFS) and overall survival (OS) correlate with the extent of residual disease in the breast and axillary nodes following NAC. The addition of paclitaxel or docetaxel, either in combination with an anthracycline or as a separate regimen administered before or after anthracycline-based therapy, increases clinical and pathologic response rates and may improve DFS. With the possible exception of patients with IBC, BCS does not compromise outcome. Partial mastectomy should be accompanied by standard nodal dissection in patients with clinically or radiographically positive axillae; in patients with negative axillae, sentinel lymph node (SLN) sampling, with subsequent axillary dissection reserved for patients with involved nodes, may reduce postoperative morbidity. Patients who received only anthracycline-based NAC who are found to have significant residual disease in the breast or involved axillary nodes at surgery should receive adjuvant chemotherapy with paclitaxel. Postoperative radiation to the residual breast or chest wall and regional nodal areas reduces locoregional recurrences, but its impact on OS remains controversial. Adjuvant hormonal therapy with tamoxifen improves DFS and OS in patients with hormone receptor (HR)-positive tumors, and ovarian ablation should be considered in premenopausal patients with HR-positive tumors and multiple involved nodes or stage IIIB disease. Neoadjuvant hormonal therapy with either tamoxifen or an aromatase inhibitor may benefit frail or elderly patients with HR-positive tumors for whom chemotherapy is not an option. No advantage has been demonstrated for highdose chemotherapy requiring hematopoietic stem-cell support as either NAC or adjuvant therapy in LABC. Newer treatment approaches, including trastuzumab (Herceptin, Genentech, Inc., South San Francisco, CA), in patients with Her-2-overexpressing tumors or other biologic agents, do not have a proven role in the management of LABC at this time.     

Adjuvant aromatase inhibitors following tamoxifen for early-stage breast cancer in postmenopausal women: what do we really know?

Adjuvant hormonal therapy in the treatment of women with early-stage, hormone receptor (HR)-positive breast cancer is now considered the standard of care. Adjuvant tamoxifen decreases the risk of breast cancer recurrence and death in women with early-stage breast cancer when taken for 5 years. The benefits of tamoxifen are counterbalanced by toxicities including an increased risk of endometrial cancer and thromboembolic events. The selective aromatase inhibitors (AIs)--including anastrozole, letrozole, and exemestane--are challenging the role of tamoxifen as the adjuvant hormonal therapy of choice in postmenopausal women. Results of the Arimidex and Tamoxifen Alone or in Combination trial favor the use of anastrozole over tamoxifen as initial adjuvant hormonal therapy, with improvement in disease-free survival (DFS) and a favorable toxicity profile. The results of 2 large adjuvant trials using AIs sequentially with tamoxifen in postmenopausal women with early-stage, HR-positive breast cancer have been reported. The MA-17 study randomized women to placebo or letrozole for 5 years after completion of 4.5-6 years of initial tamoxifen. The Intergroup Exemestane Study (IES) randomized women following 2-3 years of adjuvant tamoxifen to continue to receive tamoxifen or switch to exemestane for a total of 5 years of adjuvant hormonal therapy. The MA-17 and IES trials demonstrated superior DFS with the AI and corroborated the smaller GROCTA-4B and Italian Tamoxifen Arimidex trials, which studied sequential therapy with aminoglutethamide or anastrozole. There is now substantial medical evidence supporting the use of AIs in postmenopausal women with early-stage, HR-positive breast cancer.     

HER3 status by immunohistochemistry is correlated with poor prognosis in hormone receptor-negative breast cancer patients

Breast cancer is a highly heterogeneous malignancy. The triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2) breast cancer subtypes are highly aggressive and are associated with a poor prognosis. The therapeutic targets for TNBC remain undefined, and many patients with the HER2 subtype acquire resistance to therapy after prolonged treatment. The objective of this study was to evaluate the prognostic significance of HER3 expression in invasive breast carcinoma. We established matched tissue microarray (TMA) blocks and clinical data from 950 cases of invasive breast carcinoma with long-term clinical follow-up data (median 109.7 months). Using the TMAs, we characterized the expression of ER, PR, HER2, EGFR, and HER3 by immunohistochemistry. Each case was classified as one of four IHC-based subtypes based on the expression of hormonal receptor (HR) and HER2. The clinicopathological characteristics and survival of 950 patients were analyzed by subtype. In the TNBC subtype, the HER3(+) group showed poorer disease-free survival (DFS, P = 0.010) and overall survival (OS, P = 0.015) than the HER3(?) group. In the HER2 subtype, the HER3(+) group also showed poorer DFS (P = 0.022) and OS (P = 0.077) than the HER3(?) group. However, there was no difference in patients with HR-positive breast cancer. HER3 expression was associated with poor DFS in both the TNBC and HER2 subtypes and poor OS in the TNBC subtype. HER3 overexpression is an important prognostic marker in hormone receptor-negative breast cancer, and further study is needed to clarify the role of HER-3 targeted treatment.     

