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Escalation and de-escalation in HER2 positive early breast cancer

Dieci, Maria Vittoriaa,b; Vernaci, Graziaa; Guarneri, Valentinaa,b

doi: 10.1097/CCO.0000000000000492
BREAST CANCER: Edited by Giuseppe Curigliano

Purpose of review Current standard for HER2+ early breast cancer patients includes chemotherapy and trastuzumab for 1 year. The purpose of this article is to review available evidence on escalated treatment strategies for high-risk patients and de-escalated treatments for patients at low risk of relapse or high risk of cardiac toxicity.

Recent findings Recent results have led to the approval of two adjuvant escalated treatment strategies: pertuzumab and trastuzumab combined with chemotherapy for up to 1 year for high-risk patients; extension of adjuvant anti-HER2 treatment with 1 year of neratinib. However, these treatments are associated with increased costs and toxicity, therefore careful patients’ selection is highly required. With regard to de-escalated treatments, the anthracycline-free regimen of adjuvant paclitaxel and 1 year trastuzumab has entered clinical practice for early-stage patients. One year of trastuzumab remains the standard; however, shorter trastuzumab could be an option for low-risk patients and in case of increased risk of cardiotoxocity. Chemotherapy-free regimens are attractive but deserve further evaluation.

Summary There have been advances in treatment individualization for HER2+ early breast cancer patients. Integration of promising biomarkers into risk classification will further help progressing in the field.

aDepartment of Surgery, Oncology and Gastroenterology, University of Padova

bMedical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy

Correspondence to Valentina Guarneri, Department of Surgery, Oncology and Gastroenterology, University of Padova, Medical Oncology 2, Istituto Oncologico Veneto IRCCS via Gattamelata 64, 35128 Padova, Italy. Tel: +39 049 821 5291; fax: +39 049 821 5932; e-mail: valentina.guarneri@unipd.it

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

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INTRODUCTION

The advent of anti-HER2 therapies has dramatically improved the prognosis of HER2+ breast cancer patients [1]. One year of adjuvant trastuzumab added to chemotherapy is the current standard. In a metanalysis of pivotal trials, adding trastuzumab to chemotherapy resulted in a 40 and 34% reduction in the risk of relapse and death, respectively [2]. In the 8th edition of the American Joint Commission on Cancer staging system, HER2 is one of the biomarkers adopted to refine the classic anatomical staging classification into the new prognostic stage groups [3▪▪]. In this classification, which applies to countries where biomarkers assessment is available together with the possibility to treat patients accordingly, HER2 positivity can contribute to downstage from the classic anatomical stage categories.

However, several questions remain unsolved. On the one hand, still some patients will relapse despite receiving optimal treatment. A recent update of the HERA trial showed a 10-year disease-free survival (DFS) of 69% for patients treated with 1-year trastuzumab [4▪▪].

On the other hand, cardiac toxicity remains a concern [2,5,6]. It is known that HER2+ patients from the clinical practice present more frequently features associated with lower risk of relapse, such as small tumors, negative nodes and hormone receptor positive status as compared to patients from randomized trials [7]. In addition, they are generally older and often affected by cardiac comorbidities [7].

Therefore, researchers’ attention is focused on potentiating the efficacy of standard treatment to improve outcome of high-risk patients and developing de-escalated treatments for patients at lower risk of relapse and/or increased risk of cardiac toxicity in order to improve the risk/benefit ratio.

Box 1

Box 1

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ESCALATED TREATMENT FOR EARLY HER2+ BREAST CANCER

The main escalating strategies include extended anti-HER2 therapy beyond 1 year and combining anti-HER2 agents.

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Extended duration of anti-HER2 therapy

At a median 11 years follow up of the HERA trial, 2 years trastuzumab did not improve DFS vs. 1 year [hazard ratio = 1.02, 95% confidence interval (CI) 0.89–1.17], but was associated with higher rate of cardiac events (7.3 vs. 4.4% for 1 year vs. 0.9% for observation) [4▪▪].

