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A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2-positive breast cancer

A prospective trial of treatment de-escalation following neoadjuvant... www.nature.com/npjbcancer ARTICLE OPEN A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2- positive breast cancer 1,2,3,13 3,4,13 5 1,2,3 1,2,3 3,6 Adrienne G. Waks , Neelam V. Desai , Tianyu Li , Philip D. Poorvu , Ann H. Partridge , Natalie Sinclair , 3,7 3,8 3,6 1,2,3 1 1,10 Laura M. Spring , Meredith Faggen , Michael Constantine , Otto Metzger , Jillian Alberti , Julia Deane , 1,2,3,11 1,2 1,2,3 1,3,12 3,4 3,5 Shoshana M. Rosenberg , Elizabeth Frank , Sara M. Tolaney , Ian E. Krop , Nadine M. Tung , Nabihah Tayob , 2,3,9 2,3,9 1,2,3,12 Tari A. King , Elizabeth A. Mittendorf and Eric P. Winer De-escalating adjuvant therapy following pathologic complete response (pCR) to an abbreviated neoadjuvant regimen in human epidermal growth factor receptor 2-positive (HER2+) breast cancer is the focus of international research efforts. However, the feasibility of this approach and its appeal to patients and providers had not been formally investigated. We aimed to assess adherence to de-escalated adjuvant antibody doublet therapy (trastuzumab and pertuzumab [HP], without chemotherapy) among patients with pCR following neoadjuvant paclitaxel/HP (THP). In this single-arm prospective trial, patients with treatment-naïve stage II-III HER2+ breast cancer received neoadjuvant weekly paclitaxel ×12 and HP every 3 weeks ×4. The primary endpoint was receipt of adjuvant non-HER2-directed cytotoxic chemotherapy. Ninety-eight patients received ≥1 dose of THP on study. Patients had median age of 50 years, 86% had stage II tumors, and 34% were hormone receptor-negative. Five patients had incomplete clinical response following THP and received doxorubicin and cyclophosphamide before surgery; they were classified as non-pCR and censored from further analyses. The overall pCR rate was 56.7%. Among patients with pCR, the adherence rate to de-escalated antibody-only therapy (HP) was 98.2% (95% CI 90.3–100.0%), and the primary feasibility endpoint was reached. The majority of patients felt positive or neutral about their adjuvant treatment plans. With brief follow-up (median 19.1 months), there were no breast cancer recurrences. De-escalation of adjuvant chemotherapy among patients who experience pCR in early-stage HER2+ breast cancer is a practicable approach for both patients and physicians. Planned and ongoing prospective trials will determine the long-term efficacy of this approach. Trial registration clinicaltrials.gov, NCT03716180, https://clinicaltrials.gov/ct2/show/NCT03716180. npj Breast Cancer (2022) 8:63 ; https://doi.org/10.1038/s41523-022-00429-7 INTRODUCTION Pathologic complete response (pCR) at surgery following neoadjuvant therapy is a strong favorable prognostic biomarker Modern treatment regimens for human epidermal growth factor in all subtypes of breast cancer, including HER2+ breast cancer receptor 2-positive (HER2+) breast cancer produce favorable long- treated with standard modern regimens incorporating HER2- term outcomes in the vast majority of patients with non- 4–6 targeted therapy . pCR is associated with an excellent long-term metastatic disease. The APHINITY trial demonstrated 3-year outcome and may identify patients who are prime candidates for invasive disease-free survival (DFS) of 92% among node-positive de-escalated adjuvant treatment. Preliminary data indicate that early-stage HER2+ breast cancer patients treated with trastuzu- pCR correlates with excellent long-term outcomes in HER2+ mab (H) and pertuzumab (P) plus adjuvant chemotherapy . breast cancer even when the neoadjuvant regimen is However, current standard-of-care neo/adjuvant regimens for 7,8 chemotherapy-sparing or otherwise non-standard . The stage II-III HER2+ breast cancer involve 2–3 chemotherapy agents CompassHER2-pCR trial (NCT04266249) is ongoing and will plus HER2-directed therapy , and these regimens are associated determine recurrence-free survival among patients with HER2+ with both serious and burdensome short- and long-term breast cancer who receive an abbreviated neoadjuvant regimen toxicities . It is of great interest to determine if a subset of and experience pCR, then omit additional standard cytotoxic patients with anatomic stage II-III HER2+ breast cancer can be chemotherapy. adequately treated with curative intent using less toxic therapy. 1 2 3 Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Breast Oncology Program, Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA, USA. Harvard 4 5 Medical School, Boston, MA, USA. Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Data Sciences, Dana-Farber Cancer 6 7 Institute, Boston, MA, USA. Hematology/Oncology, Dana-Farber/Brigham and Women’s Cancer Center at Milford, Milford, MA, USA. Hematology/Oncology, Massachusetts 8 9 General Hospital, Boston, MA, USA. Hematology/Oncology, Dana-Farber/Brigham and Women’s Cancer Center at South Shore Hospital, South Weymouth, MA, USA. Division of 10 11 Breast Surgery, Department of Surgery, Brigham and Women’s Hospital, Boston, MA, USA. Present address: Clinical Affairs, TransMedics, Inc, Andover, MA, USA. Present 12 13 address: Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA. Present address: Yale Cancer Center, New Haven, CT, USA. These authors contributed equally: Adrienne G. Waks, Neelam V. Desai. email: Eric.winer@yale.edu Published in partnership with the Breast Cancer Research Foundation 1234567890():,; A.G. Waks et al. Patients’ and providers’ acceptance of a pCR-based de- Table 1. Patient and tumor characteristics. escalated treatment approach has not been formally investigated. One recent survey found that 43% of breast cancer patients were Characteristic No. of patients (%) (N = 98) not interested in clinical trials investigating chemotherapy de- Age, years escalation, with fear of cancer recurrence and fear of regret being the most commonly cited reasons for concern . Understanding Median (range) 49.5 (24–78) concerns and preferences around this paradigm will be important Sex for optimizing communication with patients about the new Female 97 (99%) potential strategy and encouraging its uptake among appropriate Male 1 (1%) patients. Race The goal of this trial (DAPHNe: De-escalation to Adjuvant White 82 (83.7%) antibodies Post-pCR to Neoadjuvant THP) was to assess the feasibility of de-escalating therapy from a multi-agent to a single- Black 5 (5.1%) agent chemotherapy backbone plus HP in select patients with Asian 7 (7.1%) anatomic stage II-III HER2+ breast cancer, based on pCR as a Other 4 (4.1%) prognostic biomarker. All patients were planned to receive Ethnicity neoadjuvant paclitaxel-HP (THP), and patients who experienced Hispanic or Latino 5 (5.1%) pCR were recommended to receive adjuvant HP only, without further adjuvant cytotoxic chemotherapy. The primary objective Non-Hispanic 89 (90.8%) was to assess adherence to the protocol-specified de-escalated Unknown 4 (4.1%) adjuvant regimen (HP only) among patients with pCR. Post- ECOG PS at baseline operative patient questionnaires were administered to all patients 0 93 (94.9%) and physician rationales were reviewed in the medical record to 1 4 (4.1%) explore patient and provider attitudes in adjuvant therapy Unknown 1 (1%) decision-making. Stage at initial diagnosis II 84 (85.7%) RESULTS III 14 (14.3%) Patient characteristics T status Table 1 summarizes patient and tumor characteristics for 98 Tx 1 (1%) patients who began treatment on trial. The large majority of T1 17 (17.3%) patients had clinical anatomic stage II disease (85.7%), and approximately one-third of patients had hormone receptor- T2 72 (73.5%) negative (HR-) tumors (33.7%). Supplementary Table 1 shows all T3 8 (8.2%) neoadjuvant treatments received: 84.7% of patients completed all T4 0 (0%) 12 doses of neoadjuvant paclitaxel, and 99%/98% of patients N status completed at least 4 doses of neoadjuvant H/P, respectively. One N0 65 (66.3%) patient withdrew early for toxicity and is not included in N1 30 (30.6%) subsequent analyses. Five patients (5.1%) had obvious residual disease at the completion