Dose-dense adjuvant chemotherapy in HER2-positive early breast cancer patients before and after the introduction of trastuzumab: Exploratory analysis of the GIM2 trial

Dose-dense adjuvant chemotherapy is standard of care in high-risk early breast cancer patients. However, its role in HER2-positive patients is still uncertain. In this exploratory analysis of the GIM2 trial, we investigated the efficacy of dose-dense chemotherapy in HER2-positive breast cancer patients with or without exposure to trastuzumab. In the GIM2 trial, node-positive early breast cancer patients were randomized to receive four cycles of (fluorouracil)epirubicin/cyclophosphamide followed by four cycles of paclitaxel administered every 2 (dose-dense) or 3 (standard-interval) weeks. After approval of adjuvant trastuzumab, protocol was amended in April 2006 to allow use of trastuzumab for 1 year after chemotherapy completion in HER2-positive patients. The efficacy of dose-dense chemotherapy in terms of disease-free survival (DFS) and overall survival (OS) was assessed according to HER2 status and trastuzumab use. Out of 2,003 breast cancer patients, HER2 status was negative/unknown in 1,551 patients; among the 452 patients with HER2-positive breast cancer, chemotherapy alone or followed by trastuzumab was given to 320 and 132 patients, respectively. Median follow-up was 8.1 years. No significant interaction between HER2 status, trastuzumab use and chemotherapy treatment was observed for both DFS (p = 0.698) and OS (p = 0.708). Nevertheless, there was no apparent benefit in the HER2-positive group treated with trastuzumab (DFS: HR, 0.99; 95% CI 0.52–1.89; OS: HR, 0.95; 95% CI 0.37–2.41). Although dose-dense chemotherapy was associated with a significant survival improvement in high-risk breast cancer patients, its benefit appeared to be smaller (if any) in patients with HER2-positive disease who received adjuvant trastuzumab.     

Superimposable outcomes for sequential and concomitant administration of adjuvant trastuzumab in HER2-positive breast cancer: Results from the SIGNAL/PHARE prospective cohort

AimAdjuvant clinical trials in early human epidermal growth factor receptor 2 (HER2)-positive breast cancer have assessed either sequential or concomitant incorporation of trastuzumab with chemotherapy; only the North Central Cancer Treatment Group (NCCTG)-N9831 trial prospectively compared both modalities. In routine trastuzumab has been incorporated into a concurrent regimen with taxane chemotherapy instead of sequential modality on the basis of a positive risk-benefit ratio. This present study assessed sequential versus concomitant administration of adjuvant trastuzumab.MethodsA population combining patients from Protocol for Herceptin^® as Adjuvant therapy with Reduced Exposure (PHARE) a randomised phase III clinical trial (NCT00381901) and SIGNAL (RECF1098) a prospective study specifically designed for Genome-wide Association Studies (GWAS) analyses was studied. In this cohort with 58 months of median follow-up, the comparison in the HER2-positive group of adjuvant trastuzumab and chemotherapy modalities was based on a propensity score methodology. Treatment modalities were based on physician's choice and comparisons adjustment were made by a propensity score methodology. Overall Survival (OS) and Disease-Free Survival (DFS) were estimated using the Kaplan–Meier method, and comparisons between groups were based on the log rank test.ResultsThe SIGNAL/PHARE cohort included 11,728 breast cancer cases treated in adjuvant setting; some 5502 of them with HER2-positive tumour: 34.5% (1897/5502) were treated by sequential and 65.5% (3605/5502) by concomitant modality of administration for taxane-chemotherapy and trastuzumab. The adjusted comparison found similar OS (HR = 1.01; 95% CI: 0.86–1.19) and similar DFS (HR = 1.08; 95% CI: 0.96–1.21).ConclusionThese results suggest that the sequential administration of trastuzumab given after the completion of adjuvant chemotherapy might be as valid as the concomitant administration of trastuzumab and taxane chemotherapy in the adjuvant setting.     