The ExteNET (n = 2840) randomized placebo-controlled study explored the benefit of neratinib, an oral irreversible pan-HER inhibitor, administered for 1 year after completion of chemotherapy and trastuzumab [8]. Enrolled patients were predominantly node-positive (77%). The last update confirmed a numerically small, but statistically significant, difference in invasive-DFS in favor of neratinib: 5-years rates 90.2 vs. 87.7% (hazard ratio = 0.73, 95% CI 0.57–0.92, P = 0.0083). In subgroup analyses, this advantage was more evident among hormone receptorpositive patients and those starting neratinib less than 1 year after trastuzumab completion. In the absence of prophylaxis, diarrhea occurred in 95% of patients (40% G3) [9▪▪]. A phase II trial evaluating the incidence of diarrhea in HER2+ early breast cancer patients receiving neratinib and different prophylactic regimens is ongoing (NCT02400476).

Food and Drug Administration (FDA) approved neratinib in 2017 for the extended adjuvant treatment of adult patients with early-stage HER2+ breast cancer, to follow adjuvant trastuzumab [10]. The Committee for Medical Products for Human Use of European Medicines Agency (EMA) released in 2018 a positive opinion, limiting the indication to hormone receptor-positive patients at less than 1 year from trastuzumab [11].

However, the safety profile challenges the use of neratinib in the clinical setting. Moreover, although biological rationale for the observed efficacy in hormone receptor-positive patients exists (potent inhibition of cross-talk between the estrogen receptor and HER2 pathways), translational work is encouraged to identify potential predictive biomarkers.

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Dual HER2-blockade

A series of anti-HER2 agents have been evaluated in association with trastuzumab, with the aim to prevent/overcome treatment resistance and improve patients’ outcome.

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Dual blockade with trastuzumab and lapatinib

A metanalysis of six trials evaluating lapatinib/trastuzumab as compared to trastuzumab in addition to neoadjuvant chemotherapy showed a significant 13% absolute increase in pCR rate with dual blockade. This difference was wider in hormone receptor-negative vs. hormone receptor-positive patients (18 vs. 8%) and in patients treated with taxane-only vs. polychemotherapy (16 vs. 10%) [12].

The role of lapatinib in the adjuvant setting was explored in the randomized phase III ALTTO Trial, in which 8381 patients were randomly assigned to receive chemotherapy with either trastuzumab, lapatinib, trastuzumab/lapatinib or trastuzumab and sequential lapatinib, for a 1-year overall duration [13]. After an interim analysis in 2011, the lapatinib alone arm was closed because of futility to show noninferiority to trastuzumab, a result anticipated by the NeoALTTO data. The last study update (median follow up 6.9 years) confirms the primary analysis results [13], showing that lapatinib/trastuzumab is not superior to trastuzumab: hazard ratio for DFS = 0.86 (95% CI 0.74–1.00), 6 years DFS rates 85% (trastuzumab/lapatinib) and 82% (trastuzumab). No difference was observed comparing trastuzumab followed by lapatinib to trastuzumab (DFS hazard ratio = 0.93, 95% CI 0.81–1.08) [14▪▪].

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Dual blockade with trastuzumab and pertuzumab

The neoadjuvant phase II NeoSphere Trial randomized 417 patients to trastuzumab/docetaxel, pertuzumab)/docetaxel, trastuzumab/pertuzumab/docetaxel or trastuzumab/pertuzumab. The results showed a higher pCR rate for the trastuzumab/pertuzumab/docetaxel as compared to trastuzumab/docetaxel (46 vs. 29%, P = 0.0141); pCR rates in the other two arms were lower [15]. After surgery, patients received anthracycline-based chemotherapy (and docetaxel if not previously received) and trastuzumab up to 1 year. A recent survival analysis showed that 5 years PFS rate was the highest among patients treated with trastuzumab/pertuzumab/docetaxel (86%), although no significant difference was observed as compared to docetaxel/trastuzumab (hazard ratio = 0.69, 95% CI 0.34–1.40) [16].

Cardiac safety of trastuzumab/pertuzumab combined with neoadjuvant chemotherapy was the primary endpoint of the TRYPHAENA [17] (randomization to three chemotherapy backbones) and BERENICE [18▪] (single-arm, anthracycline-taxane backbone) studies, both reporting low rates of cardiac events. In TRYPHAENA, pCR rates ranged from 57 to 66% and DFS rates at 3 years from 87 to 90% across the three arms [17,19▪].

On the basis of the pCR results from the NeoSphere and TRYPHAENA trials, neoadjuvant pertuzumab in combination with trastuzumab and chemotherapy gained FDA accelerated approval in 2013 [20].

