Expert Review of Anticancer Therapy

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Trastuzumab emtansine (T-DM1) as adjuvant treatment of HER2-positive early breast cancer: safety and efficacy

Chiara Molinelli, Francesca Parisi, Maria Grazia Razeti, Luca Arecco, Maurizio Cosso, Piero Fregatti, Lucia Del Mastro, Francesca Poggio & Matteo Lambertini

To cite this article: Chiara Molinelli, Francesca Parisi, Maria Grazia Razeti, Luca Arecco, Maurizio Cosso, Piero Fregatti, Lucia Del Mastro, Francesca Poggio & Matteo Lambertini (2021) Trastuzumab emtansine (T-DM1) as adjuvant treatment of HER2-positive early breast cancer: safety and efficacy, Expert Review of Anticancer Therapy, 21:3, 241-250, DOI: 10.1080/14737140.2021.1857243 To link to this article: https://doi.org/10.1080/14737140.2021.1857243

Published online: 17 Dec 2020. Submit your article to this journal

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Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=iery20 EXPERT REVIEW OF ANTICANCER THERAPY 2021, VOL. 21, NO. 3, 241–250 https://doi.org/10.1080/14737140.2021.1857243

DRUG PROFILE Trastuzumab emtansine (T-DM1) as adjuvant treatment of HER2-positive early breast cancer: safety and efficacy Chiara Molinellia, Francesca Parisib, Maria Grazia Razetib, Luca Areccob, Maurizio Cossoc, Piero Fregattid,e, Lucia Del Mastro a,f, Francesca Poggioa and Matteo Lambertini b,f aDepartment of Medical Oncology, Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy; bDepartment of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy; cDepartment of Radiology, IRCCS Ospedale Policlinico San Martino, Genova, Italy; dDepartment of Surgery, U.O.C. Clinica di Chirurgia Senologica, IRCCS Ospedale Policlinico San Martino, Genova, Italy; eDepartment of Integrated Diagnostic Surgical Sciences, School of Medicine, University of Genova, Genova, Italy; fDepartment of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova, Italy

ABSTRACT ARTICLE HISTORY Introduction: The prognosis of patients with HER2-positive early breast cancer has radically improved Received 4 September 2020 after the introduction of (neo)adjuvant anti-HER2 targeted therapy. Trastuzumab emtansine (T-DM1) is Accepted 24 November an antibody-drug conjugate combining the anticancer properties of the anti-HER2 agent trastuzumab 2020 and the antineoplastic cytotoxic drug DM1. After demonstrating to be an effective and safe treatment KEYWORDS for patients with HER2-positive advanced breast cancer, the development of T-DM1 has moved to the Antibody-drug conjugate; early setting. breast cancer; HER2-positive; Areas covered: The aim of this review is to explore the current role of T-DM1 in the treatment trastuzumab emtansine; landscape of HER2-positive early breast cancer, focusing specifically on the efficacy and safety data t-DM1 available in the adjuvant setting. Expert opinion: T-DM1 is an effective and safe treatment option in the adjuvant setting for patients with HER2-positive breast cancer without pathologic complete response after standard neoadjuvant chemotherapy plus anti-HER2 targeted therapy. With the availability of more effective anti-HER2 targeted agents, including T-DM1, there is an urgent need for more chemotherapy de-escalation research efforts in the early setting.

1. Introduction after demonstrating to be an effective and safe option in patients previously exposed to trastuzumab-based therapy. Human epidermal growth factor receptor-2 (HER2) positivity The EMILIA study was the pivotal trial leading to the accounts for approximately 15–20% of breast cancers [1]. In approval of T-DM1 in the metastatic setting [10]. In this the past and before the availability of effective targeted phase III trial, patients with HER2-positive advanced breast agents, HER2-positive disease was characterized by poor prognosis and aggressive biological behavior [2]. Patients cancer progressing on prior trastuzumab-based therapy were diagnosed with HER2-positive early disease were character­ randomized to receive T-DM1 (n = 495) or lapatinib plus ized by particularly poor outcomes [3]. The introduction of capecitabine (n = 496). In the final analysis at a median agents targeting HER2 also in the early setting has led to an follow-up of 24.1 months, median overall survival (OS) was outstanding turning point in the treatment of HER2-positive significantly longer with T-DM1 than with lapatinib plus breast cancer by radically changing the natural history of capecitabine (29.9 vs 25.9 months; hazard ratio [HR] 0.75, this disease and patients’ prognosis [4]. 95% confidence intervals [CI] 0.64–0.88). A better safety Trastuzumab is the first anti-HER2 targeted agent to enter profile was also reported for T-DM1, with fewer grade ≥3 clinical use in both the metastatic and early settings [5–7]. adverse events as compared to the control arm (48% vs Beyond trastuzumab, several other anti-HER2 targeted thera­ 60%). The most frequently reported grade ≥3 adverse events pies with different mechanisms of action have been devel­ in patients receiving T-DM1 were decreased platelet count oped and approved for clinical use in the last years [8]. (14%), increased liver enzymes (5%), and anemia (4%). In the Following monoclonal antibodies and tyrosine kinase inhibi­ T-DM1 arm, the treatment discontinuation rate was 74.%, tors, complex engineered therapeutics named antibody-drug mostly due to disease progression [10]. The phase III conjugates have been developed more recently [9]. Among TH3RESA trial was conducted to demonstrate the efficacy them, trastuzumab-emtansine (T-DM1) has been the first to of T-DM1 in a more pretreated population of patients with enter clinical practice (Table 1). HER2-positive advanced breast cancer that was previously In 2013, T-DM1 was added to the treatment armamentar­ exposed to at least two lines of anti-HER2 agents [11]. ium of patients with HER2-positive advanced breast cancer Patients were randomized in a 2:1 ratio to receive T-DM1

CONTACT Matteo Lambertini [email protected] Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, Genova 16132, Italy © 2020 Informa UK Limited, trading as Taylor & Francis Group 242 C. MOLINELLI ET AL.

positive early breast cancer, focusing specifically on the effi­ Article highlights cacy and safety data available in the adjuvant setting.

