Trastuzumab

Recurrence rates in patients with HER2+ breast cancer who achieved a pathological complete response after neoadjuvant pertuzumab plus trastuzumab followed by adjuvant trastuzumab: a real‑world evidence study

Joyce O’Shaughnessy , · Nicholas Robert · Srinivas Annavarapu3 · Jie Zhou3 · Jesse Sussell · Anna Cheng4 · Anita Fung4

Abstract

Purpose This study assessed real-world risk of invasive disease recurrence (IDR) and associated factors in patients with human epidermal growth factor receptor-2 positive (HER2+) early breast cancer (BC) with pathological complete responses (pCR) after neoadjuvant pertuzumab plus trastuzumab (nPT) plus chemotherapy, followed by adjuvant trastuzumab (aT). Methods Patients with HER2+ BC with pCR after nPT from 2013 to 2015 who received aT were identified in the US Oncology Network and followed until IDR or censoring. Kaplan–Meier and Cox regression methods were used to assess invasive disease-free survival (iDFS) and correlation between iDFS and patient characteristics.
Results A total of 217 pCR patients’ charts were reviewed; median age was 52 years. Most had stage IIA or IIB disease (62%), Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1 (84%), tumor size > 2 cm (75%), positive nodes (N+, 62%) and negative estrogen and progesterone receptor (ER− and PR−) expression (52%). Four-year iDFS rates were 90.0% overall (95% CI 84.6%, 93.6%), 86.2% for the N+ cohort and 96.0% for the N− cohort. Cox regression suggested that age, body mass index, ECOG PS, N+ status, stage T3 or T4, and ER+ or PR+ status were risk factors for IDR but were not statistically significant.
Conclusions Consistent with previous studies, this real-world study observed that patients with HER2+ BC showing pCR with nPT remain at risk for IDR, especially with node-positive disease at diagnosis. Alternatives to adjuvant trastuzumab alone, including combined trastuzumab and pertuzumab, should be considered to improve outcomes for initially N+ patients showing pCR with nPT.

Keywords Breast cancer · Trastuzumab · Pertuzumab · Disease recurrence

Introduction

Breast cancer is one of the most frequently diagnosed cancer types and the second leading cancer-related cause of death in women. It is estimated that in 2020, 276,480 women will have been diagnosed with breast cancer in the United States (US), and 42,170 will have died from the disease [1]. HER2+ breast cancer is a subtype that overexpresses the human epidermal growth factor receptor-2 (HER2) protein, which promotes the growth and survival of cancer cells. Approximately 15–20% of breast cancers are HER2-positive and overexpression of HER2 is associated with a poor prognosis [2, 3]. Pertuzumab is a humanized monoclonal antibody that binds to HER2 [4]. Preclinical studies have shown that it acts as an antitumor agent by binding to the HER2 receptor and blocking its pairing with other HER receptors, and it is an important targeted therapy for patients with HER2+ breast cancer [5–11]. Pertuzumab was granted accelerated approval by the FDA on 30 September 2013 for use in combination with trastuzumab and chemotherapy as neoadjuvant treatment of patients with HER2+, locally advanced, inflammatory, or early stage breast cancer (either > 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer [12]. The APHINITY trial demonstrated that patients receiving adjuvant pertuzumab plus trastuzumab (and chemotherapy) showed significant improvement in invasive-disease-free survival (iDFS) compared with adjuvant trastuzumab and chemotherapy alone, leading to the approval of pertuzumab-based therapy for 1 year of treatment (up to 18 cycles) in high-risk early breast cancer [13]. The neoadjuvant accelerated approval of pertuzumab was also converted to regular approval based on the APHINITY results [14].
Pathological complete response (pCR), defined as no invasive disease in breast or axillary lymph nodes at surgery following neoadjuvant therapy, is associated with improved breast cancer survival [15]. The current study examines long-term risk of recurrence and factors associated with risk of recurrence in patients who had a pCR after neoadjuvant treatment. Although pCR is associated with improved disease-free and overall survival, there are still patients who have recurrent disease despite having a pCR. Two recent studies demonstrated that lymph node involvement and T3/4 status at baseline are prognostic for worse outcomes in early breast cancer [16, 17]. Huober et al. performed a retrospective analysis of five breast cancer trials that included neoadjuvant therapy to identify risk factors indicative of recurrence in patients who developed a pCR. The findings demonstrated that despite patients having an overall favorable prognosis following a pCR, approximately 15% of patients had an iDFS event and 10% had a distant recurrence within 5 years of having the pCR. The investigators concluded that lobular histology, greater tumor size and initially involved lymph nodes consistently indicated higher risk for recurrence and death in patients who had a pCR [16]. Loibl et al. analyzed 11 clinical trials of patients with early breast cancer who received neoadjuvant treatment to determine prognostic factors associated with iDFS. They observed that earlier tumor stage (1–2 vs 3–4) and absence of nodal involvement were associated with improved iDFS regardless of whether patients had a pCR [17].
Trastuzumab plus pertuzumab-based therapies are administered as standard neoadjuvant regimens for HER2+ breast cancer. For patients who have a pCR with neoadjuvant trastuzumab, pertuzumab, and chemotherapy (nPT), practice patterns vary regarding administration of continued trastuzumab plus pertuzumab versus trastuzumab alone as adjuvant therapy, to complete 1 year of HER2-based antibody therapy. Real-world outcomes among patients receiving adjuvant trastuzumab after achieving pCR with nPT and who did not receive post-operative pertuzumab are therefore of interest. The primary objective of this study was to measure risk of invasive disease recurrence (IDR) in patients with HER2+, locally advanced, inflammatory, or high-risk early stage breast cancer who received nPT, had a pCR, and then received adjuvant trastuzumab (aT) alone (together with adjuvant endocrine therapy for patients with ER+ disease). Secondary objectives of the study include a descriptive analysis of the demographic and clinical profiles of patients, a description of treatment patterns including duration of neoadjuvant therapy and duration of adjuvant therapy, neoadjuvant pertuzumab or trastuzumab-related cardiac toxicities and diarrhea, and identification of patient characteristics associated with iDFS.