The phase III APHINITY Trial randomly assigned 4804 patients to chemotherapy and trastuzumab with pertuzumab or placebo. The addition of pertuzumab was associated with a significantly better invasive DFS (hazard ratio = 0.81, 95% CI 0.66–1.00, P = 0.045). However, in absolute terms, the benefit was narrow (3 years invasive DFS rates of 94.2 vs. 93.1%) and the overall patients outcome was excellent. The subgroups analysis showed a more pronounced benefit for node-positive patients (63% of trial population), with an absolute difference in 3 years invasive DFS of 1.8% (92.0 vs. 90.2%; hazard ratio = 0.77, 95% CI 0.62–0.96, P = 0.02), whereas no difference was observed for node-negative patients [21▪▪]. The incidence of cardiac toxicity was low and comparable between arms, although potential bias in safety reporting has been suggested [22▪].

On the basis of this evidence, pertuzumab recently gained FDA [23] and EMA [24] approval for adjuvant treatment of HER2-positive breast cancer patients at high risk of recurrence, in association with trastuzumab and chemotherapy.

It has to be noted that the definition of high-risk patients, intended as node-positive or hormone receptor-negative, is wide and consists of a spectrum of possible situations, potentially including patients who may be optimally treated by trastuzumab. Moreover, adding pertuzumab to trastuzumab for 1 year is associated with increased costs, an issue not to be neglected. Clearly, patients with clinically evident nodal involvement at diagnosis are at increased risk of relapse and deserve escalated treatment; however, they are candidate for neoadjuvant chemotherapy and if pertuzumab is added, continuation of adjuvant dual blockade after surgery, even if clinically sound, is lacking a dedicated trial and therefore is not supported by recommendations and guidelines [25▪▪,26▪▪].

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Combination of anti-HER2 agents including trastuzumab-emtansine (T-DM1)

T-DM1 is an antibody-drug conjugate composed of the microtubule toxin emtansine and trastuzumab. The KRISTINE trial randomized 444 stage II/III patients to six courses of docetaxel/carboplatin/trastuzumab or T-DM1/pertuzumab, showing higher pCR rates for the standard arm (56 vs. 44%, P = 0.016), whereas safety profile favored T-DM1/pertuzumab (grade ≥ 3 events 13 vs. 64%) [27▪].

The adjuvant KAITLIN trial (NCT01966471) comparing adjuvant T-DM1/pertuzumab vs. taxane/trastuzumab/pertuzumab after anthracycline-based chemotherapy has completed accrual (n = 1846). Sample size was reduced following the MARIANNE trial's results showing no superiority of T-DM1 or T-DM1/pertuzumab over trastuzumab/taxane in the first-line metastatic setting [28▪].

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DE-ESCALATED ANTI-HER2 STRATEGIES

De-esclated strategies include shorter trastuzumab administration and reducing the duration or amount of chemotherapy, with the particular case of triple-positive breast cancer.

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Shorter anti-HER2 therapy

Building on the data from the FinHER trial, showing a 35% relative improvement in distant-DFS for 9 weeks trastuzumab vs. no trastuzumab added to chemotherapy and no increase in cardiac toxicity [29], a series of randomized trials [30▪▪,31,32,33▪,34▪,35] have investigated the noninferiority of a shorter duration of trastuzumab vs. 1 year, as shown in Table 1.

Table 1

Table 1

The only study that succeeded in demonstrating the noninferiority of shorter trastuzumab is the PERSEPHONE trial, in which more than 4000 women were randomized to trastuzumab for 6 months vs. 1 year. The majority of patients had node-negative (59%) and hormone receptor-positive (69%) disease. Rates of 4 years DFS were 89.4% (6-months) and 89.8% (1 year); hazard ratio = 1.07, 95% CI 0.93–1.24, P = 0.01 (noninferiority margin 1.31). A higher number of patients in the 1-year arm stopped trastuzumab because of cardiotoxicity (8 vs. 4%, P < 0.0001) [30▪▪].

Although other studies could not claim the noninferiority of short trastuzumab, most are consistent in demonstrating a significantly decreased risk of cardiac toxicity [30▪▪,31,32,33▪,34▪]. Moreover, some subgroup analyses suggest a comparable efficacy of short and long treatments in patients at lower risk of relapse.