Association between the HER2 Ile655Val polymorphism and response to trastuzumab in women with operable primary breast cancer

BackgroundHuman epidermal growth factor receptor 2 (HER2) Ile655Val polymorphism may affect the efficacy of trastuzumab treatment of breast cancer.Patients and methodsHER2 Ile655Val polymorphism was determined in 4167 patients with primary breast cancer using a polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) assay. We investigated the associations between the HER2 Ile655Val polymorphism and clinical outcomes in women with HER2-negative breast cancer and with HER2-positive breast cancer who received trastuzumab or who did not.ResultsAt a median follow-up of 44 months, HER2 Ile655Val polymorphism was not significantly associated with survival either in the entire study population of 4167 patients or in 2976 HER2-negative breast cancer patients. Among 816 HER2-positive patients who received adjuvant chemotherapy and/or endocrine therapy without trastuzumab treatment, patients with the Val/Ile or the Val/Val genotype had a significantly worse disease-free survival (DFS) and distant DFS (DDFS) than those with the Ile/Ile genotype (DFS, adjusted hazard ratio [HR] 1.5; 95% confidence interval [CI] 1.0–2.3; P = 0.037; DDFS, adjusted HR 1.9; 95% CI 1.2–2.9 P = 0.005). In contrast, among 212 HER2-positive patients who received chemotherapy in combination with trastuzumab treatment, patients with the Val/Ile or the Val/Val genotype had a significantly better DFS and DDFS than those with the Ile/Ile genotype (5-year DFS, 100% versus 83%; P = 0.008; 5-year DDFS, 100% versus 89%; P = 0.031).ConclusionsHER2 Ile655Val polymorphism affects the function of HER2 gene only restricted in HER2-positive breast cancers. HER2-positive breast cancer patients with the Val variant have an aggressive phenotype, but are sensitive to trastuzumab treatment.     

Long-term treatment efficacy in primary inflammatory breast cancer by hormonal receptor- and HER2-defined subtypes

BackgroundSubtypes defined by hormonal receptor (HR) and HER2 status have not been well studied in inflammatory breast cancer (IBC). We characterized clinical parameters and long-term outcomes, and compared pathological complete response (pCR) rates by HR/HER2 subtype in a large IBC patient population. We also compared disease-free survival (DFS) and overall survival (OS) between IBC patients who received targeted therapies (anti-hormonal, anti-HER2) and those who did not.Patients and methodsWe retrospectively reviewed the records of patients diagnosed with IBC and treated at MD Anderson Cancer Center from January 1989 to January 2011. Of those, 527 patients had received neoadjuvant chemotherapy and had available information on estrogen receptor (ER), progesterone receptor (PR), and HER2 status. HR status was considered positive if either ER or PR status was positive. Using the Kaplan–Meier method, we estimated median DFS and OS durations from the time of definitive surgery. Using the Cox proportional hazards regression model, we determined the effect of prognostic factors on DFS and OS. Results were compared by subtype.ResultsThe overall pCR rate in stage III IBC was 15.2%, with the HR-positive/HER2-negative subtype showing the lowest rate (7.5%) and the HR-negative/HER2-positive subtype, the highest (30.6%). The HR-negative, HER2-negative subtype (triple-negative breast cancer, TNBC) had the worst survival rate. HR-positive disease, irrespective of HER2 status, had poor prognosis that did not differ from that of the HR-negative/HER2-positive subtype with regard to OS or DFS. Achieving pCR, no evidence of vascular invasion, non-TNBC, adjuvant hormonal therapy, and radiotherapy were associated with longer DFS and OS.ConclusionsHormone receptor and HER2 molecular subtypes had limited predictive and prognostic power in our IBC population. All molecular subtypes of IBC had a poor prognosis. HR-positive status did not necessarily confer a good prognosis. For all IBC subtypes, novel, specific treatment strategies are needed in the neoadjuvant and adjuvant settings.     

