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Original Study|Articles in Press

A Real-World Data Retrospective Cohort Study of HER2-positive, Early-Stage Breast Cancer in Patients 70 Years of Age or Older: Natural History, Treatment Patterns, and Outcomes

Open AccessPublished:February 03, 2023DOI:https://doi.org/10.1016/j.clbc.2023.01.013

      Abstract

      Purpose

      Early-stage human epidermal growth factor receptor 2-positive (HER2-positive) breast cancers (BCs) are routinely treated with intense perioperative chemotherapy combined with HER2-targeted agents. There is thus an unmet need for knowledge about treatment patterns and outcomes among patients 70 years of age or older, as this is an under-represented subset of patients in large clinical trials.

      Methods

      We used a deidentified cohort derived from a nationwide electronic health record database to conduct a retrospective cohort study of patients with HER2-positive BCs. Descriptive statistics were used to evaluate tumor characteristics, treatment patterns across age groups, and pathologic complete response rates. We used Kaplan–Meier survival curves to estimate recurrence-free and overall survivals; Cox proportional methods were used for adjustments with covariates of interest, including age as a categorical variable.

      Results

      We included 395 patients with HER2-positive stage I to III BCs who were 70 years of age or older. Most patients had tumors with high nuclear-grade T2 tumors, and received surgical treatment first. Most patients (61.7%) who received HER2 therapies underwent treatment in the adjuvant setting; paclitaxel and trastuzumab combination was the most commonly used adjuvant regimen. Older age was associated with increased hazard of recurrence or death. We did not detect significant evidence of decline in performance status, but there was modest weight drop after perioperative HER2 treatments.

      Conclusion

      Findings suggest that patients in this older-age cohort were treated with de-escalated perioperative strategies and had poorer outcomes; our findings should be validated in future studies.

      Keywords

      Introduction

      Over 170,000 women are diagnosed annually with breast cancer (BC) in the United States.
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      BCs driven by the human epidermal growth factor receptor 2 (HER2) gene encompass as many as 25% of the cases.
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      HER2-positive BCs (historically associated with poor clinical outcomes) are effectively treated with a growing number of options of HER2-targeted agents.
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      Treatment of patients with early-stage HER2-positive BC has been significantly improved with targeted monoclonal antibodies (eg, trastuzumab and pertuzumab). Since the mid-2000s, HER2-targeted therapy has shown to improve disease-free survival in numerous trials when started in the adjuvant setting.
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      As an example, the Aphinity trial, in which 2404 patients with HER2-positive BC were treated with standard chemotherapy (ie, anthracycline and taxane combinations), combined with 52 weeks of trastuzumab and pertuzumab, and showed a 6.8% invasive-disease recurrence rate within 3 years from study entry.
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      These agents, however, are more commonly initiated preoperatively in combination with polychemotherapy regimens, leading to improved rates of pathologic complete responses (pCR).
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      A common feature of currently used perioperative regimens is, however, the use of intense chemotherapy in combination with single or dual HER2 blockade for an extended time (ie, 12 months). As corollary, current standard perioperative systemic therapies present a significantly higher burden to older patients, who are inherently prone to develop adverse events (AEs) as a function of fragility and associated comorbidities. To illustrate, a Surveillance Epidemiology and End Results database study showed the 10-year incidence of cardiac failure in women aged 66 to 70 years was as high as 38% in patients receiving anthracyclines.
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      Other AEs are also commonly observed (eg, neuropathy, neutropenia, febrile neutropenia) among older patients being treated with nonanthracycline-containing regimens.
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      Hence, optimized strategies are already being developed to treat subsets of patients with HER2-positive BC in hopes for better balance between antitumor efficacy and tolerability.
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      In the real world, medical oncologists and older patients struggle to balance the need for treatment of this aggressive subset of BC against the risk of clinically relevant AEs and overall health decline in a clearly more vulnerable patient population. Moreover, recommendations have not been made based on a high level of evidence as older patients are underrepresented in the major drug-approving phase 3 trials.
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      To fill this knowledge gap, we conducted a large real-world retrospective study of patients with early-stage HER2-positive BC to improve the current understanding of the prevalence and natural history of these tumors in patients 70 years or older while describing real-world treatment patterns and clinical outcomes.

      Methods

      Data Source

      This retrospective cohort study used a database derived from the nationwide Flatiron Health electronic health record. This is a real-world longitudinal database that comprises deidentified, patient-level structured and unstructured data, which were curated via technology-enabled abstraction.