● T-DM1 is an anti-HER2 antibody–drug conjugate, the first one approved for patients with solid tumors, constituted by trastuzumab and a microtubule inhibitor (DM1, a derivative of maytansine). ● The phase III KATHERINE trial demonstrated the efficacy of adjuvant 2. Pharmacodynamic and pharmacokinetic of T-DM1 T-DM1, compared with trastuzumab, in patients with residual inva­ sive disease at surgery after a neoadjuvant treatment including anti- T-DM1 (trastuzumab emtansine; Kadcyla®) is an anti-HER2 HER2 therapy. antibody–drug conjugate, being the first one approved for ● To date, there are no potential predictive biomarkers of benefit to adjuvant T-DM1, except from HER2 positivity. patients with solid tumors. ● The concurrent use of radiotherapy during T-DM1 treatment is Antibody-drug conjugates are constituted of a monoclonal feasible. antibody, a cytotoxic agent, and a linker with good stability ● There is a lack of solid data about the possible impact of T-DM1 on gonadal function, and future studies are needed to better investigate binding the two parts [9]. In T-DM1, the monoclonal compo­ this crucial issue. nent is directed toward HER2 and it allows the delivery of the cytotoxic drug through receptor-mediated endocytosis in a selective way, in order to reduce the toxicity on the off- target tissue [9]. The cytotoxic agent or payload, is Table 1. FDA-approved anti-HER2 targeted agents in the adjuvant setting. a microtubule inhibitor (DM1, a derivative of maytansine) [15]. Category and mechanism of Current indications for HER2- Trastuzumab and the cytotoxic agent are conjugated through Drugs action positive early breast cancer a non-reducible thioether linker that is stable in the circulation Trastuzumab Monoclonal antibody binding In combination with (N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxy­ to the extracellular chemotherapy as (neo) late) [16]. For every trastuzumab molecule, there are 3.5 DM1 subdomain IV of HER2 adjuvant therapy Pertuzumab Monoclonal antibody binding In combination with molecules. to subdomain II of the trastuzmab and Trastuzumab is a humanized monoclonal antibody of the extracellular part of HER2 chemotherapy as (neo) immunoglobulin G1 type directed against the extracellular and inhibiting receptor adjuvant therapy dimerization domain of the HER2 receptor. As a consequence of the bind­ T-DM1 HER2-targeted antibody-drug As adjuvant therapy in ing action of trastuzumab, HER2-positive cancer cells are conjugate, constituted of patients who did not recognized by natural killer lymphocytes determining NK- Trastuzumab and experience a pathologic a cytotoxic agent (DM1, complete response after mediated lysis. Regarding the intracellular mechanism of derivative of maytansine) neoadjuvant action, the transduction of intracellular HER2 signaling is inhib­ conjugated through a non- chemotherapy plus anti- ited, eventually causing apoptosis and inhibiting DNA reducible thioether linker HER2 therapy Neratinib Irreversible pan-HER tyrosine Extended adjuvant treatment damage-repair mechanism [17,18]. Trastuzumab have also an kinase inhibitor binding and after 1 year of anti-angiogenetic effect [19], down-regulates HER2 on the inhibiting EGFR, HER2, HER4 trastuzumab, in patients plasma membrane [20], inhibits HER2 ectodomain cleavage with high risk of relapse [21], and inactivates the PTEN-PI3K/AKT signaling pathway [22]. The affinity of trastuzumab to HER2 is not modified by the linker with DM1 [18]. (n = 404) or therapy of physician’s choice (n = 198). At DM1 is a derivative of maytansine binding to the β subunit a median follow-up of 30.5 months, a longer median OS of tubulin. It inhibits microtubule assembly, arresting the cell was observed in the T-DM1 group compared with the treat­ cycle in the G2-M phase causing subsequent apoptosis. The ment of physician’s choice (22.7 vs. 15.8 months; HR 0.68, mechanism of action is concentration-dependent [23]. 95% CI 0.54–0.85). The favorable safety profile of T-DM1 was Particularly in the case of long-term treatment, T-DM1 can confirmed. Similarly, to the EMILIA study, the incidence of determine the so-called ‘mitotic catastrophe’ into breast can­ grade ≥3 adverse events was lower in the T-DM1 group (40% cer cells, a histopathological finding characterized by apopto­ vs. 46%). The most frequently observed grade ≥3 adverse sis, cells with multinucleated giant morphology, and aberrant events with T-DM1 were thrombocytopenia (6%) and hemor­ mitoses (defined as ‘arrows’) [23]. The inhibition of microtu­ rhage of any type (4%). In the T-DM1 arm, treatment dis­ bule assembly can also determine the disruption of intracel­ continuation rate was 58%, in most cases due to disease lular trafficking [24,25]. progression [11]. More recently, observational evidence has Thanks to trastuzumab, T-DM1 binds the HER2 receptor on become available to support the activity of T-DM1 also in the plasma membrane, determining the entry of the HER2/T-DM1 patients with HER2-positive advanced breast cancer progres­ complex into HER2-positive cells, through a mechanism of recep­ sing on the current standard first-line treatment consisting of tor-mediated passive endocytosis [26]. This mechanism reduces the combination of pertuzumab, trastuzumab, and single- the toxicity of the drug to non-pathological tissue, targeting the agent taxane chemotherapy [12–14]. action of T-DM1 directly into cancer cells. After the internalization In recent years, based on the consistent and relevant of the HER2/T-DM1 complex, the lysosomal degradation deter­ results obtained in the advanced setting, T-DM1 has been mines the release of DM1 with subsequent apoptosis. tested also in patients with early breast cancer, in both the Based on the results of phase I and II trials, the maximum neoadjuvant and adjuvant settings. This review summarizes tolerated dose of T-DM1 has been fixed at 3.6 mg/kg given the current role of T-DM1 in the treatment landscape of HER2- every 3 weeks with a half-life of 3.5 days [27,28]. EXPERT REVIEW OF ANTICANCER THERAPY 243

3. T-DM1 in the neoadjuvant and adjuvant setting breast cancer. The first analysis showed higher pCR rates for patients treated with chemotherapy plus pertuzumab and After the approval of T-DM1 in the metastatic setting, several trastuzumab, as compared to T-DM1 plus pertuzumab trials have assessed the potential role of this agent in the early (55.7% vs 44.4%; p = 0.016). More recently, the three-year setting. Many trials investigated T-DM1 as neoadjuvant ther­ efficacy data in terms of EFS and invasive-disease free- apy [29]. An in-depth overview of neoadjuvant T-DM1 is survival (IDFS) have been reported [35]. At a median follow- beyond the scope of the present article focusing on the role up of 37 months, 3-year EFS was 85.3% in the T-DM1 plus of this agent as adjuvant treatment. However, notably, for pertuzumab arm compared to 94.2% in the TCHP arm (HR patients with HER2-positive early breast cancer, neoadjuvant 2.61, 95% CI 1.36–4.98). No significant differences in IDFS (HR treatment has become the preferred approach for the majority 1.11, 95% CI 0.52–2.40) nor in OS (HR 1.21, 95 CI % 0.37–3.96) of patients. Pre-operative treatment offers a similar survival were observed between the two treatment arms. In the sub­ benefit to adjuvant therapy [30]. However, neoadjuvant ther­ group analysis, patients with hormone receptor-negative dis­ apy presents some advantages, such as downstaging of both ease experienced a higher probability of achieving pCR, the primary tumor and the axilla resulting in a more conser­ irrespective of the neoadjuvant treatment received (73% vative surgery but also the possibility to adapt the adjuvant and 54%, respectively) [34,36]. As regards to safety, treat­ treatment according to the pathologic response obtained at ment with T-DM1 plus pertuzumab was associated with surgery [31]. A meta-analysis including 12 trials and 11,955 fewer adverse events as compared to the TCHP arm during breast cancer patients showed the strong prognostic value of the neoadjuvant period (88.3% vs 98.6%). On the contrary, in achieving a pathologic complete response (pCR) after neoad­ the adjuvant phase, adverse events were more common in juvant therapy, and this was particularly true for the HER2- patients treated with T-DM1 plus pertuzumab (88.8% vs. positive subtype [32]. Recent results from the I-SPY2 trial are 83.5%, respectively). The most common adverse events in consistent with previous findings, reporting a strong and con­ the adjuvant phase were anemia (4.1%), neutropenia (4.1%), sistent association between individual pCR and event-free peripheral neuropathy (3.1%), and febrile neutropenia (2%) in survival (EFS), among all breast cancer subtype (HR 0.19, 95% the T-DM1 plus pertuzumab arm; diarrhea (0.9%), anemia CI 0.12–0.31). These results are highly relevant particularly for (0.5%), hypokalemia (0.5%), and hypertension (0.5%) were patients with HER2-positive disease and both hormone- those more often observed in the TCHP arm. Patient- receptor positive (HR 0.15, 95% CI 0.03–0.63) and negative reported outcomes favored the T-DM1 and pertuzumab arm (HR 0.14, 95% CI 0.05–0.41) status [33]. in the neoadjuvant phase and were similar in both groups Among the different studies that investigated T-DM1 in the throughout the adjuvant phase [34,35]. neoadjuvant setting, almost all of them allowed its adminis­ Despite some encouraging results, the evidence deriving tration only before surgery with the adjuvant anti-HER2 treat­ from the trials that have assessed T-DM1 use only in the ment being trastuzumab in most of the cases. Among the neoadjuvant phase has not been sufficient so far to open different trials using T-DM1 as neoadjuvant treatment, only the door to the use of T-DM1 in clinical practice for patients the KRISTINE trial allowed the use of this drug also in the with early breast cancer candidates to receive a preoperative adjuvant setting (Table 2). treatment. However, these results support the need to further The KRISTINE trial compared with T-DM1 plus pertuzumab investigate de-escalation chemotherapy strategies with its with a regimen including docetaxel and carboplatin in addi­ potential omission in selected patients. tion to dual anti-HER2-blockade with trastuzumab and pertu­ zumab (TCHP) in 444 patients with HER2-positive early breast cancer [34,35]. Notably, patients in the T-DM1 plus pertuzu­ mab group continued this anti-HER2 combination in both the 4. T-DM1 in the adjuvant setting neoadjuvant and adjuvant phases, whereas patients included Several trials have investigated the role of T-DM1 in the adju­ in the TCHP group continued dual anti-HER2 blockade with vant setting (Table 3). The most important results that have trastuzumab and pertuzumab in the adjuvant setting. The led to a radical change in clinical practice are with its use as median age was 50 years, most of the patients (83%) had ‘post-neoadjuvant treatment,’ in patients without pCR at the stage IIA-IIIA disease, and 62% hormone receptor-positive time of surgery after neoadjuvant treatment [32].