In the PHARE trial, comparing 6 months vs. 1 year of trastuzumab, the authors defined in a posthoc analysis four prognostic groups based on clinicopathological features and showed that patients at low risk experienced an excellent prognosis with shorter treatment [36].

The ShortHER Trial randomized 1253 patients to trastuzumab for 9 weeks or 1 year associated with anthracycline and taxane chemotherapy. At a median follow up of 5.2 years, the study failed to demonstrate the noninferiority of the short arm (hazard ratio = 1.15, 90% CI 0.91–1.46, crossing the noninferiority margin of 1.29); however, a Bayesian approach estimated an 80% probability of noninferiority [34▪]. Subgroups analysis showed a significant interaction between treatment and disease burden. In particular, there was clear DFS benefit for the long treatment for N2 patients (hazard ratio = 2.07, 90% CI 1.33–3.22), whereas N0–N1 patients experienced similar outcomes when treated with short or long trastuzumab. In a recent analysis, risk-based classification was able to identify patients’ subgroups at good prognosis deriving no benefit from prolonging trastuzumab beyond 9 weeks [37▪]. Tumor infiltrating lymphocytes (TILs) have been associated with increased pCR rates and improved outcomes for HER2+ early breast cancer patients [38,39▪▪]. TILs were assessed on 857 samples from the ShortHER study, showing independent prognostic value for MFS in both hormone receptor+ and hormone receptor– subgroups. Patients with low TILs appeared to benefit from 1-year trastuzumab, whereas in case of high TILs prognosis was extremely good with both treatments [40▪].

At present, 1-year trastuzumab remains the standard. Nevertheless, these data suggest that clinicians could consider a short trastuzumab treatment for patients at low risk of relapse and/or high risk of cardiac toxicity. Pooled analysis of individual data would help in getting further insights in patients’ subgroups.

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De-escalating chemotherapy

Anthracycline-free chemotherapy

The trastuzumab-containing anthracycline-free arm of the BCIRG006 trial was superior to anthracycline-based chemotherapy alone and showed a safer profile as compared to trastuzumab added to anthracycline and taxane [41]. On the basis of these results, anthracycline-free adjuvant strategies were further evaluated.

The single-arm phase II APT Trial (N = 406) assessed the efficacy of adjuvant paclitaxel (12-weeks) amd concomitant trastuzumab for 1 year for low-risk breast cancer patients (N0 and T≤3 cm) [42]. At the last update, 7 years invasive disease free survival and overall survival were 93 and 95%, respectively [43▪▪]. Cardiac events were reassuringly low [44]. Similar outcomes were reported in another study assessing docetaxel-cyclophosphamide and trastuzumab for early-stage patients [45].

Because of favorable safety profile, the APT regimen has entered clinical use for low-risk patients, although some concerns still exist on the indication for patients with tumors of 2–3 cm and in case of negative estrogen receptor (10 and 35% of APT patients, respectively).

The currently ongoing phase II ATEMPT trial compares 1-year T-DM1 with the APT regimen for stage I patients (NCT01853748).

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Chemotherapy-free regimens

The chemotherapy-free arm of the NeoSphere trial with trastuzumab+pertuzumab led to an intriguing pCR rate of 16.8%, which was of particular interest in the hormone receptor-positive group (27.3%) [15].

This observation has prompted a more extensive investigation of chemotherapy-free neoadjuvant regimens, most frequently exploiting the efficacy of dual blockade.

In the HER2+/hormone receptor– cohort of the phase II WSG-ADAPT Trial (n = 134, 57% cN0 and 93% cT1-2), the comparison between neoadjuvant trastuzumab/pertuzumab/taxane vs. trastuzumab/pertuzumab showed significantly increased pCR rates when chemotherapy was added (90.5 vs. 36%) [46▪].

A number of studies specifically focused on HER2+/hormone receptor+, a subgroup known to be less sensitive to chemotherapy, with the main rationale being the potential to exploit the synergism between anti-HER2 and endocrine therapy. The most recent are discussed hereafter.

In the HER2+/hormone receptor+ cohort of the WSG ADAPT Trial, 375 patients were assigned to 12 weeks of: T-DM1, T-DM1/endocrine therapy or trastuzumab/endocrine therapy. Most of the patients showed clinical stage I–II (94%, 49% stage I). T-DM1 arms resulted in higher similar pCR rates compared to trastuzumab, (41, 42 and 15% for T-DM1, T-DM1/endocrine therapy, trastuzumab/endocrine therapy). Patients with a Ki67 molecular response assessed at 3 weeks were more likely to achieve a pCR [47▪].

