De-escalating treatment in the adjuvant setting in HER2-positive breast cancer

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1 Special Report For reprint orders, please contact: De-escalating treatment in the adjuvant setting in HER2-positive breast cancer Romualdo Barroso-Sousa1,2, Pedro Exman1,2 & Sara M Tolaney*,1,2 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA Harvard Medical School, Boston, MA 02115, USA * Author for correspondence: Tel.: ; Fax: ; sara tolaney@dfci.harvard.edu 2 The decision to offer adjuvant therapy to patients with early-stage cancer relies on factors related to the risk of disease recurrence, degree of benefit with the proposed therapy and the associated risk of toxicities. For patients with stages II and III HER2-positive breast cancer, administering 1 year of trastuzumab plus comprehensive chemotherapy is the standard of care. However, the pivotal adjuvant trials had very few older patients and patients with small HER2-positive tumors. In this review, we will discuss the clinical data regarding strategies to de-escalate adjuvant systemic therapy in patients with early stage HER2-positive disease. First draft submitted: 5 October 2017; Accepted for publication: 19 December 2017; Published online: 28 March 2018 Keywords: adjuvant therapy breast cancer de-escalating elderly HER2 stage I T1abN0 trastuzumab Breast cancer is the most frequently diagnosed cancer and the second cause of cancer death in the western world [1,2]. Approximately 15 20% of breast cancers overexpress HER2 and are classified as HER2-positive tumors [3 5]. Before the era of trastuzumab, even in the early stage setting, patients with HER2-positive tumors used to have a poor prognosis compared with other kinds of breast cancer [6,7]. The addition of trastuzumab to chemotherapy improved objective response rate, progression-free survival and overall survival (OS) compared with chemotherapy alone in patients with metastatic HER2-positive breast cancer [8]. Rapidly, different groups designed clinical trials to evaluate the benefits of trastuzumab in the early stage setting. Data from four Phase III randomized studies, evaluating a total of more than 8000 patients, showed that when trastuzumab was administered in combination with or after chemotherapy for 1 year, the risk of recurrence decreased by approximately 40% and both disease-free survival (DFS) and OS were improved [9 11]. Because of these trials, administering 1 year of trastuzumab plus comprehensive chemotherapy regimens, such as doxorubicin plus cyclophosphamide followed by paclitaxel (ACTH) or docetaxel plus carboplatin (TCH), became the standard of care for most women with early-stage HER2-positive breast cancer. However, these pivotal trials focused mainly on patients with high-risk tumors (stage II or stage III), a population more likely to derive the greatest absolute benefits from therapy (Table 1), and such regimens can be associated with both short- and long-term adverse events. Additionally, because these trials included a young population, with a median age of approximately 49 years, data regarding the risk of toxicity in older and frailer women are limited. In this review, we will discuss the clinical data regarding different approaches to de-escalating adjuvant systemic therapy in patients with HER2-positive breast cancer. Is 1 year of trastuzumab necessary? At the time the four Phase III pivotal clinical trials were designed, there was no information regarding the optimal duration of trastuzumab therapy; 1 year of treatment was explored in all of these trials. Differently, the FinHER trial [12] explored a shorter duration of therapy; in this study, patients were randomized to receive chemotherapy versus chemotherapy plus 9 weeks of trastuzumab. The addition of trastuzumab to chemotherapy was associated with similar survival benefits to those receiving 12 months of treatment in previous trials. Concerns regarding cardiac safety as well as costs of the 1-year treatment period led different investigators to evaluate shorter trastuzumab C 2018 Future Medicine Ltd /fon Future Oncol. (Epub ahead of print) ISSN