Table 2. Main results of the KRISTINE trial testing T-DM1 in both the neoadjuvant and adjuvant settings. AUTHOR – YEAR PHASE N° PTS TREATMENT ARMS PRIMARY ENDPOINT MAIN EFFICACY RESULTS MAIN SAFETY RESULTS Hurvitz S, et al 2019 3 444 T-DM1 plus Pertuzumab −3 years-IDFS ITT −3 years IDFS 93% vs 92% (HR G ≥ 3 AEs 31% vs 67% [34,35] for 6 cycles population 1.11; CI 95% 0.52–2.40) Most frequent adverse Vs. -3 yrs-EFS ITT -3 years EFS 85% vs 94% events: neutropenia (3.6% Docetaxel, Carboplatin population (HR 2.61; CI 95% 1.36–4.98) vs 25%), diarrhea, febrile and Trastuzumab plus -HR+ vs HR- – pCR HR+ vs HR – neutropenia, anemia Pertuzumab for 6 cycles population population 54% vs 38% – pCR T-DM1 arm and 71% vs 46% CT arm Abbreviations: T-DM1: Trastuzumab emtansine; IDFS: invasive disease-free survival; EFS: event-free survival; HR+: hormone receptor-positive; HR-: hormone receptor-negative; G: grade; AEs: adverse events; pCR: pathologic complete response; CT: chemotherapy; HR: hazard ratio; CI: confidence intervals; ITT: intention to treat population. 244 C. MOLINELLI ET AL.

Table 3. Main results of trials testing T-DM1 in the adjuvant setting. N° PRIMARY MAIN EFFICACY MAIN SAFETY AUTHOR – YEAR PHASE PATIENTS Population TREATMENT ARMS ENDPOINT RESULTS RESULTS von Minckwitz 3 1486 HER2-positive breast cancer – T-DM1 every 3 weeks for 14 IDFS 3 yrs IDFS: 88.3% G ≥ 3 AEs 25.7% G et al, 2019 with residual disease at cycles vs. Trastuzumab every vs 77.0% (HR vs. 15.4%. [37] surgery after neoadjuvant 3 weeks for 14 cycles 0.50; 95% CI, Most frequent taxane-based chemotherapy 0.39–0.64) adverse event: plus anti-HER2 therapy with decreased trastuzumab (with or platelet count without pertuzumab) (5.7% vs 0.3%) Tolaney SM et al, 2 497 Stage I HER2-positive breast – T-DM1 every 3 weeks for 17 IDFS 5 yrs IDFS 97.5% G ≥ 3 AEs 25% in 2020 [42] cancer patients cycles vs. weekly Paclitaxel vs. 93.2% the T-DM1 arm plus Trastuzumab for vs 36% in the 12 weeks followed by standard arm Trastuzumab every 3 weeks for additional 13 cycles Harbeck N et al, 3 1846 HER2-positive early breast Anthracyclines for 3–4 cycles IDFS in node- 3 yrs-IDFS in the G ≥ 3 AEs 55.4% 2020 [43] cancer with node-positive followed by Taxanes for positive and node-positive vs 51.8% disease or node-negative 12 weeks and Trastuzumab + ITT population Most frequent and HR-negative and tumor Pertuzumab (up to 18 cycles) population 94.1% vs adverse ≥2 cm vs. Anthracyclines for 3–4 92.8% (HR events: cycles followed by T-DM1 0.97; 95% CI, hepatotoxicity + Pertuzumab (up to 18 0.71–1.32) (15.6% vs cycles) 3 yrs-IDFS in 47.6%) the ITT population 94.2% vs. 93.1% (HR 0.98; 95% CI, 0.72–1.32) Abbreviations T-DM1: Trastuzumab-emtansine; IDFS: invasive-disease free survival; HR: hazard ratio; IC: interval of confidence; G: grade; AEs: adverse events; HR-: hormone receptor-negative; ITT: intention-to-treat