      Ma X, Long L, Moon S, Adamson BJS, Baxi SS Comparison of population characteristics in real-world clinical oncology databases in the US: Flatiron Health, SEER, and NPCR. medRxiv. 2020, doi:10.1101/2020.03.16.20037143.

      ,

      Benjamin Birnbaum NN, Seidl-Rathkopf K, Agrawal M, et al. Model-assisted cohort selection with bias analysis for generating large-scale cohorts from the EHR for oncology research. arXiv:2001.09765 Available at: https://arxiv.org/abs/2001.09765. 2020. Accessed: January 5, 2021.

      The database originated from approximately 280 cancer clinics (approx 800 sites of care) in the United States. The majority of patients were from community oncology settings, and relative community/academic proportions may vary depending on the study cohort.
      Our cohort included patients with early-stage BC diagnosed between January 1, 2011 and October 22, 2021. Institutional Review Board approval of the study was obtained before the study was conducted and included a waiver for informed consent. The data were deidentified and subjected to obligations to prevent re-identification and protect patient confidentiality. The dataset included patient-related and tumor-related variables, including epidemiological, clinical stage, and pathologic data as well as age at diagnosis, race, ethnicity, menopausal status, tumor size, grade, number of lymph nodes involved, chemotherapy, HER2-targeted therapy, endocrine-therapy (ET) histories, ECOG performance status (PS), and weight in kilograms before and after completing chemotherapy. Hormone receptors (HRs) and HER2 expressions were assessed locally in accordance with standard immunohistochemistry nuclei staining by a local pathologist. Expressions of HRs and HER2 were measured as the percentages of nuclei staining and membrane staining, respectively. HER2 amplification was assessed according to locally assessed fluorescent in situ hybridization.
      Recurrence-free survival (RFS) was defined as the time in months from the date of curative surgical treatment to the date of diagnosis of metastasis, first local recurrence, or death, whichever occurred first; patients without these data were censored at the last date known alive. Recurrence-free interval (RFI) was defined as time in months from date of curative surgical treatment to the date of documented breast cancer recurrence. Overall survival was defined as the time from the date of curative surgical treatment to the date of death; patients without these data were censored at the last date known alive. Sensitivity analysis was conducted omitting cases diagnosed prior to 2020 as suboptimal treatment could be associated with COVID-19. pCR was defined as the absence of invasive cancer in breast and/or lymph nodes at the time of surgical treatment with curative intent. All efficacy analyses were performed on patients who received at least one cycle of perioperative systemic therapy with chemotherapy or HER2-targeted agents.

      Real-World Cohort Key Inclusion and Exclusion Criteria

      The inclusion criteria used to select cases from the Flatiron Health electronic health record BC cohort included having a diagnosis of histologically proven stage I to III BC and receiving surgical treatment for BCs with curative intent. The exclusion criteria were having carcinoma in situ, metastatic BC, and having HER2-negative BC. Patients who received chemotherapy before or after surgical treatment were classified as having received perioperative chemotherapy. Information on perioperative chemotherapy, HER2-targeted therapy, ET, and radiation therapy was abstracted. Chemotherapy regimens were classified as (i) paclitaxel alone; (ii) carboplatin combined with docetaxel; (iii) adriamycin, cyclophosphamide followed or preceded by paclitaxel; (iv) docetaxel and carboplatin; and (vi) other. HER2-targeted therapies included trastuzumab, pertuzumab, T-DM1, lapatinib, and neratinib. Anastrozole, exemestane, letrozole, fulvestrant, goserelin, leuprolide, and tamoxifen were classified as ET. Patients were followed from the date of resection (index date) until the date of biopsy-proven tumor recurrence, death, or last follow-up. Patients with more than 90 days between diagnosis and first Flatiron Health—reported structured activity were excluded to avoid missing treatment data.

      Statistical Methods

      Patient characteristics were summarized using descriptive statistics, including median and quantile 25th and 75th percentiles for continuous measures; proportions and frequencies were used for categorical measures. P values for continuous variables were assessed using Kruskal–Wallis tests, and categorical variables were evaluated using chi-squared tests or Fisher's exact tests when the expected frequencies were fewer than 5 in some cells. Time-to-event variables for RFS (our primary endpoint of interest), RFI and overall survival, were compared using the log-rank test. The univariate Cox proportional-hazards model was applied to evaluate the association of overall survival, RFS or RFI with age as a continuous variable or age group measured in years (<70, 70-75, 76-80, and >80). Hazard ratios with 95% CI, and P values based on log-rank test are presented. In addition, we randomly split our cohort into training set (2/3) and validation set (1/3) to assess the validity of our findings in the entire cohort. The multivariate Cox proportional-hazards model was conducted to evaluate the associations between RFS with age as a continuous variable or age group as a categorical variable adjusted for covariates of interest by Cox backward selection. Kaplan–Meier survival curves were built and stratified for variables of interest; overall P value was derived from log-rank test to compliment the Kaplan–Meier survival curves. All statistical analyses were performed using the R 4.2.0 software (https://www.R-project.org).