of THP and received preoperative N2 2 (2%) doxorubicin and cyclophosphamide (AC); all other patients N3 1 (1%) underwent surgery following THP (Fig. 1). Hormone receptor status ER+/PR+ 45 (45.9%) Neoadjuvant therapy responses and adjuvant therapy ER+/PR− 18 (18.4%) received ER−/PR+ 2 (2%) The overall pCR rate was 56.7%, with residual cancer burden (RCB) ER−/PR− 33 (33.7%) I, II, and III responses in 9.3%, 26.8%, and 2.1% of patients, HER2 status respectively. The pCR rate was 42.2% for hormone receptor- positive (HR+) patients, and 84.8% for HR- patients (Fig. 2). Table 2 Positive 98 (100%) shows all adjuvant therapies received by RCB category. Among Size of breast tumor by physical exam (cm) patients who experienced pCR following neoadjuvant THP (N = Median (range) 3 (0–6) 55), the rate of adherence to de-escalated antibody-only therapy Breast surgery (HP) was 98.2% (95% confidence interval [CI] 90.3–100.0%). Thus, Lumpectomy 54 (55.1%) the trial met its primary feasibility endpoint (p value from binomial Mastectomy 44 (44.9%) test: <0.001). Among the remaining 37 patients with non-pCR responses to neoadjuvant THP, 16 patients received adjuvant ECOG PS Eastern Cooperative Oncology Group Performance Status, ER chemotherapy (AC) [N = 14]; cyclophosphamide alone [N = 2], and estrogen receptor, HER2 human epidermal growth factor receptor 2, PR 21 patients did not receive adjuvant chemotherapy (19 of whom progesterone receptor. received adjuvant T-DM1). Overall, 29/37 patients who did not have a pCR (78%) received at least one dose of adjuvant T-DM1. Patient and provider attitudes toward chemotherapy and de- 84.4% of patients with HR+ disease (54/64 patients) initiated escalation adjuvant hormonal therapy. With 19.1 months of median follow-up, there were no breast Post-operative questionnaires were administered to 100% of cancer recurrences, new primary breast cancers, or deaths. One patients to query patients’ experiences with neoadjuvant che- patient was diagnosed with metastatic small cell carcinoma of motherapy, attitudes toward additional adjuvant chemotherapy, likely pancreatic primary. and perceived alignment with their treating physician about the npj Breast Cancer (2022) 63 Published in partnership with the Breast Cancer Research Foundation 1234567890():,; A.G. Waks et al. Fig. 1 Trial flow diagram. pCR pathologic complete response, THP paclitaxel/trastuzumab/pertuzumab. numerically most likely to report a better than expected preoperative chemotherapy experience (Fig. 3a). The large majority of patients felt positive or neutral about their adjuvant treatment plans, regardless of whether they planned to omit or receive additional chemotherapy such as AC. Among patients who did not plan to receive adjuvant chemotherapy, though most felt positive or neutral about that decision (score 1–3), a small minority (3.7% who had experienced pCR, and 9.5% who had not experienced pCR) reported feeling that they “should” receive more chemotherapy (score 4–5)—despite not planning to receive more. Among patients who planned to receive adjuvant chemotherapy after not experiencing pCR, 100% felt positive or neutral about that decision (score 3–5; Fig. 3b). 61.5% of patients overall felt aligned with their treating physician about adjuvant chemotherapy decisions while 20.9% of patients felt non-aligned (with 17.6% missing data for this two-question analysis; Fig. 3c). Patient and physician rationale for administering or omitting adjuvant chemotherapy were also explored through questionnaires and medical record review, with opportunity for prespecified or free- Fig. 2 Pathologic response results. Non-pCR indicates patients text responses. For patients who did not achieve pCR and did not who received additional neoadjuvant chemotherapy following receive adjuvant chemotherapy such as AC (N= 21), the most paclitaxel/trastuzumab/pertuzumab. HR hormone receptor, pCR common reason cited for omitting adjuvant chemotherapy was plan pathologic complete response, RCB residual cancer burden. for adjuvant T-DM1 (cited by 14 patients and 17 physicians), and the second most common reason was a good response to neoadjuvant need for additional adjuvant chemotherapy. Response data are chemotherapy (cited by 8 patients and 7 physicians; Supplementary shown according to the following patient categories: no pCR and Table 3). Themes that emerged from free-text responses were did not receive adjuvant chemotherapy; yes pCR and did not grouped by omission or receipt of adjuvant chemotherapy such as AC receive adjuvant chemotherapy; no pCR and did receive adjuvant after either pCR or lack of pCR, respectively. Among patients with pCR, chemotherapy (Fig. 3, associated data in Supplementary Table 2). themes related to omission of adjuvant chemotherapy included (1) Non-de-escalator patient data (yes pCR and did receive adjuvant following physician advice, (2) emphasizing the importance of pCR chemotherapy) are included only in the supplement as only one found at surgery, and (3) worry about chemotherapy toxicity. Among patient was in this category. There was a 10–20% non-response patients without pCR, themes related to receipt of adjuvant rate for all questions, with approximately equivalent non-response chemotherapy included (1) high disease risk, and (2) following the rates across patient categories. In all patient categories, ≥50% of most evidence-based treatment approach regardless of side effects. patients felt that preoperative chemotherapy went better than Supplementary Table 4 contains all patient-written responses. expected (score 4–5), and patients who experienced pCR were Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 63 A.G. Waks et al. Table 2. All non-hormonal adjuvant systemic therapies received. pCR status Adjuvant cytotoxic chemotherapy received Adjuvant antibody therapy received Regimen No. patients (%) Regimen No. patients (%) pCR aka RCB 0 AC ×4 cycles 1 (1.8%) H (trastuzumab) 1 (100%) (N = 55) (95% CI 0.05–9.7%) P (pertuzumab) 1 (100%) T-DM1 0 None 54 (98.2%) H 54 (100%) (95% CI 90.3–100%) P 50 (92.6%) T-DM1 0 RCB I AC ×4 cycles 1 (11.1%) H 0 (N = 9) P0 T-DM1 1 (100%) None 8 (88.9%) H 5 (62.5%) P 4 (50%) T-DM1 7 (87.5%) RCB II AC ×4 cycles 12 (46.2%) H 6 (50%) (N = 26) P 6 (50%) T-DM1 7 (58.3%) Cyclophosphamide x4 cycles 2 (7.7%) H 1 (50%) P0 T-DM1 1 (50%) None 12 (46.2%) H 5 (41.7%) P 2 (16.7%) T-DM1 11 (91.7%) RCB III AC x4 cycles 1 (50%) H 0 (N = 2) P0 T-DM1 1 (100%) None 1 (50%) H 0 P0 T-DM1 1 (100%) Patients who received neoadjuvant AC are not included in this table. AC doxorubicin + cyclophosphamide, CI confidence interval, pCR pathologic complete response, RCB residual cancer burden. In one patient 4 cycles of AC were planned, but stopped early (after 2 cycles) for toxicity. DISCUSSION therapy, pCR was significantly more likely for those with HR- tumors compared to HR+ tumors. Though patients with HR+/HER2+ This trial demonstrated the feasibility of de-escalating from multi- tumors are less likely to experience pCR, pCR carries less prognostic agent to single-agent cytotoxic chemotherapy in combination importance in this subset compared to HR−/HER2+ tumors, with dual anti-HER2 antibody therapy in patients with pCR after presumably due to the long-term benefits of adjuvant endocrine neoadjuvant THP. In this cohort, where the majority of patients therapy . had clinical anatomic stage II disease, just over half (56.7%) of The DAPHNe trial represents a formal assessment of feasibility patients experienced pCR. With brief follow-up in this small cohort, for a pCR-based de-escalation approach to therapy in HER2+ no breast cancer recurrences were seen. If ongoing larger trials breast cancer. HER2+ breast cancer is well suited to systemic (e.g. CompassHER2-pCR) demonstrate favorable long-term efficacy therapy de-escalation due to the development of relatively low- associated with this treatment approach, then the majority of toxicity, high-efficacy targeted therapies beginning with the U.S. patients with anatomic stage II-III HER2+ breast cancer may be Food and Drug Administration approval of adjuvant trastuzumab able to avoid the substantial toxicities associated with standard in 2006. The use of pCR as a patient-level surrogate for de- combined chemotherapy regimens. 