2 Special Report Barroso-Sousa, Exman & Tolaney Table 1. Pivotal trials evaluating the efficacy of adding 1 year of trastuzumab to adjuvant chemotherapy for patients with early-stage HER2-positive breast cancer. Trial name Year/journal of original publication Total HER2+ patients in primary analysis Treatment regimens compared HERA 2005/NEJM 3387 Multiple trial-approved chemo regimens +/- H N0 patients eligible? Yes, if: pt1c or higher Number of N0 patients in primary analysis Number of pt1 patients in primary analysis Inclusion of pt1n0 patients? No pt1abn0 patients NSABP B /NEJM 1736 ACT vs ACTH No No N0 patients [10] NCCTG N /NEJM 1615 ACT vs ACTH Yes, if: pt1c or higher (for ER/PR-neg) pt2 or higher (for ER/PR-pos) BCIRG /NEJM 3322 ACT vs ACTH versus TCH Yes, if: At least one of: pt2 or higher, ER/PR-neg, grades 2 3, or age 35 years No pt1abn0 patients pt1ab patients, pt1n0 subset not specified Data reported are from original trial publications, as referenced. ACT: Doxorubicin/cyclophosphamide-paclitaxel; ACTH: Doxorubicin/cyclophosphamide-paclitaxel/trastuzumab; ER: Estrogen receptor; FEC: Fluorouracil/epirubicin/cyclophosphamide; H: Trastuzumab; neg: Negative; NCCN: National Comprehensive Cancer Network; NEJM: New England Journal of Medicine; pos: Positive; PR: Progesterone receptor; TCH: Docetaxel/carboplatin/trastuzumab. Ref. [9] [10] [11] regimens. In this regard, different groups have studied whether a similar efficacy to 1-year adjuvant trastuzumab could be achieved with shorter trastuzumab exposure. The PHARE [13] trial was an open-label, multicenter, randomized, Phase III trial conducted in France, and evaluated whether 6 months of adjuvant trastuzumab would be noninferior to 12 months of therapy in terms of DFS. The trial included a total of 3384 patients that were randomly assigned 1:1 to one of the two arms. After a median follow-up of 42.5 months, there were 175 DFS events noted in the 12-month group and 219 in the 6-month group (hazard ratio [HR]: 1.28, 95% CI: ; p = 0.29), and the trial was declared negative for its primary end point, because the HR crossed the prespecified noninferiority margin of 1.5. Notably, there were more patients in the 12-month group who experienced a cardiac event than did those in the 6-month group (respectively, 96 [5.7%] of 1690 patients vs 32 [1.9%] of 1690 patients; p < ). Similarly, the Hellenic Oncologic Research Group trial [14] also failed to show noninferiority of 6 months of trastuzumab versus 12 months. Other studies have evaluated even shorter durations of trastuzumab. Recently, Conte et al. reported the results of the Italian, randomized, multicenter, Phase III, SHORT-HER trial [15]. Designed to evaluate the noninferiority of a short course of adjuvant trastuzumab (9 weeks) compared with the standard 1 year (long group) regarding DFS, the study assigned 1:1, 1253 patients to one of the two arms. Interestingly, the study planned both frequentist and Bayesian analyses. With a median follow-up of 5.2 years, the 5-year DFS was 87.5 versus 85.4% in the long and short groups, respectively (HR: 1.15; 90% CI: ), and the trial was declared negative because the HR crossed prespecified noninferiority margin of Conversely, in the Bayesian analysis, the probability that short is not inferior to long treatment had an HR of Additionally, the 5-year OS was very similar between the two arms (95.1 vs 95.0%) in the long and short groups, respectively (HR: 1.06; 90% CI: ). As expected, there were significantly more cardiac events in the long group compared with the short group. Based on the above results and on data from the HERA trial, which showed that 2 years of adjuvant trastuzumab is not more effective than 1 year of treatment [16], 1 year remains the standard of care. De-escalating therapy for small tumors Because the pivotal trials focused mainly on patients with high-risk tumors, the benefit of adjuvant chemotherapy for patients with stage I HER2-positive tumors is less clear. Retrospective case series have shown that patients with T1N0 ( 2 cm) have a significant risk for recurrence of breast cancer, with distant recurrences occurring in up to 20 30% of patients not treated with adjuvant systemic therapy (Table 2) [6,7,17 23]. In this regard, different groups conducted clinical trials focusing on patients with stage I disease, evaluating the efficacy of trastuzumab combined with less toxic chemotherapy regimens /fon Future Oncol. (Epub ahead of print) future science group