In the phase III KATHERINE trial, 1,486 patients with resi­ arm. The most common adverse events of any grade dual invasive disease at surgery after neoadjuvant treatment included fatigue (49.5% vs 33.8%), nausea (41.6% vs 13.1%), with a taxane-based chemotherapy regimen, with or without thrombocytopenia (28.5% vs 2.4%), increased transaminase anthracycline, plus anti-HER2 targeted therapy including tras­ (28.4% vs 5.6%), headache (28.4% vs 16.9%), arthralgia (25.9% tuzumab with or without pertuzumab were randomized to vs 20.6%) and peripheral sensory neuropathy (18.6% vs receive 14 cycles of adjuvant T-DM1 or trastuzumab alone 6.9%). Particularly, grade ≥3 adverse events were observed (743 patients in each arm) to complete 1 year of anti-HER2 in 25.7% in the T-DM1 arm (most frequently decreased plate­ treatment [37]. The median age of the included patients was let count, radiation-related skin injury, and peripheral sensory 49 years. Approximately 77% of the patients was treated with neuropathy) and in 15.4% of the patients in the trastuzumab an anthracycline-containing neoadjuvant chemotherapy regi­ arm (most frequently radiation-related skin injury). As regards men, and about 20% received dual anti-HER2 blockade with grade ≥3 cardiotoxicity events, they were scarce in both arms trastuzumab plus another anti-HER2 targeted therapy (pertu­ of treatment: three cases in the T-DM1 arm (<1%), and one zumab in the majority of the patients). The majority of patient in the trastuzumab arm [37]. T-DM1-associated cardi­ patients (72%) had hormone receptor-positive disease and otoxicity seems a rare event, usually low grade, and reversi­ 42.8% had none or minimal residual disease (ypT1a and ble [41]. The overall rate of treatment discontinuation was ypT1b) after surgery. At a median follow-up of 41.4 months, 28.5% in the T-DM1 arm and 18.2% in the trastuzumab arm. a statistically significant improvement in 3-yr IDFS was A higher percentage of adverse events leading to treatment observed for patients in the T-DM1 group compared to discontinuation was reported in the T-DM1 group compared those in the trastuzumab one, with an absolute gain of to the trastuzumab group (18% versus 2.1%, respectively), 11.3% (88.3% vs 77.0%; HR 0.50, 95% CI 0.39–0.64). The due mostly to thrombocytopenia, blood bilirubin and transa­ benefit of T-DM1 was observed in all subgroups, irrespective minase increase, ejection fraction decline, and peripheral of hormone receptor status, pathologic nodal status after sensory neuropathy [37]. Based on the impressive results of preoperative therapy, patients’ age at the time of treatment, the KATHERINE study, T-DM1 was approved by FDA and EMA and single or dual anti-HER2 blockade as neoadjuvant ther­ as adjuvant therapy in patients with residual disease after apy. Notably, despite the benefit given by T-DM1, about 5.9% neoadjuvant treatment, and it should now be considered the of the patients had their first recurrence in the brain in the standard of care in this setting [37]. T-DM1 arm as compared to 4.3% in the trastuzumab arm [37]. On the other side of disease recurrence risk, patients with These data are probably due to the so-called ‘competing risk’ newly diagnosed stage I breast cancer might benefit from [38] considering the lower rates of non-encephalic recurrence a de-escalating treatment strategy. This approach has been with T-DM1 [39,40]. A higher incidence of adverse events was investigated in the ATEMPT trial, a phase II study that com­ observed in the T-DM1 arm compared to the trastuzumab pared adjuvant T-DM1 alone versus paclitaxel plus EXPERT REVIEW OF ANTICANCER THERAPY 245 trastuzumab in patients with stage I HER2-positive breast nowadays should be offered a neoadjuvant approach also cancer [42]. A total of 497 women with HER2-positive, node- for the possibility to escalate the anti-HER2 blockade with negative breast cancer and tumor size ≤ 2 cm, were rando­ T-DM1 in the case of no pCR after chemotherapy plus tras­ mized to receive T-DM1 every 3 weeks for 17 cycles (n = 383) tuzumab and pertuzumab. or standard treatment with paclitaxel plus trastuzumab every Many trials are ongoing to investigate the role of T-DM1 in week for 12 weeks, following by trastuzumab alone for a total the adjuvant setting, both as a de-escalating or escalating of 1 year of treatment (n = 114). The majority of patients had strategy (Table 4). hormone receptor-positive tumors (75%), and 57% had tumors greater than 1 cm. After a median follow-up of 3 years, IDFS in the T-DM1 group was 97.5% (95% CI 95.9–99.3%) with only 11 5. Biomarkers of benefit to adjuvant T-DM1 IDFS events (1 distant recurrence) and 93.2% (95% CI 88.1–­ Biomarker analyses within the KATHERINE trial have tried to 98.7%) in the paclitaxel plus trastuzumab arm with 6 IDFS evaluate the presence of potential predictive biomarkers of ben­ events (2 distant recurrences). Incidence of clinically relevant efit to adjuvant T-DM1 (PIK3CA mutation, HER2, PD-L1, CD8, toxicities was 25% in patients treated with T-DM1 and 36% in predefined immune signatures by gene expression) [44]. patients receiving paclitaxel plus trastuzumab with no new A consistent benefit of T-DM1 therapy as compared to trastuzu­ identified T-DM1-related toxicities. Notably, an early disconti­ mab was observed regardless of PIK3CA mutational status and nuation of therapy was found in 17% of the patients in the the other immune markers. Interestingly, T-DM1 benefit was T-DM1 arm [42]. The results of this study are promising in maintained in both patients with low and high HER2 gene order to obtain a regimen with fewer side effects for patients expression. In the KATHERINE trial, 70 patients (of whom 28 in with low-risk HER2-positive early breast cancer. However, the T-DM1 and 42 in the Trastuzumab arm) experience a change a longer follow-up is needed before deriving strong conclu­ in HER2 status, with the residual disease becoming HER2- sions on this trial; in addition, the high discontinuation rate in negative at the time of surgery. In this group of patients, no the T-DM1 arm and its potential financial toxicity are also of IDFS events were observed among those randomized to T-DM1 concern. and 11 events in those randomized to trastuzumab arm. Despite Another attempt in using T-DM1 for de-escalating the the small sample size, this exploratory analysis suggests that adjuvant chemotherapy burden in a population of patients treatment with T-DM1 should be offered also to patients with at higher risk of disease recurrence than the ones included in HER2-negative residual disease at surgery, suggesting that HER2 the ATEMPT trial comes from the KAITLIN study [43]. This is retesting may not be necessary for this population [45]. a phase III trial that assessed the efficacy and safety of In addition to tumor biomarkers, molecular imaging is adjuvant T-DM1 plus pertuzumab (AC-KP arm) versus trastu­ a promising strategy to predict individual responses to zumab plus pertuzumab plus a taxane (AC-THP arm) after T-DM1. In the metastatic setting, a successful example of the anthracycline-based chemotherapy. The trial included 1,846 utility of molecular imaging to select patients unlikely to patients with early-stage HER2+ breast cancer with a tumor benefit from T-DM1 was shown by the ZEPHIR trial [46]. In size larger than 2 cm. Approximately 10% of the included this phase II trial, 60 patients with HER2-positive advanced patients were node-negative, 56% had 1–3 positive nodes disease eligible for T-DM1 treatment received a HER2- and 34% had 4 or more positive nodes, more than half (56%) positron emission tomography (PET)/computed tomography had a hormone-responsive tumor. The two co-primary end­ (CT) with (89) Zr-radiolabeled trastuzumab before treatment, points were IDFS in the node-positive population and IDFS in and [18F]2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT at baseline the intention to treat (ITT) population [43]. The first results of and before the second cycle of T-DM1, and standard CT scans the trial at a median follow-up of 57 months showed no following three cycles of therapy for response assessment. The significant difference between the two treatment arms in primary endpoint was negative predictive value (NPV) for terms of IDFS. T-DM1 plus pertuzumab did not reduce the a response to T-DM1. Among pre-therapy imaging, 29% of risk of IDFS event compared to AC-THP arm either in the the patients had no uptake on HER2 imaging. Combining node-positive cohort (HR 0.97, 95% CI 0.71–1.32) or in the both molecular imaging results, all patients with negative ITT population (HR 0.98, 95% CI 0.72–1.32) with consistent HER2 imaging showed stable or progressed metabolic data in all subgroups [43]. In terms of safety, the incidence of response after one cycle of T-DM1 (NPV of 100%). In contrast, AEs was similar in both arms (55.4% in the AC-THP group and all patients with uptake on HER2-positive imaging showed 51.8% in the AC-KP group). Nevertheless, a higher percen­ evidence of metabolic response after one cycle of T-DM1 tage of patients in the AC-KP arm than in the AC-THP arm (positive predictive value of 100%). The authors also correlated discontinued treatment with T-DM1 or trastuzumab (26.8% the imaging results with treatment discontinuation: the med­ versus 4.0%) due to AEs. A significant 29% lower risk of ian time to treatment failure was only 2.8 months in those deterioration in global health status from the beginning of with negative HER2 imaging and early metabolic stability or anti-HER2 targeted therapy was observed with T-DM1 as progression, while it was 15 months in the group of patients compared to taxane plus trastuzumab and pertuzumab, with positive HER2 imaging and early metabolic response [46]. mainly due to taxane use [43]. Based on these results, the The potential value of predicting anti-HER2 treatment ben­ association of taxane plus trastuzumab plus pertuzumab efit using PET in the early setting has been shown for trastu­ remains the standard of care in high-risk HER2-positive zumab plus pertuzumab in the PHERGAIN trial [47] and early breast cancer. Notably, these are patients that TBCRC026 trial [48]. 246 C. MOLINELLI ET AL.