13 escalation candidacy is supported by the excellent outcomes for The overall pCR rate of 56.7% seen in this trial is comparable to patients with HER2+ breast cancer and pCR regardless of pCR rates previously reported in other cohorts of stage II-III HER2+ neoadjuvant regimen. In the KRISTINE trial, patients who breast cancer treated with various chemo-plus-HP regimens. In the experienced pCR after neoadjuvant T-DM1 plus P had 96.7% NeoSphere trial, 4 cycles of docetaxel/HP produced a pCR rate 3-year invasive DFS (despite only 9.1% receiving adjuvant (ypT0/isN0) of 39.3% (N= 107) ; in the KRISTINE trial, 6 cycles of chemotherapy), and the I-SPY2 trial reported a 93–97% 3-year docetaxel/carboplatin/HP (TCHP) or T-DM1/P produced pCR rates event-free survival for patients with pCR following varied (ypT0/isN0) of 55.7% (N= 221) and 44.4% (N= 223), respectively ; neoadjuvant regimens for stage II–III HER2+ breast cancer, 7,8 and in the TRYPHAENA trial, 6 cycles of 5-fluorouracil/epirubicin/ including investigational regimens . Therefore, prospectively cyclophosphamide-docetaxel/HP (FEC-THP) or TCHP produced pCR evaluating the efficacy of pCR-based de-escalation in HER2+ rates (ypT0N0) of 45.3% (N= 75) and 51.9% (N= 76) .Asin all breast cancer is essential. The ongoing CompassHER2-pCR trial will other cohorts of HER2+ breast cancer treated with neoadjuvant enroll 1250 patients with stage II-IIIA HER2+ breast cancer and npj Breast Cancer (2022) 63 Published in partnership with the Breast Cancer Research Foundation A.G. Waks et al. Fig. 3 Patient responses to questionnaire regarding neoadjuvant and adjuvant chemotherapy. a Patient reflections on neoadjuvant chemotherapy. Specifically, this panel shows responses to the question, “How would you describe your experience with the chemotherapy you received before surgery”? b Patient perspectives on adjuvant chemotherapy. Specifically, this panel shows responses to the question, “How strongly do you feel that you should or should not receive more chemotherapy after your surgery?” Patients who selected score 1–2(“I feel I should not receive more chemo”) or score 3 (“I feel neutral”) and did not have adjuvant chemotherapy planned were classified as feeling positive/neutral about their planned adjuvant regimen. Patients who selected score 4–5(“I feel I should receive more chemo”) or score 3 (“I feel neutral”) and had adjuvant chemotherapy planned were classified as feeling positive/neutral about their planned adjuvant regimen. c Patient-physician alignment in planning for adjuvant chemotherapy, as rated by patients. “Aligned” was defined as: patient gave a response of 1 or 2 on question describing patient’s feeling about adjuvant chemotherapy and question describing treating physician’s feeling about adjuvant chemotherapy; or patient gave a response of 3 on both questions; or patient gave a response of 4 or 5 on both questions. “Not aligned” was defined as everything else. pCR pathologic complete response. determine recurrence-free survival with a treatment approach chemotherapy. This underscores the importance of thorough nearly identical to the DAPHNe trial. A similarly structured communication about the risks and benefits of de-escalation as European trial (DECRESCENDO) is planned for 1065 patients with well as acknowledgment of the potential for psychological ER−/HER2+ stage I–II breast cancer (tumor size 15–50 mm) . discomfort. Conversely, the fact that planned use of T-DM1 was Patients with stage III disease likely will not be well-represented in the top reason cited for de-escalation among patients without these trials (with stage IIIB/C entirely excluded), as we observed in pCR highlights patients’ and physicians’ relative comfort with the the DAPHNe trial: only 14 stage III patients participated, though all substitution of a more targeted, less toxic agent for a standard non-inflammatory stage III tumors were eligible. combination chemotherapy regimen—and likely reflects the fact For patients without pCR on DAPHNe, several themes in that de-escalation of toxic therapy is easier to consider when adjuvant therapy administration are notable. While all adjuvant something alternative is offered in its place. therapy was administered off-trial and therefore up to clinician Our trial data have several limitations. Most patients were discretion, the protocol specifically recommended adjuvant T-DM1 enrolled at a single tertiary academic cancer center (DFCI) where in all patients with residual disease, and additional chemotherapy providers already had familiarity with adjuvant de-escalation trials in patients with RCB III residual disease at surgery or otherwise in HER2+ breast cancer based on participation in prior protocols, high risk. At least one dose of adjuvant T-DM1 was administered in which may have impacted their comfort level with this approach 78% of patients with residual disease. Adjuvant chemotherapy and experience presenting it to prospective participants. Off- was omitted in most patients with RCB I and approximately half of setting this, approximately one in three enrolled patients were patients with RCB II residual disease at surgery. This reflects the from other centers including community satellite practices. While fact that long-term disease outcomes are strongly associated with even large trials of a similar de-escalation approach (Com- RCB categorization, with increasing (less favorable) RCB score passHER2-pCR and DECRESCENDO) will be potentially subject to predicting worse relapse-free survival . Though ongoing and the same enrollment biases related to provider experience/ planned trials will inform adjuvant therapy decisions for patients comfort, we expect that given larger sample sizes and broad with pCR, it is unlikely that prospective trials will be performed to recruitment base, those efficacy results will be generalizable for determine the optimal adjuvant regimen for patients with good community uptake. The patient questionnaires used to assess but non-pCR response to THP. Accordingly, these decisions will adjuvant therapy decision-making were developed by the study continue to be made on an individualized basis, as was the case in team and not previously validated. Finally, we did not gather data the DAPHNe cohort. For patients with significant residual disease on the number or characteristics of patients who declined to at surgery, the use of adjuvant anthracycline-based chemotherapy participate in the trial, though the rapidity of accrual (>7 patients/ (e.g. AC) will remain an important consideration. If used, AC should month) highlights broad patient interest. be administered in a dose-dense fashion (every 2 weeks) as this The DAPHNe trial formally assessed patients’ acceptance of de- schedule was associated with improved 10-year breast cancer escalated adjuvant therapy in clinical anatomic stage II-III HER2+ outcomes in a large meta-analysis . breast cancer. Given the landscape of ongoing trials, we anticipate Patients’ and treating physicians’ reports offer insights into the that this may be a major emerging treatment paradigm in non- reasoning and confidence level underlying adjuvant therapy metastatic HER2+ breast cancer. While larger cohorts will be decisions. Most patients reported feeling positive or neutral about instrumental in establishing the long-term efficacy of this their adjuvant regimen, regardless of whether further chemother- treatment strategy, this trial was unique in its focus on patient apy was planned or not. However, there were modestly attitudes toward chemotherapy, patient-physician alignment with numerically higher rates of positive/neutral feelings toward respect to adjuvant chemotherapy, and patients’ sources of adjuvant therapy plan and slightly higher rates of perceived reassurance and reservation about adjuvant therapy de- patient–physician alignment among patients who were planned escalation within this specific patient population. We must for adjuvant chemotherapy, potentially suggestive of a higher continue to evaluate patients’ and physicians’ perspectives on level of ambivalence among patients who did not plan adjuvant de-escalation in order to optimize