3 De-escalating therapy in HER2-positive breast cancer Special Report Table 2. Outcomes of patients with small HER2-positive breast cancer. Study (year) Type of cohort Patients (n) HR+ (%) CT-treated (%)/Htreated (%) Time period (years) DFS/RFS (%) DDFS/DRFS (%) BCSS (%) OS (%) Ref. pt1n0 (pt1abc) Joensuu et al. (2003) Retrospective 65 NR NR/0 9 NR 72 NR NR [7] Chia et al. (2008) Retrospective NR/ [6] Jones et al. (2013) Prospective / NR NR 98.7 [24] Tolaney et al. (2015) Prospective / NR [25] ATEMPT (NCT ) Prospective, randomized 500 NR 100 Ongoing Ongoing Ongoing Ongoing pt1ab Gonzalez-Angulo et al. (2009) Retrospective / NR NR [19] Curigliano et al. (2009) Retrospective / NR NR NR [20] Retrospective / NR NR NR Rouanet et al. (2014) Retrospective / NR 84 [21] Jones et al. (2013) Prospective 95 NR 100/ NR NR 100 [24] Fehrenbacher et al. (2014) Retrospective / NR NR [23] pt1b Vaz-Luis et al. (2014) Retrospective /0 5 NR [22] Retrospective /0 5 NR pt1a Vaz-Luis et al. (2014) Retrospective /0 5 NR [22] Retrospective /0 5 NR Data reported are from original publications, as referenced. Point estimates for outcomes are included in table; original publications include CIs. Point estimates must be interpreted in context of CIs. These trials also included tumors more than 2 cm and/or node positive. Data reported are recurrence-free interval (invasive disease only). Data reported are metastasis-free survival. BCSS: Breast cancer-specific survival; CT: Chemotherapy; DDFS: Distant disease-free survival; DFS: Disease-free survival; DRFS: Distant recurrence-free survival; H: Trastuzumab; HR: Hazard ratio; NR: Not recorded; OS: Overall survival; RFS: Recurrence-free survival. future science group /fon

4 Special Report Barroso-Sousa, Exman & Tolaney Jones et al. [24] conducted an open-label, single-arm, Phase II study to assess the efficacy of four cycles of every 3 weeks infusion of docetaxel and cyclophosphamide, given concomitantly with weekly trastuzumab, followed by trastuzumab every 3 weeks for the remainder of 1 year. A total of 493 patients were enrolled, and approximately 79% of patients had node-negative disease. After a median follow-up of 36.1 months, the 3-year DFS and OS rates were, respectively, 96.9% (CI: ) and 98.7% (95% CI: ). In the 486 patients, who received at least one dose of study drug, the most common grade 3 4 adverse events were neutropenia (47.1%), febrile neutropenia (6.2%), fatigue (4.3%) and diarrhea (3.3%); only two patients developed symptomatic congestive heart failure (0.5%) on study. Tolaney et al. [25] conducted the APT trial: a multicenter, single-arm study evaluating 12 weeks of adjuvant paclitaxel and trastuzumab followed by 9 months of trastuzumab monotherapy in 406 patients with HER2-positive, node-negative tumors measuring up to 3 cm in size. The primary end point was DFS. Recurrence-free interval, breast cancer-specific survival (BCSS) and OS were also analyzed. The importance of this study is highlighted by the fact that a low-risk population was very well represented; approximately 50% of patients had tumors that were 1 cm, and 9% of patients had tumors between 2 and 3 cm. Six patients had a nodal micrometastasis. After a median follow-up period of 4 years, the 3-year rate of survival free from invasive disease was 98.7% (95% CI: ). Importantly, the regimen was very well tolerated. Grade 3 neuropathy was reported at least once among 13 patients (3.2%; 95% CI: ), and two patients developed symptomatic congestive heart failure, both of whom had normalization of the left ventricular ejection fraction after discontinuation of trastuzumab. Significant asymptomatic declines in ejection fraction occurred in 13 patients (3.2%; 95% CI: ), as defined by the study; however, 11 of these patients resumed trastuzumab therapy after a brief interruption. Recently, an updated analysis with a median follow-up of 6.5 years was presented at the American Society for Clinical Oncology Annual Meeting [26]. A total of 23 DFS events were observed: four (1.0%) distant recurrences, five local/regional recurrences (1.2%), six new contralateral BC (1.5%) and eight deaths without documented recurrence (2.0%). The 7-year DFS was 93.3% (95% CI: ); 7-year recurrence-free interval was 97.5% (95% CI: ); 7-year BCSS was 98.6% (95% CI: ); and 7-year OS was 95.0% (95% CI: ). Based on the above data, treatment with paclitaxel and trastuzumab can be considered a standard option for the majority of patients with stage I HER2-positive breast cancer for whom adjuvant systemic therapy is indicated. There are certainly some patients for whom adjuvant treatment is not required, particularly those patients with T1aN0 disease. Additionally, given the efficacy seen in the APT trial, it seems unlikely that adding other biologic agents, such as pertuzumab or neratinib, would add substantial benefit in this patient population. However, work is ongoing to further minimize the toxicity of adjuvant therapy in this population. The ATEMPT trial (NCT ), a multicenter, randomized, Phase II study, recently completed accrual (n = 500). The