Table 4. Ongoing clinical trials testing T-DM1 in the adjuvant setting. Clinicaltrial.gov EXPECTED SAMPLE number TITLE PHASE STATUS TREATMENT ARMS SIZE NCT03587740 ATOP TRIAL: T-DM1 in HER2 Positive II Recruiting Single arm with adjuvant T-DM1 in patients older 82 pts Breast Cancer than 60 years NCT04197687 TPIV100 and Sargramostim for the II Recruiting Arm A: adjuvant T-DM1, TPIV100, sargramostim in 480 pts Treatment of HER2 Positive, Stage pts who did not obtain pCR at surgery II–III Breast Cancer in Patients With Arm B: adjuvant T-DM1, placebo, sargramostim Residual Disease After in pts who did not obtain pCR at surgery Chemotherapy and Surgery Arm C: adjuvant pertuzumab and trastuzumab in pts with pCR at surgery NCT04419181 Feasibility of Chemotherapy De- II Not yet recruiting Arm A: adjuvant trastuzumab in pts who achieve 20 pts escalation in Early-Stage HER2 pCR at surgery after neoadjuvant TCHP. Positive Breast Cancer Arm B: adjuvant TCHP followed by T-DM1 plus pertuzumab or T-DM1 plus pertuzumab without TCHP (at oncologist’s discretion) in pts who have residual disease at surgery after neoadjuvant TCHP NCT04266249 CompassHER2-pCR: Decreasing II Recruiting Arm A: adjuvant trastuzumab and pertuzumab in 1,250 pts Chemotherapy for Breast Cancer pts who achieve pCR at surgery after Patients After Pre-surgery Chemo neoadjuvant taxane-based CT plus and Targeted Therapy trastuzumab and pertuzumab Arm B: adjuvant T-DM1 or adjuvant CT (at physician’s choice) followed by T-DM1 in pts who do not achieve pCR at surgery after neoadjuvant taxane-based CT plus trastuzumab and pertuzumab Not available Destiny-BREAST 05: Trastuzumab III In preparation In pts with high-risk HER2-positive primary breast 1,600 pts deruxtecan versus Trastuzumab cancer who have residual invasive disease in emtansine breast or axillary lymph nodes following neoadjuvant therapy Arm A: adjuvant T-DXd Arm B: adjuvant T-DM1 Abbreviations Pts: patients; T-DM1: Trastuzumab-emtansine; pCR: pathologic complete response; TCHP: docetaxel, carboplatin, trastuzumab and pertuzumab; CT: chemotherapy; T-DXd: Trastuzumab deruxtecan.

Molecular imaging as a noninvasive strategy to improve (in case of mastectomy). Radiotherapy had to be started within treatment personalization also for the use of T-DM1 in the 60 days of surgery and it was given concurrently with study early setting merits further investigations. therapy [37]. In a subgroup analysis of the KATHERINE trial, among the subgroup of patients treated with concurrent radiotherapy, 3-yrs IDFS was 77.4% in the trastuzumab arm 6. Practical issues and 88.3% in the T-DM1 arm (HR = 0.50, 0.38–0.66). Grade≥3 adverse events were more common in the T-DM1 arm (27.4% 6.1. Timing for radiotherapy administration vs 15.6%). About 18.0% of the patients in the T-DM1 subgroup Radiotherapy is strongly recommended after conservative sur­ experienced adverse events leading to study treatment with­ gery as well as after mastectomy in patients with involved drawal compared with 2.2% in the trastuzumab subgroup [45]. resection margins, the involvement of more than 4 axillary Despite the limited data, the concurrent use of radiother­ nodes, and T3–T4 breast cancer [49,50]. apy during T-DM1 treatment can be considered feasible. The possible concurrent use of radiotherapy during sys­ temic treatment administration is a practical issue to be con­ 6.2. Gonadotoxicity sidered of high relevance. Prior studies have suggested the safety of administering radiotherapy during trastuzumab [51]. When counseling premenopausal patients about the toxicity Regarding T-DM1, a recent study evaluated its use concur­ profile of the proposed anticancer treatments, their potential rently with radiotherapy in 14 patients [52]. Particularly, 10 gonadotoxicity should also be considered [53,54]. While the patients underwent lymph node radiation, and 4 got also risk of gonadotoxicity with the use of chemotherapy in breast a tumor bed boost. The most common adverse event was cancer patients has been more extensively assessed [55,56], grade 1 radiodermatitis and 2 patients experienced reversible the potential negative effects of targeted agents on gonadal grade 2 left ventricular ejection fraction decline [52]. function and fertility are largely unknown [57]. In the KATHERINE trial, whole-breast irradiation was per­ Trastuzumab does not seem to increase the risk of treat­ formed in patients undergoing conservative surgery, and ment-related amenorrhea [58–60]. Regarding T-DM1, amenor­ tumor bed boost was administered according to local guide­ rhea data within the ATEMPT trial have been presented at the lines. In patients with clinical T3 node-positive tumor, T4 and/ 2019 San Antonio Breast Cancer Symposium [61]. A total of or with clinical N2 or N3 tumor, regional node irradiation was 130 premenopausal women enrolled in the ATEMPT trial were administered with whole-breast irradiation (in case of breast- surveyed about the menstrual cycle at baseline and every conserving surgery) or chest wall and regional node irradiation 6 months for 36 months of follow-up. Among them, 51 EXPERT REVIEW OF ANTICANCER THERAPY 247 patients were excluded from the analysis (42 did not complete cycles should be considered in patients with residual disease the 18-month survey and 7 were administered gonadotropin- at surgery. So far, this is the only clinical application of T-DM1 releasing hormone agonist before 18 months after treatment) in the adjuvant setting. In fact, all the trials that have assessed leaving 81 patients eligible for the amenorrhea analysis. Even adjuvant T-DM1 as a way to de-escalate the chemotherapy if median age was higher in the T-DM1 arm (46 vs 44 years), burden have not led to a change in clinical practice yet. chemotherapy-related amenorrhea at 18 months was less However, some issues are still unsolved in this field and common in the T-DM1 arm: 75% of the patients reported further investigations in this regard are warranted. To date, no menstruation after treatment, compared with 45% in the tras­ biomarkers beyond HER2 positivity and lack of pCR after tuzumab arm (p = 0.011). neoadjuvant therapy is available to select patients who Due to the small sample of this analysis, despite suggesting needs or not treatment escalation or de-escalation strategies. the lack of gonadotoxicity, it is not sufficient to draw solid For a more tailored approach in patients with HER2-positive conclusions about the possible impact of T-DM1 on gonadal disease, further data on mechanisms of resistance and predic­ function, and future studies are needed to better investigate tive biomarkers are required. Considering that hormone this crucial issue. receptor expression identifies two distinct subtypes of breast cancer within the HER2-positive population [63,64], future trials focusing separately on patients with hormone receptor- 7. Conclusion positive and hormone receptor-negative disease are needed to obtain a more personalized approach. After the revolutionary results obtained with the use of T-DM1 in the adjuvant setting following neoadjuvant therapy, the treatment algorithm for HER2-positive early breast cancer 8. Expert Opinion patients have changed dramatically (Figure 1). The neoadjuvant approach (with taxane-based chemother­ The adjuvant treatment landscape of patients with HER2- apy, with or without the anthracycline component of treat­ positive early breast cancer has radically improved over the ment, plus dual anti-HER2 blockade with pertuzumab and last years with the introduction of several effective new anti- trastuzumab) remains the standard for patients with tumor HER2 targeted agents, with T-DM1 being the most recently size ≥2 cm and/or nodal involvement. Following this neoadju­ approved in this setting (Figure 2). vant treatment, patients with pCR should continue the adju­ After approval in the metastatic setting, T-DM1 has now vant therapy with trastuzumab (±pertuzumab, based on the become a key therapeutic option also in the early setting [65]. initial stage at presentation and country availability) until the So far, adjuvant T-DM1 has entered clinical use only as an completion of 1 year of anti-HER2 treatment [62]. On the escalation approach, based on the impressive data from the contrary, an escalating approach switching to T-DM1 for 14 KATHERINE trial, for the treatment of patients without pCR at