The advent of CDK4/6 inhibitors prompted the evaluation of a combination of neoadjuvant trastuzumab/pertuzumab/fulvestrant/palbociclib for preoperative treatment of HER2+/hormone receptor+ patients in the small NA-PHER2 study (N = 36). pCR rate was 27% and a significant impact on cells proliferation was observed from baseline to 2 weeks and surgery [48▪].

However, molecular heterogeneity of HER2+ breast cancer, beyond the simple distinction based on hormone receptor status, is a major determinant of sensitivity to anti-HER2 treatments. In the PAMELA study, n = 151 patients received neoadjuvant trastuzumab/lapatinib (and letrozole if hormone receptor+) for 18 weeks. The overall breast pCR rate was 30%, significantly higher for the HER2-enriched vs. non-HER2-enriched subtypes (41 vs. 10%, odds ratio = 6.2, 95% CI 2.3–16.8, P = 0.0004). In the HER2+/hormone receptor+ subgroup, breast pCR rate was 32% for HER2-enriched and 5% for non-HER2-enriched [49▪▪]. Therefore, in order to improve patients’ selection for de-escalated treatments, molecular biology is a key factor.

The PER-ELISA study further confirmed this concept. In this study, 64 postmenopausal, HER2+/hormone receptor+, stage II–IIIA breast cancer patients received 2 weeks of neoadjuvant letrozole and then underwent a rebiopsy to evaluate Ki67. Molecular responders (n = 44, with Ki67% relative reduction ≥20% from baseline) continued letrozole in association with pertuzumab/trastuzumab for five cycles, whereas molecular nonresponders were treated with paclitaxel for 13 weeks combined with pertuzumab/trastuzumab. The study showed a pCR rate (breast and axilla) of 20.5% among molecular responders, suggesting that a selection based on Ki67 inhibition after short-term letrozole may allow to identify patients with meaningful pCR without chemotherapy. Moreover, PAM50 molecular subtyping was able to further refine patients’ selection: in the molecular responders group, 45% of patients with HER2-enriched tumor achieved pCR [50▪].

In the adjuvant setting, a recently reported small study comparing trastuzumab/chemotherapy vs. trastuzumab for elderly patients unselected for molecular-based characteristics showed inconclusive results because of very limited number of events [51▪].

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CONCLUSION

In the last years, important efforts have been pursued to improve treatment individualization for HER2+ early breast cancer patients [25▪▪,26▪▪].

Accurate risk stratification is mandatory to correctly identify optimal candidate for escalated or de-escalated strategies. Although of unquestionable value, classic clinicopathological features are inadequate to capture the complexity of HER2+ breast cancer. Numerous promising biomarkers, such as molecular subtyping [49▪▪,50▪], TILs [38,39▪▪,40▪] and on-treatment markers [50▪,52▪], have been identified and need to be integrated in the design of future trials as selection or stratification factors. Another useful parameter is pCR after neoadjuvant treatment. Although de-escalation randomized trials for patients achieving pCR are challenging because of large required sample size, escalation trials for nonpCR patients are more feasible (NCT01772472). Finally, the development of markers predictive for cardiac toxicity and the prospective evaluation of preventive measures for patients at risk will further help in optimizing treatment for HER2+ early breast cancer [53▪,54▪].

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

1. Cossetti RJ, Tyldesley SK, Speers CH, et al. Comparison of breast cancer recurrence and outcome patterns between patients treated from 1986 to 1992 and from 2004 to. J Clin Oncol 2015; 33:65–73.
2. Moja L, Tagliabue L, Balduzzi S, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev 2012; 4:CD006243.
3▪▪. Giuliano AE, Connolly JL, Edge SB, et al. Breast cancer-major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 2017; 67:290–303.

This article summarizes the major changes in the last version of the breast cancer staging manual. Important changes have been made, including the description of the new prognostic groups based on the integration of anatomical stage and biomarkers.

4▪▪. Cameron D, Piccart-Gebhart MJ, Gelber RD, et al. Herceptin Adjuvant (HERA) Trial Study Team, 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 2017; 389:1195–1205.

This article reports the last update of the pivotal HERA trial.