study randomized patients in a 3:1 fashion to 1 year of the antibody-drug conjugate trastuzumab emtansine (T-DM1) every 3 weeks for 1 year versus paclitaxel plus trastuzumab for 12 weeks followed by trastuzumab every 3 weeks for 1 year in patients with stage I HER2-positive breast cancer. The study was designed both to compare clinically relevant toxicities between the two arms and to evaluate the 3-year DFS among those enrolled to the T-DM1 arm. Results from this study are anticipated in De-escalating therapy in older patients Work by Freedman et al. evaluated the incidence of early-stage HER2-positive disease by age within the National Comprehensive Cancer Network [27] and showed that 20% of cases arise in patients older than the age of 60. More importantly, the study also demonstrated that older patients were less likely to receive adjuvant trastuzumab and those with notable comorbidities appeared to be less likely to complete adjuvant trastuzumab therapy. The risk of toxicity associated with standard regimens among older patients is unknown. The pivotal adjuvant trials [9 11] that established ACTH or TCH regimens as the standard of care included very few older patients, with woman older than 60 years of age comprising approximately 15% of all participants. In addition, patients older than age 70, as well as those with cardiac conditions, were either excluded or poorly represented in such trials. Using Surveillance, Epidemiology, and End Results-Medicare data from 2005 to 2013, Reeder-Hayes et al. [28] compared the outcomes of ACTH versus TCH among 1077 patients older than 65 years. A propensity score matching analysis, used to balance cohort characteristics between treatment arms, was performed in a subsample of 416 women. Among propensity score-matched patients, the authors did not find difference between regimens in healthcare use overall or for chemotherapy-related adverse events (ACTH: 34% vs TCH: 36.5%; p = 0.46) /fon Future Oncol. (Epub ahead of print) future science group

5 De-escalating therapy in HER2-positive breast cancer Special Report Additionally, there was no statistically significant difference in 5-year BCSS (ACTH: 92% vs TCH: 96%; HR: 2.08; 95% CI: ) or OS between the two treatment arms. To date, available data suggest that older patients without comorbidities should be considered for standard adjuvant treatment regimens based on their risk of recurrence (ACTH, TCH or TH). However, older patients with significant comorbidities may be considered for less toxic regimens. Two ongoing trials may improve data for de-escalating therapy in older patients. The RESPECT trial (NCT ) is an ongoing Phase III study that is randomizing patients older than 70 years to receive trastuzumab monotherapy versus trastuzumab plus chemotherapy. This trial will help us to evaluate if there is any role for trastuzumab monotherapy in this population. In addition, the ATOP trial (NCT ) is a Phase II trial evaluating 1 year of T-DM1 monotherapy in patients olderthan60years. Future perspective Using biomarkers to de-escalating therapy Efforts have been made to identify biomarkers that may help us select patients who could be good candidates for de-escalation of therapy. It has been recognized that the subgroup of HER2-positive breast cancers, defined by immunohistochemistry or fluorescence in situ according the current guidelines, represent a molecularly heterogeneous disease. Prat et al. [29] confirmed that while the genomic-enriched HER2 subtype (HER2E) largely overlaps with the clinically HER2-positivity by immunohistochemistry or FISH, all the main four intrinsic breast cancer molecular subtypes (luminal A, luminal B, HER2E and basal like) can be found within HER2-positive breast cancers. Conversely, there are some clinically HER2-negative tumors that are molecularly classified as HER2E tumors [29]. In the preoperative setting, NEOALTTO [30], CALGB [31] and PAMELA [32] trials showed that pathological complete response (pcr) was markedly higher for each treatment approach among HER2E tumors than among HER2-positive tumors of any other intrinsic subtype and was more important than hormone receptor status in predicting pcr. Data from that adjuvant N9831 study showed that patients with HER2E had similar long-term outcomes to those with luminal subtypes; however, those with basal-like tumors did not have a statistically significantly better recurrence-free survival (RFS) when treated with trastuzumab plus chemotherapy compared with chemotherapy alone [33]. Altogether, while these data suggest that intrinsic subtype