Benefit of adjuvant chemotherapy with or without trastuzumab in pT1ab node-negative human epidermal growth factor receptor 2-positive breast carcinomas: results of a national multi-institutional study

Purpose

Benefit of adjuvant trastuzumab-based chemotherapy for node-positive and/or >1 cm human epidermal growth factor receptor 2-positive (HER2+) breast carcinomas has been clearly demonstrated in randomized clinical trials. Yet, evidence that adjuvant chemotherapy with or without trastuzumab is effective in pT1abN0 HER2+ tumors is still limited. The primary objective of this study was to investigate the impact of adjuvant chemotherapy ± trastuzumab on outcome in this subpopulation.

Patients and methods

A total of 356 cases of pT1abN0M0 HER2 + breast cancers were retrospectively identified from a large cohort of 22,334 patients, including 1248 HER2+ patients who underwent primary surgery at 17 French centers, between December 1994 and January 2014. The primary end point was disease-free survival (DFS). A multivariate Cox model was built, including adjuvant chemotherapy, tumor size, hormone receptor status, and Scarff Bloom Richardson (SBR) grade.

Results

A total of 138 cases (39%) were treated with trastuzumab-based chemotherapy, 29 (8%) with chemotherapy alone, and 189 (53%) received neither trastuzumab nor chemotherapy. Adjuvant chemotherapy ± trastuzumab was associated with a significant DFS benefit (3-year 99 vs. 90%, and 5-year 96 vs. 84%, Hazard ratio, HR 0.26 [0.10–0.67]; p = 0.003, logrank test) which was maintained in multivariate analysis (HR 0.19 [0.07–0.52]; p = 0.001). Metastasis-free survival was also increased (HR 0.25 [0.07–0.86]; p = 0.018, logrank test) at 3-year (99 vs. 95%) and 5-year (98 vs. 89%) censoring. Exploratory subgroup analysis found DFS benefit to be significant in hormone receptor-negative, hormone receptor-positive, and pT1b tumors, but not in pT1a tumors.

Conclusions

Adjuvant chemotherapy ± trastuzumab is associated with a significantly reduced risk of recurrence in subcentimeter node-negative HER2+ breast cancers. Most of the benefit may be driven by pT1b tumors.

     

Twenty years of systemic therapy for breast cancer

The past 2 decades of systemic therapy for breast cancer have been a period of monumental change, in terms of both theory and technology. Adjuvant therapy developed from two strands of research--one in systemic chemotherapy and one in hormonal therapy--both of which were aided by the application of higher statistical methodology to clinical trials. The agent with the single greatest public health impact in oncology has been tamoxifen, but problems with tamoxifen therapy led to the development of the aromatase inhibitors, and further research led to the use of hormonal therapy in a chemopreventive capacity. The evolution of systemic chemotherapy for breast cancer has been an interplay between theory-driven approaches and new agents. By the late 1980s, accumulating data revealed that overexpression of HER2 (erbB2) played an important role in a substantial portion of breast cancers, which prompted the development of trastuzumab (Herceptin), an agent targeting HER2-positive disease. Determining HER2 status proved essential to assessing patient eligibility for trastuzumab therapy. Decoding of the human genome and application of bioinformatics further revolutionized the possibilities in breast cancer treatment.     

Outcomes of HER2-positive early breast cancer patients in the pre-trastuzumab and trastuzumab eras: a real-world multicenter observational analysis. The RETROHER study