communication, facilitate Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 63 A.G. Waks et al. informed decision-making, and ultimately encourage uptake of Among patients with pCR to THP, de-escalation would be deemed infeasible if the true rate of adherence to HP only was ≤80%. With a sample this evolving treatment approach that seeks to minimize toxicity size of 100 patients, the study was designed to have > 90% power to reject without compromising benefit in the appropriate contexts. the null if the true rate of adherence was ≥ 95% (binomial exact test; one- sided alpha = 0.05). Patients who progressed during neoadjuvant THP, withdrew consent to participate, received neoadjuvant therapy in addition METHODS to THP, or did not have pCR were not included in the primary analysis Patient population (prespecified). Secondary endpoints included event-free survival and Eligible patients had clinical anatomic stage II-III HER2+ invasive breast overall survival. Patients who received additional non-THP neoadjuvant cancer. HER2 positivity was defined according to 2018 American Society of therapy were counted as non-pCR. Questionnaire and medical record Clinical Oncology/College of American Pathologists guidelines . Patients review results for analysis of adjuvant therapy decision-making were could have any menopausal or hormone receptor status, and were summarized descriptively and patients who received additional neoadju- required to have performance status ≤1 and adequate organ function at vant therapy following THP were not included in this analysis. SAS v9.4 was baseline. Patients with baseline cardiac ejection fraction <50% or used for data analysis and R v4.0.2 was used to make figures. significant peripheral neuropathy (grade ≥ 2 by common terminology criteria for adverse events v4.0) were excluded. All patients provided Reporting summary written informed consent and the study was carried out in accordance Further information on research design is available in the Nature Research with the Declaration of Helsinki. Reporting Summary linked to this article. Treatment protocol This was a single-arm prospective trial that enrolled patients from DATA AVAILABILITY November 2018 to January 2020 at Dana-Farber/Harvard Cancer Center The datasets generated during and/or analyzed during the current study are available (DF/HCC; composed of Dana-Farber Cancer Institute [DFCI], Massachusetts from the corresponding author on reasonable request. General Hospital, and Beth Israel Deaconess Medical Center) and affiliated community satellite practices. All patients were assigned to receive Received: 13 August 2021; Accepted: 14 March 2022; preoperative paclitaxel (T; 80 mg/m weekly for 12 weeks), trastuzumab (H; loading dose 8 mg/kg, subsequent doses 6 mg/kg, every 3 weeks for 4 cycles), and pertuzumab (P; loading dose 840 mg, subsequent doses 420 mg, every 3 weeks for 4 cycles) prior to breast surgery. Up to two additional cycles of HP were allowed in cases of surgical delay. Patients with obvious residual disease at completion of THP were allowed to REFERENCES receive additional neoadjuvant therapy at investigator discretion; 4 cycles 1. von Minckwitz, G. et al. Adjuvant pertuzumab and trastuzumab in early HER2- of AC was the recommended regimen. Pathologic response to neoadju- positive breast cancer. N. Engl. J. Med. 377, 122–131 (2017). vant therapy was quantified at surgery according to RCB score; pCR was 2. Gradishar, W. 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Novartis, Pfizer, Genentech/Roche, Immunomedics, Bristol-Myers Squibb, Eisai, 16. Wolff, A. C. et al. Human epidermal growth factor receptor 2 testing in breast Nanostring, Puma, Sanofi, Celldex, Paxman, Silverback Therapeutics, G1 Therapeutics, cancer: American Society of Clinical Oncology/College of American Pathologists Gilead, AbbVie, Anthenex, OncoPep, Outcomes4Me, Kyowa Kirin Pharmaceuticals, Clinical Practice Guideline Focused Update. J. Clin. Oncol. 36, 2105–2122 (2018). Daiichi-Sankyo, Ellipsis, and Samsung Bioepsis Inc. T.A.K.: speakers honoraria Exact 17. Symmans, W. F. et al. Measurement of residual breast cancer burden to predict Sciences (formerly Genomic Health); faculty, PrecisCa cancer information services and survival after neoadjuvant chemotherapy. J. Clin. Oncol. 25, 4414–4422 (2007). compensated service for a Global Advisory Board of Besins Healthcare. E.A.M.: 18. von Minckwitz, G. et al. Trastuzumab emtansine for residual invasive HER2- institutional research from Genentech/Roche via a SU2C grant; research funding from positive breast cancer. N. Engl. J. Med. 380, 617–628 (2019). Exact Sciences and Glaxo SmithKline; has served as an advisor/consultant to AstraZeneca, Bristol-Myers Squibb, Exact Sciences, Genentech/Roche, Lilly, Merck and Sellas. E.P.W.: institutional research funding from Genentech/Roche; consultant for ACKNOWLEDGEMENTS Athenex, Carrick Therapeutics, G1 Therapeutics, Genentech/Roche, Genomic Health, Gilead, GSK, Jounce, Lilly, Novartis, Seattle Genetics, Syros, and Zymeworks; scientific These data were presented in part at the San Antonio Breast Cancer Symposium advisory board member at Leap Therapeutics; and serves as President-Elect of the (December 2020). Abstract # PD3-05. Primary funding was provided by the Breast American Society of Clinical Oncology (ASCO). All remaining authors have declared Cancer Research Foundation (to E.P.W.). Additional funding was provided by the no conflicts of interest. Breast Cancer Research Foundation, the American Society of Clinical Oncology Conquer Cancer Foundation, and the Terri Brodeur Breast Cancer Foundation (to A.G. W.); Susan G. Komen (to E.A.M.). ADDITIONAL INFORMATION Supplementary information The online version contains supplementary material AUTHOR CONTRIBUTIONS available at https://doi.org/10.1038/s41523-022-00429-7. A.G.W.: co-first author. Concept development; trial oversight; manuscript writing and editing. N.V.D.: co-first author. Concept development; trial oversight; manuscript Correspondence and requests for materials should be addressed to Eric P. Winer. writing and editing. T.L.: concept development, statistical analyses, manuscript writing and editing. P.D.P.: patient accrual, manuscript writing and editing. A.H.P.: Reprints and permission information is available at http://www.nature.com/ patient accrual, manuscript writing and editing. 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A.H. from the copyright holder. To view a copy of this license, visit http://creativecommons. P.: travel support from Novartis. LMS declares consulting fees from Novartis. O.M.: org/licenses/by/4.0/. receives institutional research funding from Abbvie, Genentech/Pfizer, and Roche; honoraria from Roche. S.M.T.: receives institutional research funding from AstraZe- neca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Exelixis, © The Author(s) 2022 Bristol-Myers Squibb, Eisai, Nanostring, Sanofi, Cyclacel, Odonate, and Seattle Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 63 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Breast Cancer Springer Journals