5. Ganz PA, Romond EH, Cecchini RS, et al. Long-term follow-up of cardiac function and quality of life for patients in NSABP Protocol B-31/NRG Oncology: a randomized trial comparing the safety and efficacy of doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel and trastuzumab in patients with node-positive breast cancer with tumors overexpressing human epidermal growth factor receptor 2. J Clin Oncol 2017; 35:3942–3948.
6. De Azambuja E, Ponde NF, Ptocter MJ, et al. Meta-analysis of the cardiac events in the adjuvant trastuzumab trials. J Clin Oncol 2018; 36: (suppl; abstr 10066).
7. Arpino G, Michelotti A, Truini M, et al. Demographic, tumor and clinical features of clinical trials versus clinical practice patients with HER2-positive early breast cancer: results of a prospective study. J Cancer Res Clin Oncol 2016; 142:669–678.
8. Chan A, Delaloge S, Holmes FA, et al. ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2016; 17:367–377.
9▪▪. Martin M, Holmes FA, Ejlertsen B, et al. ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2017; 18:1688–1700.

This article reports the last update of the randomized ExteNET, the first to assess the role of extending anti-HER2 treatment beyond tarstuzumab with 1 year neratinib.

10. U.S. Food & Drugs Administration, Prescribing Information for Nerlynx, available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208051s000lbl.pdf. Accessed September 2018.
11. European Medicines Agency, Refusal of the marketing autorisation for nerlynx (neratinib), available at: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-Initial_authorisation/human/004030/WC500244282.pdf. Accessed September 2018.
12. Clavarezza M, Puntoni M, Gennari A, et al. Dual block with lapatinib and trastuzumab versus single-agent trastuzumab combined with chemotherapy as neoadjuvant treatment of HER2-positive breast cancer: a meta-analysis of randomized trials. Clin Cancer Res 2016; 22:4594–4603.
13. Piccart-Gebhart M, Holmes E, Baselga J, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial. J Clin Oncol 2016; 34:1034–1042.
14▪▪. Moreno-Aspitia A, McCormick Holmes E, Jackisch C, et al. Updated results from the phase III ALTTO trial (BIG 2-06; NCCTG (Alliance) N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L) or their combination (L+T) in the adjuvant treatment of HER2-positive early breast cancer. J Clin Oncol 2017; 35: (suppl; abstr 502).

This article reports the last update of the ALTTO trial, the sole to explore adjuvant dual blockade with trastuzumab and lapatinib.

15. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13:25–32.
16. Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol 2016; 17:791–800.
17. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 2013; 24:2278–2284.
18▪. Swain SM, Ewer MS, Viale G, et al. BERENICE Study Group. Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol 2018; 29:646–653.

This study reports cardiac safety of trastuzumab + pertuzumab added to neoadjuvant anthracycline and taxane-containing chemotherapy.

19▪. Schneeweiss A, Chia S, Hickish T, et al. Long-term efficacy analysis of the randomised, phase II TRYPHAENA cardiac safety study: evaluating pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer. Eur J Cancer 2018; 89:27–35.

This article reports the long-term outcomes of patients treated in the TRYPHAENA trial, whose primary endpoint was cardiac safety of tarstuzumab and pertuzumab added to neoadjuvant chemotherapy.

20. Amiri-Kordestani L, Wedam S, Zhang L, et al. First FDA approval of neoadjuvant therapy for breast cancer: pertuzumab for the treatment of patients with HER2-positive breast cancer. Clin Cancer Res 2014; 20:5359–5364.
21▪▪. Von Minckwitz G, Procter M, de Azambuja E, et al. APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 2017; 377:122–131.

This is the first study assessing adjuvant pertuzumab + trastuzumab for HER2+ breast cancer patients.

22▪. Miller KD. Questioning our APHINITY for more. N Engl J Med 2017; 377:186–187.

This editorial refers to the APHINITY trial, highlighting important messages for future trial design.

23. U.S. Food & Drugs Administration, Prescribing Information for Perjeta, available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125409s113118lbl.pdf. Accessed September 2018.
24. European Medicines Agency, Perjeta Product Information, available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002547/WC500140980.pdf. Accessed September 2018.
25▪▪. Curigliano G, Burstein HJ, P Winer E, et al. St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2017, De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early 2017. Ann Oncol 2017; 28:1700–1712.

This article summarizes the last St Gallen consensus guidelines.