Addition of trastuzumab to adjuvant chemotherapy has dramatically reduced the risk of recurrence and has become the standard of care for human epidermal growth factor receptor 2 (HER2)-positive early breast cancer patients. Since most data on trastuzumab benefits come from clinical trials, conducted in selected patient populations, we performed a retrospective analysis of HER2-positive early breast cancer patients treated in the “pre-trastuzumab” and “trastuzumab” eras, with the aim to determine patients' outcomes in real-world practice. 925 consecutive HER2-positive breast cancer patients treated with adjuvant chemotherapy in ten Italian oncologic centers were identified. Patients who had received adjuvant chemotherapy alone (cohort A, 352 patients), and patients who had received adjuvant chemotherapy followed or combined with trastuzumab (cohort B, 573 patients) were analyzed. Relapse rate at 3 years, relapse-free survival, and overall survival were significantly more unfavorable in the cohort A than in the cohort B (p < 0.0001). In multivariate analysis, factors related to relapse were younger age, advanced stage at diagnosis, absence of hormonal and of trastuzumab therapy. The benefit derived from the addition of trastuzumab was independent of nodal status and hormonal receptors expression. A subgroup analysis including 163 “triple positive” tumors with high levels of estrogen and progesterone receptor (TP50) suggested that addition of trastuzumab to adjuvant chemotherapy and hormonal therapy did not translate into better outcomes. In our analysis, trastuzumab benefit was confirmed in all but a small subset of TP50 tumors subgroups. In this subset further investigations are needed.     

Long-term outcome of the REMAGUS 02 trial,a multicenter randomised phase II trial in locally advanced breast cancer patients treated with neoadjuvant chemotherapy with or without celecoxib or trastuzumab according to HER2 status

BackgroundThe REMAGUS-02 multicenter randomised phase II trial showed that the addition to neoadjuvant chemotherapy (NAC) of trastuzumab in patients with localised HER2-positive breast cancer (BC) increased the pathological complete response (pCR) rate and that the addition of celecoxib in HER2-negative cases did not increase the pCR rate. We report here the long-term follow-up results for disease-free survival (DFS) and overall survival (OS).Patients and methodsFrom 2004 to 2007, 340 stage II–III BC patients were randomly assigned to receive neoadjuvant EC-T (four cycles of epirubicin–cyclophosphamide followed by four cycles of docetaxel) +/− celecoxib in HER2-negative cases (n = 220) and ± trastuzumab in HER2-positive cases (n = 120). From September 2005, all patients with HER2-positive BC received adjuvant T (n = 106).ResultsMedian follow-up was nearly 8 years (94.4 months, 20–127 m). In the HER2-negative subgroup, addition of celecoxib was not associated with a DFS benefit. Favourable factors were smaller tumour size, expression of progesterone receptor status (PgR) and pCR. In the HER2-positive population, neoadjuvant trastuzumab was not associated with a DFS benefit. Axillary pCR was the only prognostic factor associated with DFS in this group [HR = 0.44, 95% CI = 0.2–0.97], p = 0.035]. To note, DFS and OS were significantly higher in the HER2-positive than in HER2-negative BC patients (HR = 0.58 [0.36–0.92], p = 0.021).ConclusionCelecoxib combined with NAC provided neither pCR nor survival benefit in patients with HER2-negative BC. Absence of PgR is a major prognostic factor. Neoadjuvant trastuzumab increased pCR rates without translation into a DFS or OS benefit compared with adjuvant trastuzumab only. Axillary pCR could be a more relevant surrogate of survival than in the breast in HER2-positive population. A retrospective comparison shows that patients with HER2-positive tumours have a better outcome than HER2-negative BC patients showing the impact of trastuzumab on the natural history of BC.     

HER2 overexpressing metastatic breast cancer

Opinion statement More than 40,000 women in the United States die each year from metastatic breast cancer. Elucidation of HER2 and its role in malignant transformation has helped define a subset of aggressive breast cancer that may be relatively resistant to non-anthracycline-based therapies and hormonal agents, but responds to targeted molecular therapy. Trastuzumab, an antibody against HER2, has proven effective as single agent therapy in women with HER2 overexpressed metastatic breast cancer. Moreover, in combination with chemotherapy, trastuzumab has been shown to delay disease progression and improve overall survival for women with HER2-positive advanced breast cancer. The combination of chemotherapy and trastuzumab is emerging as a standard of care in women with HER2 overexpressed metastatic breast cancer. Several combination regimens using trastuzumab with taxanes, vinca alkaloids, or platinum compounds have demonstrated efficacy in first- and second-line treatment settings. However, the development of anthracycline-based combinations has been limited by concerns of related cardiotoxicity. Newer multi-agent regimens are in development. The optimal combination, duration, and sequence of trastuzumab therapy remain unknown in patients with HER2-positive metastatic disease. The role of continuing treatment after disease progression is also unclear. Evidence from some retrospective analyses suggest HER2-positive tumors are relatively resistant to tamoxifen and perhaps more responsive to aromatase inhibitors, although such data are inconclusive. HER2 status should not be used routinely for clinical decision making regarding hormonal therapy options. Several ongoing trials are attempting to address these and other issues related to HER2 testing to select the most appropriate candidates for these emerging therapies. While many questions remain, the treatment of HER2 overexpressing metastatic breast cancer is rapidly evolving, and represents a new approach to treatment in oncology.     