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www.nature.com/npjbcancer ARTICLE OPEN A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2- positive breast cancer 1,2,3,13 3,4,13 5 1,2,3 1,2,3 3,6 Adrienne G. Waks , Neelam V. Desai , Tianyu Li , Philip D. Poorvu , Ann H. Partridge , Natalie Sinclair , 3,7 3,8 3,6 1,2,3 1 1,10 Laura M. Spring , Meredith Faggen , Michael Constantine , Otto Metzger , Jillian Alberti , Julia Deane , 1,2,3,11 1,2 1,2,3 1,3,12 3,4 3,5 Shoshana M. Rosenberg , Elizabeth Frank , Sara M. Tolaney , Ian E. Krop , Nadine M. Tung , Nabihah Tayob , 2,3,9 2,3,9 1,2,3,12 Tari A. King , Elizabeth A. Mittendorf and Eric P. Winer De-escalating adjuvant therapy following pathologic complete response (pCR) to an abbreviated neoadjuvant regimen in human epidermal growth factor receptor 2-positive (HER2+) breast cancer is the focus of international research efforts. However, the feasibility of this approach and its appeal to patients and providers had not been formally investigated. We aimed to assess adherence to de-escalated adjuvant antibody doublet therapy (trastuzumab and pertuzumab [HP], without chemotherapy) among patients with pCR following neoadjuvant paclitaxel/HP (THP). In this single-arm prospective trial, patients with treatment-naïve stage II-III HER2+ breast cancer received neoadjuvant weekly paclitaxel ×12 and HP every 3 weeks ×4. The primary endpoint was receipt of adjuvant non-HER2-directed cytotoxic chemotherapy. Ninety-eight patients received ≥1 dose of THP on study. Patients had median age of 50 years, 86% had stage II tumors, and 34% were hormone receptor-negative. Five patients had incomplete clinical response following THP and received doxorubicin and cyclophosphamide before surgery; they were classified as non-pCR and censored from further analyses. The overall pCR rate was 56.7%. Among patients with pCR, the adherence rate to de-escalated antibody-only therapy (HP) was 98.2% (95% CI 90.3–100.0%), and the primary feasibility endpoint was reached. The majority of patients felt positive or neutral about their adjuvant treatment plans. With brief follow-up (median 19.1 months), there were no breast cancer recurrences. De-escalation of adjuvant chemotherapy among patients who experience pCR in early-stage HER2+ breast cancer is a practicable approach for both patients and physicians. Planned and ongoing prospective trials will determine the long-term efficacy of this approach. Trial registration clinicaltrials.gov, NCT03716180, https://clinicaltrials.gov/ct2/show/NCT03716180. npj Breast Cancer (2022) 8:63 ; https://doi.org/10.1038/s41523-022-00429-7 INTRODUCTION Pathologic complete response (pCR) at surgery following neoadjuvant therapy is a strong favorable prognostic biomarker Modern treatment regimens for human epidermal growth factor in all subtypes of breast cancer, including HER2+ breast cancer receptor 2-positive (HER2+) breast cancer produce favorable long- treated with standard modern regimens incorporating HER2- term outcomes in the vast majority of patients with non- 4–6 targeted therapy . pCR is associated with an excellent long-term metastatic disease. The APHINITY trial demonstrated 3-year outcome and may identify patients who are prime candidates for invasive disease-free survival (DFS) of 92% among node-positive de-escalated adjuvant treatment. Preliminary data indicate that early-stage HER2+ breast cancer patients treated with trastuzu- pCR correlates with excellent long-term outcomes in HER2+ mab (H) and pertuzumab (P) plus adjuvant chemotherapy . breast cancer even when the neoadjuvant regimen is However, current standard-of-care neo/adjuvant regimens for 7,8 chemotherapy-sparing or otherwise non-standard . The stage II-III HER2+ breast cancer involve 2–3 chemotherapy agents CompassHER2-pCR trial (NCT04266249) is ongoing and will plus HER2-directed therapy , and these regimens are associated determine recurrence-free survival among patients with HER2+ with both serious and burdensome short- and long-term breast cancer who receive an abbreviated neoadjuvant regimen toxicities . It is of great interest to determine if a subset of and experience pCR, then omit additional standard cytotoxic patients with anatomic stage II-III HER2+ breast cancer can be chemotherapy. adequately treated with curative intent using less toxic therapy. 1 2 3 Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Breast Oncology Program, Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA, USA. Harvard 4 5 Medical School, Boston, MA, USA. Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA. Department of Data Sciences, Dana-Farber Cancer 6 7 Institute, Boston, MA, USA. Hematology/Oncology, Dana-Farber/Brigham and Women’s Cancer Center at Milford, Milford, MA, USA. Hematology/Oncology, Massachusetts 8 9 General Hospital, Boston, MA, USA. Hematology/Oncology, Dana-Farber/Brigham and Women’s Cancer Center at South Shore Hospital, South Weymouth, MA, USA. Division of 10 11 Breast Surgery, Department of Surgery, Brigham and Women’s Hospital, Boston, MA, USA. Present address: Clinical Affairs, TransMedics, Inc, Andover, MA, USA. Present 12 13 address: Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA. Present address: Yale Cancer Center, New Haven, CT, USA. These authors contributed equally: Adrienne G. Waks, Neelam V. Desai. email: Eric.winer@yale.edu Published in partnership with the Breast Cancer Research Foundation 1234567890():,; A.G. Waks et al. Patients’ and providers’ acceptance of a pCR-based de- Table 1. Patient and tumor characteristics. escalated treatment approach has not been formally investigated. One recent survey found that 43% of breast cancer patients were Characteristic No. of patients (%) (N = 98) not interested in clinical trials investigating chemotherapy de- Age, years escalation, with fear of cancer recurrence and fear of regret being the most commonly cited reasons for concern . Understanding Median (range) 49.5 (24–78) concerns and preferences around this paradigm will be important Sex for optimizing communication with patients about the new Female 97 (99%) potential strategy and encouraging its uptake among appropriate Male 1 (1%) patients. Race The goal of this trial (DAPHNe: De-escalation to Adjuvant White 82 (83.7%) antibodies Post-pCR to Neoadjuvant THP) was to assess the feasibility of de-escalating therapy from a multi-agent to a single- Black 5 (5.1%) agent chemotherapy backbone plus HP in select patients with Asian 7 (7.1%) anatomic stage II-III HER2+ breast cancer, based on pCR as a Other 4 (4.1%) prognostic biomarker. All patients were planned to receive Ethnicity neoadjuvant paclitaxel-HP (THP), and patients who experienced Hispanic or Latino 5 (5.1%) pCR were recommended to receive adjuvant HP only, without further adjuvant cytotoxic chemotherapy. The primary objective Non-Hispanic 89 (90.8%) was to assess adherence to the protocol-specified de-escalated Unknown 4 (4.1%) adjuvant regimen (HP only) among patients with pCR. Post- ECOG PS at baseline operative patient questionnaires were administered to all patients 0 93 (94.9%) and physician rationales were reviewed in the medical record to 1 4 (4.1%) explore patient and provider attitudes in adjuvant therapy Unknown 1 (1%) decision-making. Stage at initial diagnosis II 84 (85.7%) RESULTS III 14 (14.3%) Patient characteristics T status Table 1 summarizes patient and tumor characteristics for 98 Tx 1 (1%) patients who began treatment on trial. The large majority of T1 17 (17.3%) patients had clinical anatomic stage II disease (85.7%), and approximately one-third of patients had hormone receptor- T2 72 (73.5%) negative (HR-) tumors (33.7%). Supplementary Table 1 shows all T3 8 (8.2%) neoadjuvant treatments received: 84.7% of patients completed all T4 0 (0%) 12 doses of neoadjuvant paclitaxel, and 99%/98% of patients N status completed at least 4 doses of neoadjuvant H/P, respectively. One N0 65 (66.3%) patient withdrew early for toxicity and is not included in N1 30 (30.6%) subsequent analyses. Five patients (5.1%) had obvious residual disease at the completion of THP and received preoperative N2 2 (2%) doxorubicin and cyclophosphamide (AC); all other patients N3 1 (1%) underwent surgery following THP (Fig. 1). Hormone receptor status ER+/PR+ 45 (45.9%) Neoadjuvant therapy responses and adjuvant therapy ER+/PR− 18 (18.4%) received ER−/PR+ 2 (2%) The overall pCR rate was 56.7%, with residual cancer burden (RCB) ER−/PR− 33 (33.7%) I, II, and III responses in 9.3%, 26.8%, and 2.1% of patients, HER2 status respectively. The pCR rate was 42.2% for hormone receptor- positive (HR+) patients, and 84.8% for HR- patients (Fig. 2). Table 2 Positive 98 (100%) shows all adjuvant therapies received by RCB category. Among Size of breast tumor by physical exam (cm) patients who experienced pCR following neoadjuvant THP (N = Median (range) 3 (0–6) 55), the rate of adherence to de-escalated antibody-only therapy Breast surgery (HP) was 98.2% (95% confidence interval [CI] 90.3–100.0%). Thus, Lumpectomy 54 (55.1%) the trial met its primary feasibility endpoint (p value from binomial Mastectomy 44 (44.9%) test: <0.001). Among the remaining 37 patients with non-pCR responses to neoadjuvant THP, 16 patients received adjuvant ECOG PS Eastern Cooperative Oncology Group Performance Status, ER chemotherapy (AC) [N = 