      Results

      Overall Population of Patients Aged 70 and Older With HER2-positive BC

      The cohort included a total of 11,775 patients with stage I to III BC from the Flatiron Health dataset downloaded on December 20, 2021. There were 3487 patients who were 70 years of age or older with a median follow-up of 38.4 months; 20 of which were excluded as they were labeled premenopausal; perimenopausal were excluded due to error input. In our cohort of patients 70 and older, 395 (22.3%) patients had HER2-positive BC, which as expected was more frequent than triple-negative BCs; and frequencies were numerically lower among patients over 80 years old (Table 1). The majority of patients 70 years and older with HER2-positive BC were white and had intermediate- to high-grade tumors. Most patients underwent surgical treatment first (n = 369) despite that less than 50% of the patients presented with tumors smaller than 2 cm in the largest diameter at time of diagnosis. Tumor- and patient-associated characteristics did not differ when comparisons were made between younger patients and groups of patients 70 and older (Table 1). HER2-targeted therapy was administered perioperatively to 222 (56.2%) patients, and 137 (61.7%) of these patients received HER2 therapy in the adjuvant setting. When given, these agents were more commonly administered in combination with chemotherapy as a total of 68 (17.2%) patients received treatment with paclitaxel combined with trastuzumab and 31 (7.8%) patients were treated with a combination of trastuzumab combined with carboplatin and docetaxel. Trastuzumab was administered as monotherapy to 45 (11.4%) patients, and the combination of trastuzumab and pertuzumab was administered without chemotherapy to 15 (3.8%). Most of the patients 70 years or older with HER2-positive BC also had tumors harboring HR expression, and 78% of these patients were treated with ET.
      Table 1Characteristics of Patients With HER2-positive Stage I to III Breast Cancer by Age Group
      (ALL) n = 1768<7070-7576-80>80P-Value Overall
      n = 1373 (77.7%)n = 199 (11.3%)n = 156 (8.8%)n = 40 (2.3%)
      Median follow-up (mo)45.6 (0.0; 129.7)48.3 (0.1; 129.7)41.6 (0.0; 128.4)40.0 (0.2; 104.0)16.3 (0.3; 55.0)<.001
      HR status.626
      HR-negative/HER2-positive422 (23.9%)336 (24.5%)39 (19.6%)38 (24.4%)9 (22.5%)
      HR-positive/HER2-poitive1342 (75.9%)1033 (75.2%)160 (80.4%)118 (75.6%)31 (77.5%)
      Race.228
      White1113 (63.0%)841 (61.3%)146 (73.4%)99 (63.5%)27 (67.5%)
      Asian57 (3.2%)48 (3.5%)2 (1.0%)5 (3.2%)2 (5.0%)
      Black/African American193 (10.9%)162 (11.8%)12 (6.0%)15 (9.6%)4 (10.0%)
      Hispanic/Latino4 (0.2%)4 (0.3%)0 (0.0%)0 (0.0%)0 (0.0%)
      Other race242 (13.7%)195 (14.2%)23 (11.6%)22 (14.1%)2 (5.0%)
      Unknown159 (9.0%)123 (9.0%)16 (8.0%)15 (9.6%)5 (12.5%)