Variation in guideline-concordant care for elderly patients with metastatic breast cancer in the United States

Purpose

Prior studies have identified shortcomings in the quality of care for early-stage breast cancer. Guidelines recommend systemic therapy for metastatic breast cancer (MBC), but few studies have examined guideline concordance for these patients.

Methods

We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data to identify patients aged ≥ 66 diagnosed in 2010–2011 with de novo MBC who were continuously enrolled in fee-for-service Medicare. We described initial care (within 6 months of diagnosis) for hormone receptor (HR)-positive/human epidermal receptor-2 (HER2)-negative, HER2-positive, and triple-negative (TN) tumors. We identified factors independently associated with receiving no initial systemic therapy, and compared hospice and hospital utilization for treated versus untreated patients.

Results

Among 446 patients, 65% were HR-positive, 21% were HER2-positive, and 14% were TN. Most patients (76.9%) received initial systemic treatment. Among treated HR-positive patients, 15% received chemotherapy as initial treatment; among treated HER2-positive patients, 34% did not receive HER2-targeted initial therapy. Factors independently associated with receiving no initial systemic therapy included older age (OR_{age continuous/year} = 1.08, 95% CI 1.04–1.11), being not married (OR_{not married vs. married} = 2.87, 95% CI 1.42–5.81), and subtype (OR_{TN vs. HR+} = 4.95, 95% CI 2.53–9.71). Of patients who did not receive initial systemic therapy, 41.1% did not receive hospice services.

Conclusions

In this population-based MBC cohort, almost one quarter did not receive initial systemic therapy and a substantial proportion of treated patients did not receive guideline-concordant first-line therapy. Further research should explore underuse of chemotherapy and HER2-targeted therapies, investigate whether patterns of care are consistent with patient preferences, and identify opportunities to optimize hospice utilization for patients not receiving treatment.

     

Association of Tobacco Use,Alcohol Consumption and HER2 Polymorphisms With Response to Trastuzumab in HER2-Positive Breast Cancer Patients

Purpose

Although the administration of trastuzumab has improved the survival of human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, resistance remains a major clinical obstacle. We retrospectively evaluated the association of HER2 polymorphisms, tobacco use and alcohol consumption with disease-free survival (DFS) in HER2-positive breast cancer patients.

Adjuvant therapy of breast cancer

The treatment of early-stage breast cancer includes the use of chemotherapeutic and hormonal agents. Both chemotherapy and hormonal therapy have been shown by large, randomized trials to offer a survival advantage. The most commonly used chemotherapeutic agents used in the United States are doxorubicin and cyclophosphamide (AC). However, 3 studies have suggested that there may be an advantage in the use of taxanes in the adjuvant treatment of breast cancer. Furthermore the use of dose dense chemotherapy, incorporating AC and paclitaxel, has shown very promising results. It is well established that tamoxifen, a selective estrogen receptor modulator (SERM), improves overall survival (OS) in women with hormone receptor (HR) positive breast cancer. However, the results from large multicenter, randomized trials, suggest the potential superiority of aromatase inhibitors, compared to tamoxifen or an advantage of sequencing tamoxifen followed by an aromatase inhibitor (AI). The role of ovarian suppression is still being investigated in patients who have received prior chemotherapy. Newer agents, such as the monoclonal antibody against the HER2/neu receptor, trastuzumab, are now being studied as adjuvant therapy in early-stage breast cancer. In the next few years, with the completion of several large randomized trials, we will be able to answer several questions, including the optimal way of incorporating AIs into adjuvant therapy, the long-term sequella of using trastuzumab in the adjuvant treatment of breast cancer and the role of ovarian suppression combined with an aromatse inhibitor in premenopausal women with breast cancer.     