14]; cyclophosphamide alone [N = 2], and estrogen receptor, HER2 human epidermal growth factor receptor 2, PR 21 patients did not receive adjuvant chemotherapy (19 of whom progesterone receptor. received adjuvant T-DM1). Overall, 29/37 patients who did not have a pCR (78%) received at least one dose of adjuvant T-DM1. Patient and provider attitudes toward chemotherapy and de- 84.4% of patients with HR+ disease (54/64 patients) initiated escalation adjuvant hormonal therapy. With 19.1 months of median follow-up, there were no breast Post-operative questionnaires were administered to 100% of cancer recurrences, new primary breast cancers, or deaths. One patients to query patients’ experiences with neoadjuvant che- patient was diagnosed with metastatic small cell carcinoma of motherapy, attitudes toward additional adjuvant chemotherapy, likely pancreatic primary. and perceived alignment with their treating physician about the npj Breast Cancer (2022) 63 Published in partnership with the Breast Cancer Research Foundation 1234567890():,; A.G. Waks et al. Fig. 1 Trial flow diagram. pCR pathologic complete response, THP paclitaxel/trastuzumab/pertuzumab. numerically most likely to report a better than expected preoperative chemotherapy experience (Fig. 3a). The large majority of patients felt positive or neutral about their adjuvant treatment plans, regardless of whether they planned to omit or receive additional chemotherapy such as AC. Among patients who did not plan to receive adjuvant chemotherapy, though most felt positive or neutral about that decision (score 1–3), a small minority (3.7% who had experienced pCR, and 9.5% who had not experienced pCR) reported feeling that they “should” receive more chemotherapy (score 4–5)—despite not planning to receive more. Among patients who planned to receive adjuvant chemotherapy after not experiencing pCR, 100% felt positive or neutral about that decision (score 3–5; Fig. 3b). 61.5% of patients overall felt aligned with their treating physician about adjuvant chemotherapy decisions while 20.9% of patients felt non-aligned (with 17.6% missing data for this two-question analysis; Fig. 3c). Patient and physician rationale for administering or omitting adjuvant chemotherapy were also explored through questionnaires and medical record review, with opportunity for prespecified or free- Fig. 2 Pathologic response results. Non-pCR indicates patients text responses. For patients who did not achieve pCR and did not who received additional neoadjuvant chemotherapy following receive adjuvant chemotherapy such as AC (N= 21), the most paclitaxel/trastuzumab/pertuzumab. HR hormone receptor, pCR common reason cited for omitting adjuvant chemotherapy was plan pathologic complete response, RCB residual cancer burden. for adjuvant T-DM1 (cited by 14 patients and 17 physicians), and the second most common reason was a good response to neoadjuvant need for additional adjuvant chemotherapy. Response data are chemotherapy (cited by 8 patients and 7 physicians; Supplementary shown according to the following patient categories: no pCR and Table 3). Themes that emerged from free-text responses were did not receive adjuvant chemotherapy; yes pCR and did not grouped by omission or receipt of adjuvant chemotherapy such as AC receive adjuvant chemotherapy; no pCR and did receive adjuvant after either pCR or lack of pCR, respectively. Among patients with pCR, chemotherapy (Fig. 3, associated data in Supplementary Table 2). themes related to omission of adjuvant chemotherapy included (1) Non-de-escalator patient data (yes pCR and did receive adjuvant following physician advice, (2) emphasizing the importance of pCR chemotherapy) are included only in the supplement as only one found at surgery, and (3) worry about chemotherapy toxicity. Among patient was in this category. There was a 10–20% non-response patients without pCR, themes related to receipt of adjuvant rate for all questions, with approximately equivalent non-response chemotherapy included (1) high disease risk, and (2) following the rates across patient categories. In all patient categories, ≥50% of most evidence-based treatment approach regardless of side effects. patients felt that preoperative chemotherapy went better than Supplementary Table 4 contains all patient-written responses. expected (score 4–5), and patients who experienced pCR were Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 63 A.G. Waks et al. Table 2. All non-hormonal adjuvant systemic therapies received. pCR status Adjuvant cytotoxic chemotherapy received Adjuvant antibody therapy received Regimen No. patients (%) Regimen No. patients (%) pCR aka RCB 0 AC ×4 cycles 1 (1.8%) H (trastuzumab) 1 (100%) (N = 55) (95% CI 0.05–9.7%) P (pertuzumab) 1 (100%) T-DM1 0 None 54 (98.2%) H 54 (100%) (95% CI 90.3–100%) P 50 (92.6%) T-DM1 0 RCB I AC ×4 cycles 1 (11.1%) H 0 (N = 9) P0 T-DM1 1 (100%) None 8 (88.9%) H 5 (62.5%) P 4 (50%) T-DM1 7 (87.5%) RCB II AC ×4 cycles 12 (46.2%) H 6 (50%) (N = 26) P 6 (50%) T-DM1 7 (58.3%) Cyclophosphamide x4 cycles 2 (7.7%) H 1 (50%) P0 T-DM1 1 (50%) None 12 (46.2%) H 5 (41.7%) P 2 (16.7%) T-DM1 11 (91.7%) RCB III AC x4 cycles 1 (50%) H 0 (N = 2) P0 T-DM1 1 (100%) None 1 (50%) H 0 P0 T-DM1 1 (100%) Patients who received neoadjuvant AC are not included in this table. AC doxorubicin + cyclophosphamide, CI confidence interval, pCR pathologic complete response, RCB residual cancer burden. In one patient 4 cycles of AC were planned, but stopped early (after 2 cycles) for toxicity. DISCUSSION therapy, pCR was significantly more likely for those with HR- tumors compared to HR+ tumors. Though patients with HR+/HER2+ This trial demonstrated the feasibility of de-escalating from multi- tumors are less likely to experience pCR, pCR carries less prognostic agent to single-agent cytotoxic chemotherapy in combination importance in this subset compared to HR−/HER2+ tumors, with dual anti-HER2 antibody therapy in patients with pCR after presumably due to the long-term benefits of adjuvant endocrine neoadjuvant THP. In this cohort, where the majority of patients therapy . had clinical anatomic stage II disease, just over half (56.7%) of The DAPHNe trial represents a formal assessment of feasibility patients experienced pCR. With brief follow-up in this small cohort, for a pCR-based de-escalation approach to therapy in HER2+ no breast cancer recurrences were seen. If ongoing larger trials breast cancer. HER2+ breast cancer is well suited to systemic (e.g. CompassHER2-pCR) demonstrate favorable long-term efficacy therapy de-escalation due to the development of relatively low- associated with this treatment approach, then the majority of toxicity, high-efficacy targeted therapies beginning with the U.S. patients with anatomic stage II-III HER2+ breast cancer may be Food and Drug Administration approval of adjuvant trastuzumab able to avoid the substantial toxicities associated with standard in 2006. The use of pCR as a patient-level surrogate for de- combined chemotherapy regimens. 