      Tumor histology.067
      Ductal1626 (92.0%)1279 (93.2%)177 (88.9%)135 (86.5%)35 (87.5%)
      Lobular68 (3.8%)43 (3.1%)13 (6.5%)10 (6.4%)2 (5.0%)
      Mixed31 (1.8%)20 (1.5%)5 (2.5%)4 (2.6%)2 (5.0%)
      Others34 (1.9%)26 (1.9%)3 (1.5%)4 (2.6%)1 (2.5%)
      Unknown9 (0.5%)5 (0.4%)1 (0.5%)3 (1.9%)0 (0.0%)
      Tumor grade.086
      Grade 192 (5.2%)72 (5.2%)9 (4.5%)10 (6.4%)1 (2.5%)
      Grade 2691 (39.1%)514 (37.4%)92 (46.2%)72 (46.2%)13 (32.5%)
      Grade 3953 (53.9%)763 (55.6%)95 (47.7%)69 (44.2%)26 (65.0%)
      Unknown32 (1.8%)24 (1.7%)3 (1.5%)5 (3.2%)0 (0.0%)
      Ki-67.021
      1 ≥20%703 (39.8%)565 (41.2%)68 (34.2%)53 (34.0%)17 (42.5%)
      2 <20%138 (7.8%)96 (7.0%)20 (10.1%)21 (13.5%)1 (2.5%)
      3 unknown927 (52.4%)712 (51.9%)111 (55.8%)82 (52.6%)22 (55.0%)
      T stage.094
      T01 (0.1%)1 (0.1%)0 (0.0%)0 (0.0%)0 (0.0%)
      T1297 (16.8%)219 (16.0%)44 (22.1%)27 (17.3%)7 (17.5%)
      T2411 (23.2%)341 (24.8%)35 (17.6%)26 (16.7%)9 (22.5%)
      T3-4157 (8.9%)128 (9.3%)15 (7.5%)8 (5.1%)6 (15.0%)
      Unknown902 (51.0%)684 (49.8%)105 (52.8%)95 (60.9%)18 (45.0%)
      n stage.319
      N0515 (29.1%)407 (29.6%)56 (28.1%)37 (23.7%)15 (37.5%)
      N1251 (14.2%)204 (14.9%)28 (14.1%)14 (9.0%)5 (12.5%)
      N2-366 (3.7%)50 (3.6%)7 (3.5%)7 (4.5%)2 (5.0%)
      Unknown936 (52.9%)712 (51.9%)108 (54.3%)98 (62.8%)18 (45.0%)
      Perioperative chemo<.001
      Adjuvant918 (51.9%)694 (50.5%)123 (61.8%)82 (52.6%)19 (47.5%)
      Neoadjuvant536 (30.3%)449 (32.7%)47 (23.6%)32 (20.5%)8 (20.0%)
      Unknown314 (17.8%)230 (16.8%)29 (14.6%)42 (26.9%)13 (32.5%)
      Regimen DCPH<.001
      No1267 (71.7%)957 (69.7%)158 (79.4%)119 (76.3%)33 (82.5%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Yes296 (16.7%)265 (19.3%)19 (9.5%)12 (7.7%)0 (0.0%)
      Regimen TH.004
      No1346 (76.1%)1073 (78.2%)137 (68.8%)107 (68.6%)29 (72.5%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Yes217 (12.3%)149 (10.9%)40 (20.1%)24 (15.4%)4 (10.0%)
      Regimen DCH<.001
      No1339 (75.7%)1035 (75.4%)145 (72.9%)126 (80.8%)33 (82.5%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Yes224 (12.7%)187 (13.6%)32 (16.1%)5 (3.2%)0 (0.0%)
      Regimen ACTH.371
      No1562 (88.3%)1221 (88.9%)177 (88.9%)131 (84.0%)33 (82.5%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Yes1 (0.1%)1 (0.1%)0 (0.0%)0 (0.0%)0 (0.0%)
      Regimen ACTPH.361
      No1562 (88.3%)1221 (88.9%)177 (88.9%)131 (84.0%)33 (82.5%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Yes1 (0.1%)1 (0.1%)0 (0.0%)0 (0.0%)0 (0.0%)
      Regimen T-DM1.172
      No1563 (88.4%)1222 (89.0%)177 (88.9%)131 (84.0%)33 (82.5%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Regimen neratinib.344
      No1550 (87.7%)1211 (88.2%)175 (87.9%)131 (84.0%)33 (82.5%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Yes13 (0.7%)11 (0.8%)2 (1.0%)0 (0.0%)0 (0.0%)