alone cannot fully replace clinical HER2 status in predicting the benefit of trastuzumab therapy, it is useful to help us better select patients that may benefit from HER2-directed therapy without chemotherapy, and further work is needed in this area. Because PI3K-AKT pathway is a major downstream component of HER2 signaling [34], deregulation of elements in this pathway including loss of the tumor suppressor PTEN, that negatively regulates the PI3K pathway, or activating mutations in PIK3CA, the gene that encodes the p110a catalytic subunit of PI3K have been evaluated as possible causes of resistance to anti-her2 treatments [35 37]. In a pooled analysis from five neoadjuvant trials, Loibl et al. [38] reported that PIKCA mutations were present in 21.7% of 967 patients with HER2-positive breast cancer. Utilizing individual data, the authors showed that although PIK3CA mutation was associated with a significantly lower rate of pcr (wild-type pcr 29.6% vs mutant pcr 16.2%; p < 0.001), this did not translate into an inferior DFS. PTEN protein loss is found in approximately 20 25% HER2-positive tumors. In the neoadjuvant setting, the German GeparQuattro study showed that PTEN expression levels predicted pcr after anti-her2 treatment combined with chemotherapy [39]. Conversely, a subanalysis of the NeoALTTO trial did not find such correlation [40]. In the adjuvant setting, retrospective analysis of FINHER [41], NSABP B-31 [42] and the N9831 [43] also failed in showing an association between PIK3CA alteration and PTEN status with trastuzumab benefit. It is noting that in all these studies, patients received anti-her2 therapies concomitantly with chemotherapy, which may have had an impact on the predictive value of these analyses biomarkers. An increasing body of preclinical and clinical data suggest that the interaction with the immune system is critical for disease outcome in breast cancer [44]. Immune biomarkers, including tumor infiltrating lymphocytes (TILs) and immune gene signatures, have emerged as possible candidates that can help us select for patients for whom de-escalating therapy is feasible. Recently, Denkert et al. [45] presented a meta-analysis of six neoadjuvant clinical trials. The study included 1369 patients with HER2-positive tumors. Among this population, increased TILs were significantly associated with higher pcr rates (p < ), and improved DFS (p < ) and OS (p = 0.02). In the adjuvant setting, however, data from the N9831 study did not support these long-term data and showed that the presence of stromal TILs was associated with an improvement in RFS of patients treated with chemotherapy alone but not among patients treated with chemotherapy plus trastuzumab [46]. In another subanalysis of the future science group /fon

6 Special Report Barroso-Sousa, Exman & Tolaney N9831 study, Perez et al. [47] showed that an increased expression of a subset of immune function genes was linked to increased RFS in patients treated with trastuzumab plus chemotherapy (p < 0.001), whereas patients who did not exhibit immune gene enrichment did not benefit from the addition of trastuzumab (p = 0.53). On the other hand, an enriched immune function gene expression was not associated with increased RFS in the arm treated with chemotherapy only (p = 0.64). Altogether, given these discordant data related to TILs, immune signatures and the setting of treatment (neo vs adjuvant) are hard to explain, making it difficult to draw any definitive conclusions regarding their use, and further work is needed. New clinical trial designs: using response to pre-operative therapy to de-escalate therapy Taking advantage of the development of the new and very effective anti-her2 therapy, such as trastuzumab, pertuzumab and T-DM1, it is critical that clinical investigators start to launch clinical trials assessing whether patients who achieve pcr to different combinations of less toxic regimens could receive less therapy after surgery. A pooled analysis of 12 international trials [48] including a total of 11,955 patients confirmed the prognostic value of pcr for use in clinical practice, showing that patients (individual level) who achieved a pcr presented a 64% reduction in the risk of death compared with those who had residual tumor at the time of surgery. The study, though, could not validate pcr as an established surrogate end point for improved event-free survival and OS, showing that there was no association of the magnitude of difference in pcr rates between treatment arms (study level) and differences in long-term outcome [48]. Therefore, trials with long-term follow-up are still needed to understand the survival outcomes for specific therapies. The ultimate strategy to de-escalate therapy, though, would be to look at the presence of micrometastatic disease to determine if further therapy is needed. The Translational Breast Cancer Research Consortium 040 study (NCT ) is evaluating whether plasma tumor DNA can be used to predict pcr in newly diagnosed patients with invasive HER2-positive or triple-negative breast cancer receiving preoperative therapy. Blood collection will be performed at baseline (before starting preoperative therapy), during preoperative treatment, immediately before surgery and after surgery. The study will also investigate the prognostic value of plasma tumor DNA for 5-year invasive DFS and distant DFS in patients following completion of loco-regional and systemic therapy. This can help us to select patients more suitable for avoiding additional chemotherapy following a pcr. Conclusion There is a need to identify patients with HER2-positive breast cancer who may be suitable for de-escalating adjuvant systemic therapy. It is unlikely that regimens more intense than taxol plus trastuzumab will add any clinical meaningful benefit to patients with stage I tumors. Immune biomarkers, intrinsic subtype and specific genomic alterations may be potential indicators that could help us select for patients for whom de-escalating therapy is feasible, without impairing their survival outcomes. Finally, more work is needed to see if developing a pcr to preoperative therapy can help us identify patients who may not need further adjuvant treatment. Acknowledgements The authors kindly thank KT Bifolck for her editorial support to this work. Financial & competing interests disclosure SM Tolaney receives research funding (institutional) from Genentech, Exelixis, Novartis, Pfizer, Eli Lilly, Nektar, AstraZeneca, Eisai and Merck. SM Tolaney has also served as an advisor to Novartis, Pfizer, Nektar, AstraZeneca, Merck, Puma and Nanostring. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript /fon Future Oncol. (Epub ahead of print) future science group

7 De-escalating therapy in HER2-positive breast cancer Special Report Executive summary Background There is a need to identify patients with HER2-positive breast cancer who may be suitable for de-escalating adjuvant systemic therapy. Trastuzumab duration Although 1 year of trastuzumab therapy is the standard of care, investigation about the noninferiority of shorter durations of trastuzumab for patients with low-risk tumors should be continued. De-escalating therapy for small tumors In patients with small tumor size (stage I), it is unlikely that regimens more intense than taxol plus trastuzumab will add any clinical meaningful benefit to patients. The ATEMPT trial is evaluating efficacy of adjuvant T-DM1 in the stage I population. De-escalating therapy in older patients The current data suggest that older patients without comorbidities should be considered for standard adjuvant treatment regimens based on their risk of recurrence. Older patients with significant comorbidities may be considered for less toxic regimens. Future perspective Intrinsic subtype, genomic alterations and immune biomarkers may be potential indicators that could help us select for patients for whom de-escalating therapy is feasible, without impairing their survival outcomes. Investigations are underway if a pathologic complete response to preoperative therapy and/or the utility of circulating tumor DNA can help us identify patients who may not need further adjuvant treatment. Conclusion De-escalation therapy in early-stage HER2-positive breast cancer is feasible without impairing efficacy results in patients with small tumor size (stage I). Other biomarkers, other than tumor stage, should be investigated to select patients who can be spared more toxic adjuvant therapies. References Papers of special note have been highlighted as: of interest; of considerable interest 1. Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J. Clin. 61(2), (2011). 2. Siegel R, Desantis C, Virgo K et al. Cancer treatment and survivorship statistics, CA Cancer J. Clin. 62(4), (2012). 3. Pathmanathan N, Provan PJ, Mahajan H et al. Characteristics of HER2-positive breast cancer diagnosed following the introduction of universal HER2 testing. Breast 21(6), (2012). 4. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785), (1987). 5. Wolff AC, Hammond ME, Hicks DG et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J. Clin. Oncol. 