13 escalation candidacy is supported by the excellent outcomes for The overall pCR rate of 56.7% seen in this trial is comparable to patients with HER2+ breast cancer and pCR regardless of pCR rates previously reported in other cohorts of stage II-III HER2+ neoadjuvant regimen. In the KRISTINE trial, patients who breast cancer treated with various chemo-plus-HP regimens. In the experienced pCR after neoadjuvant T-DM1 plus P had 96.7% NeoSphere trial, 4 cycles of docetaxel/HP produced a pCR rate 3-year invasive DFS (despite only 9.1% receiving adjuvant (ypT0/isN0) of 39.3% (N= 107) ; in the KRISTINE trial, 6 cycles of chemotherapy), and the I-SPY2 trial reported a 93–97% 3-year docetaxel/carboplatin/HP (TCHP) or T-DM1/P produced pCR rates event-free survival for patients with pCR following varied (ypT0/isN0) of 55.7% (N= 221) and 44.4% (N= 223), respectively ; neoadjuvant regimens for stage II–III HER2+ breast cancer, 7,8 and in the TRYPHAENA trial, 6 cycles of 5-fluorouracil/epirubicin/ including investigational regimens . Therefore, prospectively cyclophosphamide-docetaxel/HP (FEC-THP) or TCHP produced pCR evaluating the efficacy of pCR-based de-escalation in HER2+ rates (ypT0N0) of 45.3% (N= 75) and 51.9% (N= 76) .Asin all breast cancer is essential. The ongoing CompassHER2-pCR trial will other cohorts of HER2+ breast cancer treated with neoadjuvant enroll 1250 patients with stage II-IIIA HER2+ breast cancer and npj Breast Cancer (2022) 63 Published in partnership with the Breast Cancer Research Foundation A.G. Waks et al. Fig. 3 Patient responses to questionnaire regarding neoadjuvant and adjuvant chemotherapy. a Patient reflections on neoadjuvant chemotherapy. Specifically, this panel shows responses to the question, “How would you describe your experience with the chemotherapy you received before surgery”? b Patient perspectives on adjuvant chemotherapy. Specifically, this panel shows responses to the question, “How strongly do you feel that you should or should not receive more chemotherapy after your surgery?” Patients who selected score 1–2(“I feel I should not receive more chemo”) or score 3 (“I feel neutral”) and did not have adjuvant chemotherapy planned were classified as feeling positive/neutral about their planned adjuvant regimen. Patients who selected score 4–5(“I feel I should receive more chemo”) or score 3 (“I feel neutral”) and had adjuvant chemotherapy planned were classified as feeling positive/neutral about their planned adjuvant regimen. c Patient-physician alignment in planning for adjuvant chemotherapy, as rated by patients. “Aligned” was defined as: patient gave a response of 1 or 2 on question describing patient’s feeling about adjuvant chemotherapy and question describing treating physician’s feeling about adjuvant chemotherapy; or patient gave a response of 3 on both questions; or patient gave a response of 4 or 5 on both questions. “Not aligned” was defined as everything else. pCR pathologic complete response. determine recurrence-free survival with a treatment approach chemotherapy. This underscores the importance of thorough nearly identical to the DAPHNe trial. A similarly structured communication about the risks and benefits of de-escalation as European trial (DECRESCENDO) is planned for 1065 patients with well as acknowledgment of the potential for psychological ER−/HER2+ stage I–II breast cancer (tumor size 15–50 mm) . discomfort. Conversely, the fact that planned use of T-DM1 was Patients with stage III disease likely will not be well-represented in the top reason cited for de-escalation among patients without these trials (with stage IIIB/C entirely excluded), as we observed in pCR highlights patients’ and physicians’ relative comfort with the the DAPHNe trial: only 14 stage III patients participated, though all substitution of a more targeted, less toxic agent for a standard non-inflammatory stage III tumors were eligible. combination chemotherapy regimen—and likely reflects the fact For patients without pCR on DAPHNe, several themes in that de-escalation of toxic therapy is easier to consider when adjuvant therapy administration are notable. While all adjuvant something alternative is offered in its place. therapy was administered off-trial and therefore up to clinician Our trial data have several limitations. Most patients were discretion, the protocol specifically recommended adjuvant T-DM1 enrolled at a single tertiary academic cancer center (DFCI) where in all patients with residual disease, and additional chemotherapy providers already had familiarity with adjuvant de-escalation trials in patients with RCB III residual disease at surgery or otherwise in HER2+ breast cancer based on participation in prior protocols, high risk. At least one dose of adjuvant T-DM1 was administered in which may have impacted their comfort level with this approach 78% of patients with residual disease. Adjuvant chemotherapy and experience presenting it to prospective participants. Off- was omitted in most patients with RCB I and approximately half of setting this, approximately one in three enrolled patients were patients with RCB II residual disease at surgery. This reflects the from other centers including community satellite practices. While fact that long-term disease outcomes are strongly associated with even large trials of a similar de-escalation approach (Com- RCB categorization, with increasing (less favorable) RCB score passHER2-pCR and DECRESCENDO) will be potentially subject to predicting worse relapse-free survival . Though ongoing and the same enrollment biases related to provider experience/ planned trials will inform adjuvant therapy decisions for patients comfort, we expect that given larger sample sizes and broad with pCR, it is unlikely that prospective trials will be performed to recruitment base, those efficacy results will be generalizable for determine the optimal adjuvant regimen for patients with good community uptake. The patient questionnaires used to assess but non-pCR response to THP. Accordingly, these decisions will adjuvant therapy decision-making were developed by the study continue to be made on an individualized basis, as was the case in team and not previously validated. Finally, we did not gather data the DAPHNe cohort. For patients with significant residual disease on the number or characteristics of patients who declined to at surgery, the use of adjuvant anthracycline-based chemotherapy participate in the trial, though the rapidity of accrual (>7 patients/ (e.g. AC) will remain an important consideration. If used, AC should month) highlights broad patient interest. be administered in a dose-dense fashion (every 2 weeks) as this The DAPHNe trial formally assessed patients’ acceptance of de- schedule was associated with improved 10-year breast cancer escalated adjuvant therapy in clinical anatomic stage II-III HER2+ outcomes in a large meta-analysis . breast cancer. Given the landscape of ongoing trials, we anticipate Patients’ and treating physicians’ reports offer insights into the that this may be a major emerging treatment paradigm in non- reasoning and confidence level underlying adjuvant therapy metastatic HER2+ breast cancer. While larger cohorts will be decisions. Most patients reported feeling positive or neutral about instrumental in establishing the long-term efficacy of this their adjuvant regimen, regardless of whether further chemother- treatment strategy, this trial was unique in its focus on patient apy was planned or not. However, there were modestly attitudes toward chemotherapy, patient-physician alignment with numerically higher rates of positive/neutral feelings toward respect to adjuvant chemotherapy, and patients’ sources of adjuvant therapy plan and slightly higher rates of perceived reassurance and reservation about adjuvant therapy de- patient–physician alignment among patients who were planned escalation within this specific patient population. We must for adjuvant chemotherapy, potentially suggestive of a higher continue to evaluate patients’ and physicians’ perspectives on level of ambivalence among patients who did not plan adjuvant de-escalation in order to optimize communication, facilitate Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 63 A.G. Waks et al. informed decision-making, and ultimately encourage uptake of Among patients with pCR to THP, de-escalation would be deemed infeasible if the true rate of adherence to HP only was ≤80%. With a sample this evolving treatment approach that seeks to minimize toxicity size of 100 patients, the study was designed to have > 90% power to reject without compromising benefit in the appropriate contexts. the null if the true rate of adherence was ≥ 95% (binomial exact test; one- sided alpha = 0.05). Patients who progressed during neoadjuvant THP, withdrew consent to participate, received neoadjuvant therapy in addition METHODS to THP, or did not have pCR were not included in the primary analysis Patient population (prespecified). Secondary endpoints included event-free survival and Eligible patients had clinical anatomic stage II-III HER2+ invasive breast overall survival. Patients who received additional non-THP neoadjuvant cancer. HER2 positivity was defined according to 2018 American Society of therapy were counted as non-pCR. Questionnaire and medical record Clinical Oncology/College of American Pathologists guidelines . Patients review results for analysis of