Figure 1. Treatment algorithm in patients with newly diagnosed HER2-positive early breast cancer. Abbreviations: HER2, human epithelial growth factor receptor 2; EBC, early breast cancer; T, tumor size; N, nodal status; CT, chemotherapy; pCR, pathologic complete response; T-DM1, trastuzumab emtansine. 248 C. MOLINELLI ET AL.

Figure 2. Timeline of introduction of anti-HER2 targeted agents in the adjuvant setting. surgery after neoadjuvant chemotherapy plus anti-HER2 Sandoz and Lilly. The authors have no other relevant affiliations or finan­ agents. cial involvement with any organization or entity with a financial interest in There are several additional escalating research efforts in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. this setting aiming to further improve the outcomes of patients with HER2-positive early breast cancer at high-risk of disease recurrence. Among them, considering the outstanding Reviewer disclosures results of the new antibody–drug conjugate trastuzumab- deruxtecan in the metastatic setting [66,67], leading to an Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. accelerated approval by the FDA, the DESTINY – Breast05 trial is particularly relevant. This is an ongoing phase III rando­ mized, open-label, multicentric trial that is comparing the use ORCID of trastuzumab-deruxtecan vs. T-DM1 for patients with HER2- Lucia Del Mastro http://orcid.org/0000-0002-9546-5841 positive breast cancer and residual invasive disease in the Matteo Lambertini http://orcid.org/0000-0003-1797-5296 breast or axillary lymph nodes at surgery after neoadjuvant anti-HER2 therapy (i.e. the same patient population included in the KATHERINE trial). Importantly, considering the higher References incidence of brain metastases observed in the T-DM1 arm of Papers of special note have been highlighted as either of interest (•) or of the KATHERINE study, future trials may investigate the poten­ considerable interest (••) to readers. tial preventive role of other anti-HER2 agents that have 1. Pauletti G, Dandekar S, Rong H, et al. Assessment of methods for already shown important activity on brain metastases (e.g. tissue-based detection of the HER-2/neu alteration in human breast tucatinib [68–70]). cancer: a direct comparison of fluorescence in situ hybridization In terms of de-escalating approaches, a priority is repre­ and immunohistochemistry. J Clin Oncol. 2000;18:3651–3664. 2. Slamon D, Clark G, Wong S, et al. Human breast cancer: correlation sented by decreasing the chemotherapy burden for some of relapse and survival with amplification of the HER-2/neu patients with HER2-positive disease [71,72]. T-DM1 should oncogene. Science. 1987;235:177–182. not replace the taxane-based portion of adjuvant chemother­ 3. Cossetti RJD, Tyldesley SK, Speers CH, et al. Comparison of breast apy in patients with intermediate/high risk of recurrence cancer recurrence and outcome patterns between patients treated based on the KAITLIN trial results. However, important preli­ from 1986 to 1992 and from 2004 to 2008. J Clin Oncol. 2015;33:65–73. minary results have been obtained in patients with stage 4. Lambertini M, Pondé NF, Solinas C, et al. Adjuvant trastuzumab: a I HER2-positive breast cancer with the ATEMPT trial. Long 10-year overview of its benefit. Expert Rev Anticancer Ther. term follow-up from this trial is awaited to further understand 2017;17:61–74. the possibility to move this antibody-drug conjugate as a new 5. Xie B, Zhu L, Ma C, et al. A network meta-analysis on the efficacy of standard of care. The most important unmet need that may be HER2-targeted agents in combination with taxane-containing regi­ mens for treatment of HER2-positive metastatic breast cancer. crucial to improve and tailor de-escalation research efforts is Breast Cancer. 2020;27:186–196. represented by the biomarker field [72]. Future large colla­ 6. Moja L, Tagliabue L, Balduzzi S, et al. Trastuzumab containing borative efforts in this area are highly necessary. regimens for early breast cancer. Cochrane Database Syst Rev. 2012. DOI:10.1002/14651858.CD006243.pub2. 7. Shen Y, Fujii T, Ueno NT, et al. Comparative efficacy of adjuvant Declaration of interest trastuzumab-containing chemotherapies for patients with early HER2-positive primary breast cancer: a network meta-analysis. C Molinelli has received honoraria from Novartis. L Del Mastro has acted as Breast Cancer Res Treat. 2019;173:1–9. a consultant for Roche, Novartis, MSD, Pfizer, Ipsen, AstraZeneca, Genomic 8. Perachino M, Arecco L, Martelli V, et al. Pyrotinib: a new promising Health, Lilly, Seattle Genetics, Eisai, Pierre Fabre and Daiichi Sankyo, targeted agent for human epidermal growth factor receptor received speaker honoraria from Roche, Novartis, Lilly, and MSD, and 2-positive breast cancer. Transl Breast Cancer Res. 2020;1:11. travel grants from Roche, Pfizer, and Celgene. F Poggio has received travel, 9. Birrer MJ, Moore KN, Betella I, et al. Antibody-drug conjugate-based accommodation, and expenses from Takeda, Eli Lilly, and received honor­ therapeutics: state of the science. JNCI J Natl Cancer Inst. aria from Merck Sharp & Dohme, Eli Lilly, and Novartis. M Lambertini has 2019;111:538–549. acted as a consultant for Roche, AstraZeneca, Lilly and Novartis, and •• Review focusing on the mechanism of action of antibody-drug received honoraria from Theramex, Roche, Novartis, Takeda, Pfizer, conjugates. EXPERT REVIEW OF ANTICANCER THERAPY 249

10. Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus meta-analysis of individual patient data from ten randomised trials. capecitabine plus lapatinib in patients with previously treated Lancet Oncol. 2018;19:27–39. HER2-positive advanced breast cancer (EMILIA): a descriptive ana­ 31. Caparica R, Lambertini M, Pondé N, et al. Post-neoadjuvant treat­ lysis of final overall survival results from a randomised, open-label, ment and the management of residual disease in breast cancer: phase 3 trial. Lancet Oncol. 2017;18:732–742. state of the art and perspectives. Ther Adv Med Oncol. 11. Krop IE, Kim S-B, Martin AG, et al. Trastuzumab emtansine versus 2019;11:175883591982771. treatment of physician’s choice in patients with previously treated 32. Cortazar P, Zhang L, Untch M, et al. Pathological complete HER2-positive metastatic breast cancer (TH3RESA): final overall response and long-term clinical benefit in breast cancer: the survival results from a randomised open-label phase 3 trial. CTNeoBC pooled analysis. Lancet Lond Engl. 2014;384:164–172. Lancet Oncol. 2017;18:743–754. • Important pooled analysis assessing the prognostic role of 12. Conte B, Fabi A, Poggio F, et al. T-DM1 efficacy in patients with pathologic complete response. HER2-positive metastatic breast cancer progressing after a taxane 33. Yee D, DeMichele AM, et al. I-SPY2 Trial Consortium. Association of plus pertuzumab and trastuzumab: an italian multicenter observa­ event-free and distant recurrence–free survival with individual-level tional study. Clin Breast Cancer. 2020;20:e181–e187. pathologic complete response in neoadjuvant treatment of stages 13. Fabi A, Alesini D, Valle E, et al. T-DM1 and brain metastases: clinical 2 and 3 breast cancer: three-year follow-up analysis for the I-SPY2 outcome in HER2-positive metastatic breast cancer. Breast. adaptively randomized clinical trial. JAMA Oncol. 2020;6(9):1355– 2018;41:137–143. 1362. 14. Battisti NML, Rogerson F, Lee K, et al. Safety and efficacy of T-DM1 34. Hurvitz SA, Martin M, Symmans WF, et al. Neoadjuvant trastuzu­ in patients with advanced HER2-positive breast cancer The Royal mab, pertuzumab, and chemotherapy versus trastuzumab emtan­ Marsden experience. Cancer Treat Res Commun. 2020;24:100188. sine plus pertuzumab in patients with HER2-positive breast cancer 15. Chari RVJ. Expanding the reach of antibody-drug conjugates. ACS (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Med Chem Lett. 2016;7:974–976. Lancet Oncol. 2018;19:115–126. 16. Kovtun YV, Goldmacher VS. Cell killing by antibody–drug conju­ 35. Hurvitz SA, Martin M, Jung KH, et al. Neoadjuvant trastuzumab gates. Cancer Lett. 2007;255:232–240. emtansine and pertuzumab in human epidermal growth factor 17. Diessner J, Bruttel V, Stein RG, et al. Targeting of preexisting and receptor 2–positive breast cancer: three-year outcomes from the induced breast cancer stem cells with trastuzumab and trastuzu­ phase III KRISTINE study. J Clin Oncol. 2019;37:2206–2216. mab emtansine (T-DM1). Cell Death Dis. 2014;5:e1149–e1149. 36. Aaronson NK, Ahmedzai S, Bergman B, et al. The European organi­ 18. Junttila TT, Li G, Parsons K, et al. Trastuzumab-DM1 (T-DM1) retains zation for research and treatment of cancer QLQ-C30: a quality-of- all the mechanisms of action of trastuzumab and efficiently inhibits life instrument for use in international clinical trials in oncology. growth of lapatinib insensitive breast cancer. Breast Cancer Res JNCI J Natl Cancer Inst. 1993;85:365–376. Treat. 2011;128:347–356. 37. von Minckwitz G, Huang C-S, Mano MS, et al. Trastuzumab emtan­ 19. Izumi Y, Xu L, Di Tomaso E, et al. Herceptin acts as an sine for residual invasive HER2-positive breast cancer. N Engl J Med. anti-angiogenic cocktail. Nature. 2002;416:279–280. 2019;380:617–628. 20. Dubská L, Anděra L, Sheard MA. HER2 signaling downregulation by ** Phase III trial demonstrating the efficacy of adjuvant T-DM1 in trastuzumab and suppression of the PI3K/Akt pathway: an unex­ patients without pathologic complete response after neoadju­ pected effect on TRAIL-induced apoptosis. FEBS Lett. vant treatment. 2005;579:4149–4158. 38. Pestalozzi BC, Holmes E, de Azambuja E, et al. CNS relapses in 21. Molina MA, Codony-Servat J, Albanell J, et al. Trastuzumab (her­ patients with HER2-positive early breast cancer who have and ceptin), a humanized anti-Her2 receptor monoclonal antibody, have not received adjuvant trastuzumab: a retrospective substudy inhibits basal and activated Her2 ectodomain cleavage in breast of the HERA trial (BIG 1-01). Lancet Oncol. 2013;14:244–248. cancer cells. Cancer Res. 2001;61:4744–4749. 39. Untch M, Geyer CE, Huang C, et al. Peripheral neuropathy (PN), 22. Nagata Y, Lan K-H, Zhou X, et al. PTEN activation contributes to thrombocytopenia (TCP) and central nervous system (CNS) recur­ tumor inhibition by trastuzumab, and loss of PTEN predicts trastu­ rence: an update of the phase III KATHERINE trial of zumab resistance in patients. Cancer Cell. 2004;6:117–127. post-neoadjuvant trastuzumab emtansine (T-DM1) or trastuzumab 23. Barok M, Tanner M, Köninki K, et al. Trastuzumab-DM1 causes (H) in patients (pts) with residual invasive HER2-positive breast tumour growth inhibition by mitotic catastrophe in cancer (BC). Ann Oncol. 2019;30:v854–v855. trastuzumab-resistant breast cancer cells in vivo. Breast Cancer 40. Wolkewitz M, Cooper BS, Bonten MJM, et al. Interpreting and Res. 2011;13:R46. comparing risks in the presence of competing events. BMJ. 24. Komlodi-Pasztor E, Sackett D, Wilkerson J, et al. Mitosis is not a key 2014;349:g5060–g5060. target of microtubule agents in patient tumors. Nat Rev Clin Oncol. 41. Pondé N, Ameye L, Lambertini M, et al. Trastuzumab emtansine 2011;8:244–250. (T-DM1)-associated cardiotoxicity: pooled analysis in advanced 25. Komlodi-Pasztor E, Sackett DL, Fojo AT. Inhibitors targeting mitosis: HER2-positive breast cancer. Eur J Cancer. 2020;126:65–73. tales of how great drugs against a promising target were brought 42. Tolaney SM, Trippa L, Barry W, et al. TBCRC 033: A randomized down by a flawed rationale. Clin Cancer Res. 2012;18:51–63. phase II study of adjuvant trastuzumab emtansine (T-DM1) vs 26. Lewis Phillips GD, Li G, Dugger DL, et al. Targeting HER2-positive paclitaxel (T) in combination with trastuzumab (H) for stage I breast cancer with Trastuzumab-DM1, an antibody-cytotoxic drug HER2-positive breast cancer (BC) (ATEMPT). San Antonio Breast conjugate. Cancer Res. 2008;68:9280–9290. Cancer Symposium. 2019;Abstract GS1-05. 27. LoRusso PM, Weiss D, Guardino E, et al. Trastuzumab emtansine: ** Phase II trial evaluating T-DM1 alone as adjuvant treatment. a unique antibody-drug conjugate in development for human 43. Harbeck N, Im S-A, Barrios CH, et al. Primary analysis of KAITLIN: epidermal growth factor receptor 2-positive cancer. Clin Cancer A phase III study of trastuzumab emtansine (T-DM1) + pertuzumab Res. 2011;17:6437–6447. versus trastuzumab + pertuzumab + taxane, after anthracyclines as 28. Krop IE, Beeram M, Modi S, et al. Phase I study of adjuvant therapy for high-risk HER2-positive early breast cancer trastuzumab-DM1, an HER2 antibody-drug conjugate, given every (EBC). J Clin Oncol. 2020;38:Abstract 500. 3 weeks to patients with HER2-positive metastatic breast cancer. ** Phase III trial evaluating adjuvant T-DM1 after anthracycline- J Clin Oncol. 2010;28:2698–2704. based chemotherapy. 29. Arecco L, Blondeaux E, Damassi A, et al. Moving trastuzumab 44. Denkert C, Lambertini C, Fasching PA, et al. Biomarker data from emtansine (T-DM1) to the early setting of breast cancer KATHERINE: A phase III study of adjuvant trastuzumab emtansine treatment. Ann Palliat Med. 2020;9:512–516. (T-DM1) versus trastuzumab (H) in patients with residual invasive 30. Asselain B, Barlow W, Bartlett J, et al. Long-term outcomes for disease after neoadjuvant therapy for HER2-positive breast cancer. neoadjuvant versus adjuvant chemotherapy in early breast cancer: J Clin Oncol. 2020;38:Abstract 502. 250 C. MOLINELLI ET AL.