31(31), (2013). 6. Chia S, Norris B, Speers C et al. Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of node-negative breast cancers. J. Clin. Oncol. 26(35), (2008). Retrospective series showing high rates of breast cancer recurrence among patients with small HER + tumors in pre-anti-her2 therapy era. 7. Joensuu H, Isola J, Lundin M et al. Amplification of erbb2 and erbb2 expression are superior to estrogen receptor status as risk factors for distant recurrence in pt1n0m0 breast cancer: a nationwide population-based study. Clin. Cancer Res. 9(3), (2003). 8. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N.Engl.J.Med.344(11), (2001). 9. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl.J.Med.353(16), (2005). 10. Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 353(16), (2005). 11. Slamon D, Eiermann W, Robert N et al. Adjuvant trastuzumab in HER2-positive breast cancer. N.Engl.J.Med.365(14), (2011). 12. Joensuu H, Kellokumpu-Lehtinen PL, Bono P et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N. Engl.J.Med.354(8), (2006). 13. PivotX,RomieuG,DebledMet al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised Phase III trial. Lancet Oncol. 14(8), (2013). future science group /fon

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Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized Phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J. Clin. Oncol. 34(6), (2016). 32. Llombart-Cussac A, Cortes J, Pare L et al. HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, Phase II trial. Lancet Oncol. 18(4), (2017). 33. Perez EA, Ballman KV, Mashadi-Hossein A et al. Intrinsic subtype and therapeutic response among HER2-positive Breaty st tumors from the NCCTG (Alliance) N9831 trial. J. Natl Cancer Inst. 109(2), pii:djw207 (2017) /fon Future Oncol. (Epub ahead of print) future science group

9 De-escalating therapy in HER2-positive breast cancer Special Report 34. Mayer IA, Arteaga CL. The PI3K/AKT pathway as a target for cancer treatment. Ann. Rev. Med. 67, (2016). 35. Berns K, Horlings HM, Hennessy BT et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12(4), (2007). 36. Fujita T, Doihara H, Kawasaki K et al. PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer. Br. J. Cancer 94(2), (2006). 37. Moasser MM, Krop IE. The evolving landscape of HER2 targeting in breast cancer. JAMA Oncol. 1(8), (2015). 38. Loibl S, Majewski I, Guarneri V et al. PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab. Ann. Oncol. 27(8), (2016). 39. Loibl S, Darb-Esfahani S, Huober J et al. Integrated analysis of PTEN and p4ebp1 protein expression as predictors for pcr in HER2-positive breast cancer. Clin. Cancer Res. 22(11), (2016). 40. NuciforoPG,AuraC,HolmesEet al. Benefit to neoadjuvant anti-human epidermal growth factor receptor 2 (HER2)-targeted therapies in HER2-positive primary breast cancer is independent of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) status. Ann. Oncol. 26(7), (2015). 41. Loi S, Michiels S, Lambrechts D et al. Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer. J. Natl Cancer Inst. 105(13), (2013). 42. Pogue-Geile KL, Song N, Jeong JH et al. Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in the NSABP B-31 trial. J. Clin. Oncol. 33(12), (2015). 43. Perez EA, Dueck AC, McCullough AE et al. Impact of PTEN protein expression on benefit from adjuvant trastuzumab in early-stage human epidermal growth factor receptor 2-positive breast cancer in the North Central Cancer Treatment Group N9831 trial. J. Clin. Oncol. 31(17), (2013). 44. Kroemer G, Senovilla L, Galluzzi L, Andre F, Zitvogel L. Natural and therapy-induced immunosurveillance in breast cancer. Nat. Med. 21(10), (2015). 45. Denkert C, Von Minckwitz G, Darb-Esfahani S et al. Abstract S1-09: evaluation of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarker in different subtypes of breast cancer treated with neoadjuvant therapy a metaanalysis of 3771 patients. Cancer Res. 77(Suppl. 4), S1-09 (2017). 46. Perez EA, Ballman KV, Tenner KS et al. Association of stromal tumor-infiltrating lymphocytes with recurrence-free survival in the n9831 adjuvant trial in patients with early-stage HER2-positive breast cancer. JAMA Oncol. 2(1), (2016). 47. Perez EA, Thompson EA, Ballman KV et al. Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group n9831 adjuvant trastuzumab trial. J. Clin. Oncol. 33(7), (2015). 48. Cortazar P, Zhang L, Untch M et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384(9938), (2014). future science group /fon

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