      Regimen H only.008
      No1269 (71.8%)973 (70.9%)147 (73.9%)120 (76.9%)29 (72.5%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Yes294 (16.6%)249 (18.1%)30 (15.1%)11 (7.1%)4 (10.0%)
      Regimen P only.373
      No1562 (88.3%)1221 (88.9%)177 (88.9%)131 (84.0%)33 (82.5%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Yes1 (0.1%)1 (0.1%)0 (0.0%)0 (0.0%)0 (0.0%)
      Regimen PH.364
      No1488 (84.2%)1162 (84.6%)171 (85.9%)123 (78.8%)32 (80.0%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Yes75 (4.2%)60 (4.4%)6 (3.0%)8 (5.1%)1 (2.5%)
      Regimen clinical trial.435
      No1538 (87.0%)1201 (87.5%)175 (87.9%)129 (82.7%)33 (82.5%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Yes25 (1.4%)21 (1.5%)2 (1.0%)2 (1.3%)0 (0.0%)
      ET.393
      No473 (26.8%)375 (27.3%)55 (27.6%)34 (21.8%)9 (22.5%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Yes1090 (61.7%)847 (61.7%)122 (61.3%)97 (62.2%)24 (60.0%)
      HER2 therapy<.001
      No431 (24.4%)312 (22.7%)44 (22.1%)60 (38.5%)15 (37.5%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Yes1132 (64.0%)910 (66.3%)133 (66.8%)71 (45.5%)18 (45.0%)
      Chemo<.001
      No450 (25.5%)316 (23.0%)43 (21.6%)72 (46.2%)19 (47.5%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Yes1113 (63.0%)906 (66.0%)134 (67.3%)59 (37.8%)14 (35.0%)
      Adjuvant ET.005
      No856 (48.4%)696 (50.7%)81 (40.7%)59 (37.8%)20 (50.0%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Yes707 (40.0%)526 (38.3%)96 (48.2%)72 (46.2%)13 (32.5%)
      Adjuvant HER2.002
      No973 (55.0%)769 (56.0%)87 (43.7%)94 (60.3%)23 (57.5%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Yes590 (33.4%)453 (33.0%)90 (45.2%)37 (23.7%)10 (25.0%)
      Adjuvant chemo<.001
      No984 (55.7%)769 (56.0%)88 (44.2%)102 (65.4%)25 (62.5%)
      Unknown205 (11.6%)151 (11.0%)22 (11.1%)25 (16.0%)7 (17.5%)
      Yes579 (32.7%)453 (33.0%)89 (44.7%)29 (18.6%)8 (20.0%)
      Breast surgery first.006
      No/unknown89 (5.0%)63 (4.6%)7 (3.5%)13 (8.3%)6 (15.0%)
      Yes1679 (95.0%)1310 (95.4%)192 (96.5%)143 (91.7%)34 (85.0%)
      Type of breast surgery<.001
      Mastectomy835 (47.2%)682 (49.7%)63 (31.7%)71 (45.5%)19 (47.5%)
      Other844 (47.7%)628 (45.7%)129 (64.8%)72 (46.2%)15 (37.5%)
      Unknown89 (5.0%)63 (4.6%)7 (3.5%)13 (8.3%)6 (15.0%)
      Radiotherapy<.001
      No/unknown756 (42.8%)563 (41.0%)66 (33.2%)95 (60.9%)32 (80.0%)
      Yes1012 (57.2%)810 (59.0%)133 (66.8%)61 (39.1%)8 (20.0%)
      Abbreviations: Chemo = chemotherapy; ET = endocrine therapy; HER2 = human epidermal growth factor receptor; HR = hormone receptors; Regimen H only = regimen trastuzumab (herceptin); Regimen P = regimen pertuzumab; Regimen PH = regimen pertuzumab and trastuzumab (pertuzumab herceptin); TNBC = triple-negative breast cancer.