45. Loibl S, Huang C-S, Mano MS, et al. Adjuvant trastuzumab emtansine in premenopausal women with breast cancer. Cancer. (T-DM1) vs trastuzumab (T) in patients (pts) with residual invasive 2010;116:791–798. disease after neoadjuvant therapy for HER2+ breast cancer: subgroup 60. Ruddy KJ, Guo H, Barry W, et al. Chemotherapy-related amenorrhea analysis from KATHERINE. Ann Oncol. 2020;31:S48 Abstract 96O. after adjuvant paclitaxel-trastuzumab (APT trial). Breast Cancer Res 46. Gebhart G, Lamberts LE, Wimana Z, et al. Molecular imaging as Treat. 2015;151(3):589–596. . a tool to investigate heterogeneity of advanced HER2-positive 61. Ruddy KJ, Trippa L, Hu J, et al. Chemotherapy-related amenorrhea breast cancer and to predict patient outcome under trastuzu­ (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to mab emtansine (T-DM1): the ZEPHIR trial. Ann Oncol. paclitaxel in combination with trastuzumab (TH) (TBCRC033: 2016;27:619–624. ATEMPT trial). San Antonio Breast Cancer Symposium. 2019; 47. Cortes J, Gebhart G, Ruiz Borrego M, et al. Chemotherapy (CT) Abstract P2-13-02. de-escalation using an FDG-PET/CT (F-PET) and pathological 62. Denduluri N, Chavez-MacGregor M, Telli ML, et al. Selection of response-adapted strategy in HER2[+] early breast cancer (EBC): optimal adjuvant chemotherapy and targeted therapy for early pHERGain Trial. J Clin Oncol. 2020;38:Abstract 503. breast cancer: ASCO clinical practice guideline focused update. 48. Connolly RM, Leal JP, Solnes L, et al. TBCRC026: phase II trial J Clin Oncol. 2018;36:2433–2443. correlating standardized uptake value with pathologic complete 63. Vaz-Luis I, Winer EP, Lin NU. Human epidermal growth factor response to pertuzumab and trastuzumab in breast cancer. J Clin receptor-2-positive breast cancer: does estrogen receptor sta­ Oncol. 2019;37:714–722. tus define two distinct subtypes?. Ann Oncol. 2013;24(2):283– 49. Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO 291. Clinical Practice Guidelines for diagnosis, treatment and follow-up. 64. Lambertini M, Campbell C, Gelber RD, et al. Dissecting the effect of Ann Oncol. 2019;30:1194–1220. hormone receptor status in patients with HER2-positive early ** ESMO Breast Cancer Guidelines. breast cancer: exploratory analysis from the ALTTO (BIG 2-06) 50. Punglia RS, et al. Local therapy and survival in breast cancer. N Engl randomized clinical trial. Breast Cancer Res Treat. J Med. 2007;356(23):2399–2405. 2019;177:103–114. 51. Kirova Y, et al. Benefit of post mastectomy radiation therapy 65. Goutsouliak K, Veeraraghavan J, Sethunath V, et al. Towards perso­ (PMRT) in node-positive, HER2-positive patients with breast cancer nalized treatment for early stage HER2-positive breast cancer. Nat receiving anti-HER2 treatments. Int J Radiat Oncol Biol Phys. Rev Clin Oncol. 2020;17:233–250. 2020;106(3):511–513. 66. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in 52. Zolcsák Z, et al. Adjuvant trastuzumab emtansine (T-DM1) and previously treated HER2-positive breast cancer. N Engl J Med. concurrent radiotherapy for residual invasive HER2-positive breast 2020;382:610–621. cancer: single-center preliminary results. Am J Clin Oncol. 2020. 67. Tamura K, Tsurutani J, Takahashi S, et al. Trastuzumab deruxtecan DOI:10.1097/COC.0000000000000769. (DS-8201a) in patients with advanced HER2-positive breast cancer 53. Lambertini M, Peccatori FA, Demeestere I, et al. Fertility preserva­ previously treated with trastuzumab emtansine: a dose-expansion, tion and post-treatment pregnancies in post-pubertal cancer phase 1 study. Lancet Oncol. 2019;20(6):816–826. . patients: ESMO clinical practice guidelines. Ann Oncol. 2020;31 68. Borges VF, Ferrario C, Aucoin N, et al. Tucatinib combined with (12):1664-1678. ado-trastuzumab emtansine in advanced ERBB2/HER2 -positive 54. Perachino M, Massarotti C, Razeti MG, et al. Gender-specific aspects metastatic breast cancer: a phase 1b clinical trial. JAMA Oncol. related to type of fertility preservation strategies and access to 2018;4:1214–1220. fertility care. ESMO Open. 2020;5(Suppl 4):e000771. 69. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and 55. Lambertini M, Goldrat O, Clatot F, et al. Controversies about fertility capecitabine for HER2-positive metastatic breast cancer. N Engl and pregnancy issues in young breast cancer patients: current state J Med. 2020;382:597–609. of the art. Curr Opin Oncol. 2017;29(4):243–252. 70. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and 56. Poorvu PD, Frazier AL, Feraco AM, et al. Cancer Treatment-Related survival with tucatinib plus trastuzumab and capecitabine for Infertility: A Critical Review of the Evidence. JNCI Cancer Spectr. previously treated HER2-positive breast cancer with brain 2019;3(1):pkz008. metastases in the HER2CLIMB trial. J Clin Oncol. 57. Arecco L, Perachino M, Damassi A, et al. Burning questions in the 2020;38:2610–2619. oncofertility counseling of young breast cancer patients. Breast 71. Lambertini M, Poggio F, Bruzzone M, et al. Dose-dense adjuvant Cancer (Auckl). 2020;14:1178223420954179. chemotherapy in HER2-positive early breast cancer patients before 58. Lambertini M, Campbell C, Bines J, et al. Adjuvant anti-HER2 and after the introduction of trastuzumab: exploratory analysis of Therapy, treatment-related amenorrhea, and survival in premeno­ the GIM2 trial. Int J Cancer. 2020;147:160–169. pausal HER2-Positive early breast cancer patients. J Natl Cancer 72. Gingras I, Gebhart G, de Azambuja E, et al. HER2-positive breast Inst. 2019;111:86–94. cancer is lost in translation: time for patient-centered research. Nat 59. Abusief ME, Missmer SA, Ginsburg ES, et al. The effects of paclitaxel, Rev Clin Oncol. 2017;14:669–681. dose density, and trastuzumab on treatment-related amenorrhea * Review on biomarkers in HER2-positive breast cancer.