adjuvant therapy decision-making were could have any menopausal or hormone receptor status, and were summarized descriptively and patients who received additional neoadju- required to have performance status ≤1 and adequate organ function at vant therapy following THP were not included in this analysis. SAS v9.4 was baseline. Patients with baseline cardiac ejection fraction <50% or used for data analysis and R v4.0.2 was used to make figures. significant peripheral neuropathy (grade ≥ 2 by common terminology criteria for adverse events v4.0) were excluded. All patients provided Reporting summary written informed consent and the study was carried out in accordance Further information on research design is available in the Nature Research with the Declaration of Helsinki. Reporting Summary linked to this article. Treatment protocol This was a single-arm prospective trial that enrolled patients from DATA AVAILABILITY November 2018 to January 2020 at Dana-Farber/Harvard Cancer Center The datasets generated during and/or analyzed during the current study are available (DF/HCC; composed of Dana-Farber Cancer Institute [DFCI], Massachusetts from the corresponding author on reasonable request. General Hospital, and Beth Israel Deaconess Medical Center) and affiliated community satellite practices. All patients were assigned to receive Received: 13 August 2021; Accepted: 14 March 2022; preoperative paclitaxel (T; 80 mg/m weekly for 12 weeks), trastuzumab (H; loading dose 8 mg/kg, subsequent doses 6 mg/kg, every 3 weeks for 4 cycles), and pertuzumab (P; loading dose 840 mg, subsequent doses 420 mg, every 3 weeks for 4 cycles) prior to breast surgery. Up to two additional cycles of HP were allowed in cases of surgical delay. Patients with obvious residual disease at completion of THP were allowed to REFERENCES receive additional neoadjuvant therapy at investigator discretion; 4 cycles 1. von Minckwitz, G. et al. Adjuvant pertuzumab and trastuzumab in early HER2- of AC was the recommended regimen. Pathologic response to neoadju- positive breast cancer. N. Engl. J. Med. 377, 122–131 (2017). vant therapy was quantified at surgery according to RCB score; pCR was 2. Gradishar, W. 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Long-term prognostic risk after neoadjuvant chemotherapy Statistical methods associated with residual cancer burden and breast cancer subtype. J. Clin. Oncol. The primary objective was to assess adherence to protocol-specified 35, 1049–1060 (2017). antibody doublet therapy (HP only) in the adjuvant setting among patients 15. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Increasing the dose with pCR following neoadjuvant THP. The primary endpoint was receipt of intensity of chemotherapy by more frequent administration or sequential adjuvant cytotoxic chemotherapy, assessed 3 months post-operatively. npj Breast Cancer (2022) 63 Published in partnership with the Breast Cancer Research Foundation A.G. Waks et al. scheduling: a patient-level meta-analysis of 37 298 women with early breast Genetics; has served as an advisor/consultant to AstraZeneca, Lilly, Merck, Nektar, cancer in 26 randomised trials. Lancet 393, 1440–1452 (2019). Novartis, Pfizer, Genentech/Roche, Immunomedics, Bristol-Myers Squibb, Eisai, 16. Wolff, A. C. et al. Human epidermal growth factor receptor 2 testing in breast Nanostring, Puma, Sanofi, Celldex, Paxman, Silverback Therapeutics, G1 Therapeutics, cancer: American Society of Clinical Oncology/College of American Pathologists Gilead, AbbVie, Anthenex, OncoPep, Outcomes4Me, Kyowa Kirin Pharmaceuticals, Clinical Practice Guideline Focused Update. J. Clin. Oncol. 36, 2105–2122 (2018). Daiichi-Sankyo, Ellipsis, and Samsung Bioepsis Inc. T.A.K.: speakers honoraria Exact 17. Symmans, W. F. et al. Measurement of residual breast cancer burden to predict Sciences (formerly Genomic Health); faculty, PrecisCa cancer information services and survival after neoadjuvant chemotherapy. J. Clin. Oncol. 25, 4414–4422 (2007). compensated service for a Global Advisory Board of Besins Healthcare. E.A.M.: 18. von Minckwitz, G. et al. Trastuzumab emtansine for residual invasive HER2- institutional research from Genentech/Roche via a SU2C grant; research funding from positive breast cancer. N. Engl. J. Med. 380, 617–628 (2019). Exact Sciences and Glaxo SmithKline; has served as an advisor/consultant to AstraZeneca, Bristol-Myers Squibb, Exact Sciences, Genentech/Roche, Lilly, Merck and Sellas. E.P.W.: institutional research funding from Genentech/Roche; consultant for ACKNOWLEDGEMENTS Athenex, Carrick Therapeutics, G1 Therapeutics, Genentech/Roche, Genomic Health, Gilead, GSK, Jounce, Lilly, Novartis, Seattle Genetics, Syros, and Zymeworks; scientific These data were presented in part at the San Antonio Breast Cancer Symposium advisory board member at Leap Therapeutics; and serves as President-Elect of the (December 2020). Abstract # PD3-05. Primary funding was provided by the Breast American Society of Clinical Oncology (ASCO). All remaining authors have declared Cancer Research Foundation (to E.P.W.). Additional funding was provided by the no conflicts of interest. Breast Cancer Research Foundation, the American Society of Clinical Oncology Conquer Cancer Foundation, and the Terri Brodeur Breast Cancer Foundation (to A.G. W.); Susan G. Komen (to E.A.M.). ADDITIONAL INFORMATION Supplementary information The online version contains supplementary material AUTHOR CONTRIBUTIONS available at https://doi.org/10.1038/s41523-022-00429-7. A.G.W.: co-first author. Concept development; trial oversight; manuscript writing and editing. N.V.D.: co-first author. Concept development; trial oversight; manuscript Correspondence and requests for materials should be addressed to Eric P. Winer. writing and editing. T.L.: concept development, statistical analyses, manuscript writing and editing. P.D.P.: patient accrual, manuscript writing and editing. A.H.P.: Reprints and permission information is available at http://www.nature.com/ patient accrual, manuscript writing and editing. N.S.: patient accrual, trial oversight, reprints manuscript writing and editing. L.M.S.: patient accrual, trial oversight, manuscript writing and editing. M.F.: patient accrual, trial oversight, manuscript writing and Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims editing. M.C.:trial oversight, manuscript writing and editing. O.M.: patient accrual, in published maps and institutional affiliations. manuscript writing and editing. J.A.: data management, manuscript writing and editing. J.D.: data management, manuscript writing and editing. SMR: concept development, manuscript writing and editing. E.F.: manuscript writing and editing. S. M.T.: concept development, manuscript writing and editing. I.E.K.: manuscript writing Open Access This article is licensed under a Creative Commons and editing. N.M.T. manuscript writing and editing. N.T.: Statistical analyses, Attribution 4.0 International License, which permits use, sharing, manuscript writing and editing. T.A.K.: manuscript writing and editing. E.A.M.: adaptation, distribution and reproduction in any medium or format, as long as you give manuscript writing and editing. E.P.W.: concept development, trial oversight, appropriate credit to the original author(s) and the source, provide a link to the Creative manuscript writing and editing. Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the COMPETING INTERESTS article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly A.G.W.: institutional research support from Genentech, MacroGenics, and Merck. A.H. from the copyright holder. To view a copy of this license, visit http://creativecommons. P.: travel support from Novartis. LMS declares consulting fees from Novartis. O.M.: org/licenses/by/4.0/. receives institutional research funding from Abbvie, Genentech/Pfizer, and Roche; honoraria from Roche. S.M.T.: receives institutional research funding from AstraZe- neca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Exelixis, © The Author(s) 2022 Bristol-Myers Squibb, Eisai, Nanostring, Sanofi, Cyclacel, Odonate, and Seattle Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 63

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