      Clinical Outcomes

      In our cohort, there were a total of 217 recurrences among women 70 years and older; as expected, distant recurrences were more common that local ones (60.4% vs 39.6%, respectively). Older women with HER2-positive BC across specified age groups, regardless of HR expression, had significantly poorer RFS, RFI, and overall survival in unadjusted analyses; (P < .0001) (Figure 1, Figure 2, Supplementary figure 1 for RFI). Our validity assessments showed similar results after splitting the data into training and validation sets (Supplementary Figure 2). The multivariate Cox proportional-hazards model showed significant associations between both older age as continuous or categorical variables and RFS after adjustments for variables of interest (Table 2). We did not proceed with further adjusted OS analyses due to obvious confounding associated with age-related causes of death and subsequent lines of therapy. We further explored associations between specific perioperative HER2 therapies of interest (ie, trastuzumab and pertuzumab) and clinical outcomes among the 122 patients who received HER2-targeted therapy; surprisingly, HER2-targeted therapies were not associated with improved outcomes in each of the age groups of interest regardless of the type of HER2 therapy given (see Table 3 for RFS outcomes). Univariate analyses of associations between both RFS and RFI and age including only cases diagnosed prior to 2020 showed similar results (Log-rank test for RFS and RFI were P < .0001 and P = .002, respectively). Finally, adjusted analysis for associations between RFS, age as a categorical variable and type of perioperative therapy (adjuvant vs neoadjuvant) was performed. Patients who received neoadjuvant therapy had higher hazards for RFS (HR 2.01, 95% CI, 1.20-3.0; P = .0098).
      Figure 1
      Figure 1Clinical outcomes. (A) RFS. (B) OS. Patients with HER2-positive breast cancer. AEs = adverse events; BCs = breast cancers; ETs = endocrine therapies; HER2 = human epidermal growth factor receptor 2; HER2-positive = human epidermal growth factor receptor 2-positive; HRs = hormone receptors; OS = overall survival; pCR = pathological complete response; PS = performance status; RFS, recurrence-free survival; RFS = recurrence-free survival
      Figure 2
      Figure 2Clinical outcomes. (A) RFS in HRHER2-positive. (B) RFS HR+HER2-positive. (C) OS HRHER2-positive. (D) HR+HER2-positive. Patients with HRHER2-positive and HR+HER2-positive breast cancers. HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; OS = overall survival; RFS = recurrence-free survival
      Table 2Multivariate Analyses of Recurrence-Free Survival of HER2-positive BC Aged 70 and Older
      Age-Continuous Variable
      VariableLevelHR (95% CI)P-Value
      Tumor gradeGrade 11 (reference)-
      Tumor gradeGrade 21.11 (0.60, 2.04).738
      Tumor gradeGrade 31.66 (0.92, 2.99).095
      Tumor gradeUnknown/undocumented0.73 (0.20, 2.63).632
      T stageT11 (reference)-
      T stageT21.38 (0.89, 2.16).150
      T stageT3-41.99 (1.17, 3.39).011
      T stageUnknown0.72 (0.37, 1.39).323
      n stageN01 (reference)-
      n stageN11.08 (0.70, 1.68).720
      n stageN2-32.25 (1.32, 3.82).003
      n stageUnknown1.83 (0.95, 3.51).072
      Adjuvant_ETNo1 (reference)-
      Adjuvant_ETYes0.54 (0.41, 0.72)<.001
      Adjuvant_ETUnknown0.69 (0.43, 1.09).112
      Surgery_mastMastectomy1 (reference)-
      Surgery_mastOther0.74 (0.53, 1.02).066
      Radiation therapyNo/unknown1 (reference)-
      Radiation therapyYes0.58 (0.42, 0.80)<.001
      Duration of trastuzumab≤6 mo1 (reference)-
      Duration of trastuzumab>6 mo0.66 (0.44, 0.99).044
      Duration of trastuzumabUnknown0.78 (0.50, 1.21).266
      Age at diagnosis date-1.04 (1.02, 1.05)<.001
      Age categorical variable
      VariableLevelHR (95% CI)P (Wald)
      Tumor gradeGrade 11 (reference)-
      Tumor gradeGrade 21.09 (0.59, 1.99).789
      Tumor gradeGrade 31.60 (0.89, 2.89).118
      Tumor gradeUnknown/undocumented0.77 (0.22, 2.78).694
      Age group<701 (reference)-
      Age group70-751.65 (1.15, 2.36).006
      Age group76-803.41 (2.47, 4.71)<.001
      Age groupOlder than 803.74 (1.88, 7.44)<.001
      T stageT11 (reference)-
      T stageT21.33 (0.86, 2.08).202
      T stageT3-42.01 (1.18, 3.41).010
      T stageUnknown0.69 (0.36, 1.34).275
      n stageN01 (reference)-
      n stageN11.05 (0.68, 1.63).820
      n stageN2-32.12 (1.24, 3.63).006
      n stageUnknown1.93 (1.01, 3.69).047
      Adjuvant ETNo1 (reference)-
      Adjuvant ETYes0.54 (0.41, 0.73)<.001
      Adjuvant ETUnknown0.66 (0.41, 1.05).077
      Surgical treatment mastMastectomy1 (reference)-
      Surgical treatment mastOther0.79 (0.58, 1.09).159
      Radiation therapyNo/unknown1 (reference)-
      Radiation therapyYes0.60 (0.44, 0.83).002
      Duration of trastuzumab≤6 mo1 (reference)-
      Duration of trastuzumab>6 mo0.67 (0.45, 1.02).059
      Duration of trastuzumabUnknown0.75 (0.48, 1.18).212
      Abbreviations: BC = breast cancer; ET = endocrine therapy; HER2 = human epidermal growth factor receptor 2; Mast = mastectomy.
      Table 3Multivariate Cox Proportional-Hazards Models for RFS for HER2-positive BC
      VariableLevelHR (95% CI)P-Value
      Age group<701 (reference)-
      Age group70-751.64 (0.96, 2.81).073
      Age group76-804.57 (2.92, 7.17)<.001
      Age groupOlder than 803.95 (1.43, 10.90).008
      Therapy groupno_HER2-therapy1 (reference)-
      Therapy groupTrastuzumab and pertuzumab1.69 (0.85, 3.33).134
      Therapy groupTrastuzumab1.44 (0.98, 2.12).064
      Abbreviations: BC = breast cancer; HER2-positive = human epidermal growth factor receptor 2-positive; HR = hazard ratio; RFS = recurrence-free survival.