26▪▪. Denduluri N, Chavez-MacGregor M, Telli ML, et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO Clinical Practice Guideline Focused Update. J Clin Oncol 2018; 36:2433–2443.

This article summarizes new update of the ASCO guidelines on adjuvant treatment for early breast cancer patients, including escalated therapy options for HER2+ patients.

27▪. Hurvitz SA, Martin M, Symmans WF, et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 2018; 19:115–126.

This study reports the results of the KRISTINE trial, exploring neoadjuvant regimens of dual blockade with trastuzumab/pertuzumab/chemotherapy or T-DM1 and pertuzumab.

28▪. Perez EA, Barrios C, Eiermann W, et al. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the Phase III MARIANNE Study. J Clin Oncol 2017; 35:141–148.

This is the first study comparing T-DM1 alone or combined with pertuzumab to trastuzumab and taxane as first-line treatment for HER2+ metastatic patients.

29. Joensuu H, Bono P, Kataja V, et al. Fluorouracil, epirubicin and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatment of breast cancer: final results of the FinHer Trial. J Clin Oncol 2009; 27:5685–5692.
30▪▪. Earl HM, Hiller L, Vallier A-L, et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC) – randomised phase 3 noninferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J Clin Oncol 2018; 36: (suppl; abstr 506).

This is the sole trial demonstrating the noninferiority of shorter adjuvant trastuzumab duration as compared to standard 1 year.

31. Pivot X, Romieu G, Debled M, et al. PHARE trial investigators. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol 2013; 14:741–748.
32. Pivot X, Suter T, Nabholtz JM, et al. Cardiac toxicity events in the PHARE trial, an adjuvant trastuzumab randomised phase III study. Eur J Cancer 2015; 51:1660–1666.
33▪. Joensuu H, Fraser J, Wildiers H, et al. Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD Randomized Clinical Trial. JAMA Oncol 2018; doi: 10.1001/jamaoncol.2018.1380. [Epub ahead of print].

This study is one of the noninferiority trials of shorter trastuzumab duration.

34▪. Conte PF, Bisagni G, Frassoldati A, et al. 9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: results of the phase III multicentric Italian study Short-HER. J Clin Oncol 2017; 35: (suppl; abstr 501).

This study is one of the noninferiority trials of shorter trastuzumab duration.

35. Mavroudis D, Saloustros E, Malamos N, et al. Breast Cancer Investigators of Hellenic Oncology Research Group (HORG). Athens, Greece, Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol 2015; 26:1333–1340.
36. Kramar A, Bachelot T, Madrange N, et al. Trastuzumab duration effects within patient prognostic subgroups in the PHARE trial. Ann Oncol 2014; 25:1563–1570.
37▪. Conte PF, Guarneri V, Piacentini F, et al. 9 weeks versus 1 year trastuzumab for HER2+ early breast cancer: subgroup analysis of the ShortHER trial allows to identify patients for whom a shorter trastuzumab administration may have a favourable risk/benefit ratio. European Society of Medical Oncology 2018 Congress, 19–23 October 2018, Munich, Germany.

This study provides insights into patients’ subgroups at good prognosis for whom 9 weeks trastuzumab associated with chemotherapy shows a good risk/benefit ratio.

38. Dieci MV, Prat A, Tagliafico E, et al. Integrated evaluation of PAM50 subtypes and immune modulation of pCR in HER2-positive breast cancer patients treated with chemotherapy and HER2-targeted agents in the CherLOB trial. Ann Oncol 2016; 27:1867–1873.
39▪▪. Denkert C, von Minckwitz G, Darb-Esfahani S, et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol 2018; 19:40–50.

This is the largest analysis of the association of TILs with pCR and outcome for breast cancer patients treated with neoadjuvant chemotherapy.

40▪. Dieci MV, Conte PF, Bisagni G, et al. Association of tumor-infiltrating lymphocytes with metastasis-free survival for patients with early HER2+ breast cancer treated with adjuvant chemotherapy and trastuzumab: results from the randomized ShortHER trial. European Society of Medical Oncology 2018 Congress, 19-23 october 2018, Munich, Germany.

This is the first study assessing the prognostic role of TILs in a noninferiority randomized trial of shorter trastuzumab administration.