HER2/CEP17 ratio and HER2 immunohistochemistry predict clinical outcome after first-line trastuzumab plus taxane chemotherapy in patients with HER2 fluorescence in situ hybridization-positive metastatic breast cancer

Purpose

This study aimed to elucidate the clinical implication of human epidermal growth factor receptor 2/centromeric probe for chromosome 17 (HER2/CEP17) ratio and HER2 immunohistochemistry (IHC) results in patients with HER2 fluorescence in situ hybridization (FISH)-positive metastatic breast cancer (MBC) who received first-line trastuzumab plus taxane chemotherapy.

Methods

Using clinical data of patients with HER2 FISH-positive MBC who received first-line trastuzumab plus taxane chemotherapy, we analyzed the clinical outcome according to the HER2/CEP17 ratio and HER2 IHC analysis.

Results

Fifty-two women were analyzed. The median age was 50 years (range 27–69 years). Patients with a HER2/CEP17 ratio ≥3.0 had significantly longer progression-free survival (PFS) (17.2 vs. 7.4 months; p = 0.002) with a tendency toward higher response rate (RR) (p = 0.325) and longer overall survival (OS) (p = 0.129). Patients with HER2 IHC 1+ had significantly shorter OS (14.0 vs. 42.4 months; p = 0.013) along with a tendency toward lower RR (p = 0.068) and shorter PFS (p = 0.220). In the multivariate analysis, HER2/CEP17 ratio <3.0 (p = 0.004) and Eastern Cooperative Oncology Group (ECOG) PS 2 (p = 0.015) were significant factors for shorter PFS, and HER2 IHC 1+ (p = 0.015) and ECOG PS 2 (p = 0.036) were significant factors for poor OS.

Conclusions

Our data support that HER2/CEP17 ratios and HER2 IHC scores may predict clinical outcome after first-line trastuzumab plus taxane chemotherapy in patients with HER2 FISH-positive MBC.     

Monosomy 17 in potentially curable <Emphasis Type="Italic">HER2</Emphasis>-amplified breast cancer: prognostic and predictive impact

Purpose

HER2 copy number by fluorescence in situ hybridization (FISH) is typically reported relative to the centromere enumeration probe 17 (CEP17). HER2/CEP17 ratio could be impacted by alterations in the number of chromosome 17 copies. Monosomy of chromosome 17 (m17) is found in ~ 1900 cases of early-stage HER2-positive breast cancer annually in the United States; however, the efficacy of HER2-directed trastuzumab therapy in these patients is not well characterized. Here, we retrospectively identified HER2-amplified, stage I–III breast cancers with m17 and characterized the impact of trastuzumab treatment.

Methods

From January 1, 2000 to June 1, 2011, we identified 99 women with HER2-amplified m17 breast cancers, as defined by a CEP17 signal of < 1.5 per nucleus and a HER2/CEP17 ratio of ≥ 2.0.

Results

Most HER2-amplified m17 patients were treated with trastuzumab plus chemotherapy (51%, n = 50), whereas 31% (n = 31) received chemotherapy alone and 18% (n = 18) received no chemotherapy. The 4-year overall survival (OS) was superior with trastuzumab compared to chemotherapy alone or no chemotherapy (100 vs. 93 vs. 81%, respectively; p = 0.005). OS was not influenced by estrogen/progesterone-receptor (ER/PR) status, tumor stage, or degree of FISH positivity. A proportion of patients who would be considered HER2-negative by standard immunohistochemistry staging criteria (0–1+) were HER2 amplified by FISH.

Conclusions

In the largest series reported to date, patients with HER2-amplified m17 cancers treated with trastuzumab have outcomes comparable to patients from the large phase III adjuvant trastuzumab trials who were HER2-positive, supporting the critical role of HER2-directed therapy in this patient population.

     

Neoadjuvant Pertuzumab-containing Regimens Improve Pathologic Complete Response Rates in Stage II to III HER-2/neu-positive Breast Cancer: A Retrospective,Single Institution Experience

Introduction

Several human epidermal growth factor 2 (HER2)-targeted regimens are used to treat HER2-positive (HER2⁺) breast cancer (BC). The goal of this study was to retrospectively determine the pathologic complete response (pCR) rate for trastuzumab and pertuzumab (HP)-containing regimens compared with trastuzumab (H)-containing regimens for stage II to III HER2⁺ BC.