      pCR Rates

      A total of 87 patients aged 70 years or older had HER2-targeted therapy started in the neoadjuvant setting, and 30 (34.5%) achieved pCR. pCR was numerically more frequent among patients with HR BCs: (i) 61% for patients 70 to 75; (ii) 36.4% for patients 76 to 80; and (iii) 50% for patients older than 80, which compares favorably to patients with HR+ tumors: (i) 24%, (ii) 29%, and (iii) 17%; respectively. Overall, patients with HR tumors had numerically higher pCR rates compared to patients with HR+ tumors: 51.6% vs 25%, respectively.

      Tolerability to Treatment

      A total of 81 patients aged 70 years or older had available information on their ECOG PS before and after completing perioperative chemotherapy combined with HER2-targeted therapy. Of those patients, only 29 (28%) had documented decline in their ECOG PS, which compares favorably with younger patients (72%). Furthermore, there was statistically significant weight change among the 3 distinct age categories between start and completion of polychemotherapy regimens (P = .025); and the older patients lost more weight after treatment compared with the younger patients (Figure 3).
      Figure 3
      Figure 3Percentage of weight change in patients 70 years of age or older before and after completing perioperative chemotherapy combined with HER2 therapy. HER2 = human epidermal growth factor receptor 2

      Discussion

      We conducted a large, retrospective, real-world data cohort study of 3487 patients who were 70 years of age or older; of those, 395 (22.3%) patients had stage I to III HER2-positive BCs at the time of diagnosis. Tumor pathologic characteristics, including size, grade, nodal involvement, and histologic type, were similar across age groups, including patients both younger and older than 70 (Table 1); moreover, these features indicated a more aggressive disease course, such as high nuclear grade. These results suggest that, when compared to other subsets of BCs, HER2-positive tumors are associated with worse pathologic features even among patients 70 and older. Conversely, we observed that community-treatment patterns in our cohort suggest that older patients are more commonly treated with surgical approach first followed by adjuvant HER2-targeted and chemotherapy treatments. This contrasts with the current treatment paradigm in which younger patients with HER2-positive BC are commonly treated with neoadjuvant polychemotherapy and HER2-targeted agents. The latter approach allows for increased pCR and for tailoring of subsequent adjuvant treatment recommendations which may impact clinical outcomes.
      • von Minckwitz G
      • Huang CS
      • Mano MS
      • et al.
      Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
      ,
      • Gianni L
      • Pienkowski T
      • Im YH
      • et al.
      Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.
      We hypothesize that this is likely a function of concerns regarding poor tolerance of intense neoadjuvant therapies; protracted decline in quality of life among older patients; and presumed lack of benefit of more intense neoadjuvant treatments. Perioperative HER2-targeted therapies were offered to 56.2% of patients with HER2-positive BC 70 years of age and older and more frequently in the adjuvant setting. The combination of paclitaxel and trastuzumab was the most common adjuvant regimen offered to these patients, and the majority of patients received adjuvant ET.
      We observed that older age was associated with worse RFS, both when this variable was treated as a continuous or categorical variable and even after adjustments for covariates of interest were made. Similar results were observed for unadjusted analysis for RFI, which further support our observation of worse outcomes in the elderly as RFS could have been confounded by inherently higher rates of death in this population. Conversely, the multivariate Cox proportional-hazards model did not show statistically significant favorable treatment effect when HER2-targeted therapy was administered (see Tables 2 and 3, respectively) and patients who received neoadjuvant therapy higher worse oncomes compared to patients who received adjuvant treatment; these findings are in stark contrast with current treatment paradigm. These results are, nonetheless, based on a low number of patients who received perioperative HER2 therapies (n = 222). Poorer outcomes also conflict with observed community practices in which optimized approach by administration of fewer agents might contribute to an increased hazard of recurrence or death. However, our findings are similar to those observed among patients with metastatic HER2-positive BC, as Kaufman et al
      • Kaufman PA
      • Brufsky AM
      • Mayer M
      • et al.
      Treatment patterns and clinical outcomes in elderly patients with HER2-positive metastatic breast cancer from the registHER observational study.