41. Slamon D, Eiermann W, Robert N, et al. Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365:1273–1283.
42. Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 2015; 372:134–141.
43▪▪. Tolaney SM, Barry WT, Guo H, et al. Seven-year (yr) follow-up of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC). J Clin Oncol 2017; 35: (suppl; abstr 511).

This study reports the last update of the APT trial, showing excellent prognosis for low-risk patients treated with anthracycline-free trastuzumab and taxane adjuvant treatment.

44. Dang C, Guo H, Najita J, et al. Cardiac outcomes of patients receiving adjuvant weekly paclitaxel and trastuzumab for node-negative, ERBB2-positive breast cancer. JAMA Oncol 2016; 2:29–36.
45. Jones SE, Collea R, Paul D, et al. Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol 2013; 14:1121–1128.
46▪. Nitz UA, Gluz O, Christgen M, et al. West-German Study Group (WSG)-ADAPT Investigators. De-escalation strategies in HER2-positive early breast cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR- phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel. Ann Oncol 2017; 28:2768–2772.

This study compares neoadjuvant trastuzumab/pertuzumab with or without paclitaxel for HER2+/hormone receptor– patient and shows increased pCR rates when chemotherapy is added.

47▪. Harbeck N, Gluz O, Christgen M, et al. De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): final analysis of the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early BC HER2- and Hormone Receptor-Positive Phase II Randomized Trial-Efficacy, Safety, and Predictive Markers for 12 Weeks of Neoadjuvant Trastuzumab Emtansine With or Without Endocrine Therapy (ET) Versus Trastuzumab Plus ET. J Clin Oncol 2017; 35:3046–3054.

This study explores de-escalated neoadjuvant treatment strategies for HER2+/hormone receptor+ patients.

48▪. Gianni L, Bisagni G, Colleoni M, et al. Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study. Lancet Oncol 2018; 19:249–256.

First trial to assess a regimen composed of endocrine therapy, dual HER2 blockade and CDK4/6 inhibitor as neoadjuvant treatment for HER2+/hormone receptor+ patients.

49▪▪. Llombart-Cussac A, Cortés J, Paré 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 2 trial. Lancet Oncol 2017; 18:545–554.

This study prospectively confirmed molecular intrinsic subtyping as a predictor of anti-HER2 treatment sensitivity.

50▪. Guarneri V, Dieci MV, Bisagni G, et al. De-escalated treatment with trastuzumab-pertuzumab-letrozole in patients with HR+/HER2+ operable breast cancer with Ki67 response after 2 weeks letrozole: final results of the PerELISA neoadjuvant study. J Clin Oncol 2018; 36: (suppl; abstr 507).

First study to assess a de-escalated chemotherapy-free neoadjuvant strategy for HER2+/hormone receptor+ patients based on molecular selection (Ki67 reduction after short-term letrozole).

51▪. Sawaki M, Saito T, Baba S, et al. Evaluation of trastuzumab without chemotherapy as a postoperative adjuvant therapy in HER2-positive elderly breast cancer patients: randomized controlled trial (RESPECT). J Clin Oncol 2018; 36: (suppl; abstr 510).

First prospective adjuvant trial of chemotherapy-free regimen for HER2+ elderly patients.

52▪. Nuciforo P, Pascual T, Cortés J, et al. A predictive model of pathologic response based on tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) in HER2-positive breast cancer treated with chemo-free dual HER2 blockade. Ann Oncol 2018; 29:170–177.

This study proposes a combined biomarker assessment to predict pCR after chemotherapy-free dual HER2 blockade.

53▪. Zardavas D, Suter TM, Van Veldhuisen DJ, et al. Role of troponins I and T and N-terminal prohormone of brain natriuretic peptide in monitoring cardiac safety of patients with early-stage human epidermal growth factor receptor 2-positive breast cancer receiving trastuzumab: a herceptin adjuvant study cardiac marker substudy. J Clin Oncol 2017; 35:878–884.

Important study exploring potential markers of trastuzumab-related cardiac toxicity.

54▪. Lynce F, Barac A, Tan MT, et al. SAFE-HEaRt: rationale and design of a pilot study investigating cardiac safety of HER2 targeted therapy in patients with HER2-positive breast cancer and reduced left ventricular function. Oncologist 2017; 22:518–525.

Ongoing study on preventive measures for cardiac toxicity in HER2+ patients at risk.

Keywords:

breast cancer; de-escalation; dual blockade; HER2

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