      previously reported that older patients are less frequently treated with trastuzumab in first-line settings despite associated improvements in outcomes. We also explored possible pandemic-associated treatment changes of elderly patients which could have confounded our results; sensitivity analysis including cases diagnosed prior to 2020 still showed worse outcomes RFS among order patients. Finally, we observed that pCR was less frequent when compared with published data among older patients in general. In 81 patients, we observed a clinically modest reduction in weight measured before and after completing perioperative treatment with chemotherapy and HER2-targeted therapy among older patients; this was not associated with a drop in ECOG PS. Collectively, these findings suggest appropriate selection of patients for perioperative treatments is feasible in a subset of patients and it is driven a multitude of factors including variables not captured in this dataset (eg, comorbidities and physician's familiarity with treatment offered). Furthermore, developmental therapeutics will need to account for this growing subset of patients as agents with lower absolute risks of AEs remains an unmet need for older patients; efforts are ongoing (NCT03112590 and NCT05325632).
      Our study has several limitations, and those are largely inherent to real-world retrospective cohort studies and the low number of patients over 80 years (n = 40). In addition, data were missing which, for example, prevented us from conducting exploratory analyses of the association between ECOG PS and covariates of interest. Assessments of HER2 and HRs expressions were not centrally reviewed; it is uncertain that all sites that contributed data followed strict ASCO-CAP Guidelines for estrogen receptor, progesterone receptor, and HER2 testing.
      • Allison KH
      • Hammond MEH
      • Dowsett M
      • et al.
      Estrogen and progesterone receptor testing in breast cancer: ASCO/CAP guideline update.
      In addition, the Flatiron Health database lacks information on histologic features of BC recurrences such as in situ vs invasive recurrence. Nonetheless, this is a large retrospective study that uses real-world data, which increases the external validity of our hypothesis-generating findings.Despite prior efforts, large prospective clinical trials enrolling patients of older ages likely have low feasibility as a function of slow accrual rates, making retrospective data a valuable resource for important insights.
      • Sawaki M
      • Tokudome N
      • Mizuno T
      • et al.
      Evaluation of trastuzumab without chemotherapy as a post-operative adjuvant therapy in HER2-positive elderly breast cancer patients: randomized controlled trial [RESPECT (N-SAS BC07)].
      ,
      • Wildiers H
      • Tryfonidis K
      • Dal Lago L
      • et al.
      Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer (EORTC 75111-10114): an open-label, randomised, phase 2 trial from the Elderly Task Force/Breast Cancer Group.

      Conclusion

      Findings from this real-world study suggest that older patients with HER2-positive BC have poor outcomes and are treated with optimized perioperative strategies. Notwithstanding the clinical relevance of our findings, due to the retrospective nature of our study, they need to be validated in future studies.

      Clinical Practice Points

      • Most elderly patients with resectable HER2-postive BCs are treated with surgery first.
      • The majority of patients are treated with optimized therapy (ie, paclitaxel combined with trastuzumab).
      • Age beyond 70 is associated in increased risk of cancer recurrence and death.
      • In our cohort, perioperative treatment was associated with increased of weight loss but not decline in PS.

      Ethics Approval

      Institutional Review Board approval of the study protocol was obtained from Western Copernicus Group IRB before the study was conducted and included a waiver of informed consent.

      Consent for Publication

      This article does not contain any studies with human participants that would require informed consent.

      Data Availability

      The data that support the findings of this study have been originated by Flatiron Health, Inc. These deidentified data may be available upon request and are subject to a license agreement with Flatiron Health; interested researchers should contact [email protected] to determine licensing terms.

      Disclosure

      RLB Costa received honorarium from Bristol Meyers Squib, Pfizer, Athenex Oncology, Daiichi Sankyo, and Astra Zeneca. All other authors declare no conflicts of interest.

      Acknowledgments

      This work has been supported in part by the Biostatistics & Bioinformatics Shared Resource at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-Designated Cancer Center, and funded in part by the Moffitt Cancer Center Support Grant (P30-CA076292). Editorial assistance was provided by the Moffitt Cancer Center's Office of Scientific Publishing by Daley Drucker and Gerard Hebert; no compensation was given beyond their regular salaries. Office of Graduate Medical Education, University of South Florida.

      Appendix. Supplementary materials

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