Materials and methods

Study design and data sources

This was a retrospective cohort study of US adult patients diagnosed with locally determined HER2+ locally advanced, inflammatory, or high-risk early stage breast cancer (defined as either tumor size > 2 cm in diameter or node positive) who received nPT, had a pCR (ypT0/Tis ypN0), and then received aT treatment, with endocrine therapy for patients with ER+ disease in The US Oncology Network. The US Oncology Network is affiliated with approximately 1400 physicians in more than 400 sites of care across 25 states in the US, representing approximately 12% of US patients newly diagnosed with cancer. Data were obtained via programmatic database abstraction from the iKnowMed (iKM) electronic health record (EHR) and supplemented with chart review. Vital status information was supplemented with data from the Social Security Administration’s Death Master File.
Eligible patients were ≥ 18 years of age at diagnosis with ≥ 2 US Oncology Network visits during the study period with HER2+, locally advanced, inflammatory, or high-risk early stage breast cancer who received nPT, achieved a pCR, and then received treatment with aT. pCR was defined as no evidence of residual invasive disease in the breast and no positive lymph nodes following surgery (ypT0 ypN0). HER2 status was captured as documented by physicians in The US Oncology Network iKM EHR database during the chart review process. Patients receiving post-operative pertuzumab were excluded. Patients were excluded if they were enrolled in clinical trials at any time during the study period, if they had another documented primary cancer diagnosis during the study period, or if they had residual invasive disease and/or positive lymph nodes after surgery. Patients were included who met the criteria during the period 01 June 2013 to 31 August 2015, with follow-up through 31 August 2019 or until date of last record to allow for a minimum of 4 years of potential follow-up for each patient.
This retrospective research study was conducted in accordance with legal and regulatory requirements, as well as with scientific purpose, value and rigor, and it followed generally accepted research practices. Approval for the study was obtained from the US Oncology Inc. Institutional Review Board.

Statistical analysis

The primary objective of this study was to evaluate iDFS rate in patients who received neoadjuvant pertuzumab plus trastuzumab, had a pCR, and then received adjuvant trastuzumab. A Kaplan–Meier analysis was used to estimate overall, node-positive, and node-negative iDFS rates. iDFS was defined as the time from breast cancer surgery until the date of the first occurrence of one of the following events: recurrence of ipsilateral invasive breast tumor, recurrence of ipsilateral locoregional invasive breast cancer, contralateral invasive breast cancer, a distant disease recurrence, or death from any cause.
Secondary objectives included the description of patient demographics, clinical profiles, treatment patterns including durations of neoadjuvant and adjuvant therapy, neoadjuvant pertuzumab or trastuzumab-related cardiac toxicities and diarrhea, and identification of patient characteristics associated with iDFS. Patients were censored (as applicable) at end of study period, last visit date, or death, irrespective of recurrence.

Results

Study population

A total of 604,229 patients with a documented diagnosis of breast cancer were identified in The US Oncology Network iKM database. During the study identification period, 1154 patients with breast cancer received qualifying neoadjuvant treatment with pertuzumab plus trastuzumab within the study identification period. After filtering for study inclusion/exclusion criteria, 309 patients were identified for chart review. Under chart review examination, another 91 patients were excluded after being identified as low risk based on tumor size and nodal status, leaving a total of 217 patients eligible for inclusion in the study. Of these patients, 135 were identified as having node-positive disease and 77 were identified as having node-negative disease.

Demographics

The majority of patients were White (77.4%) with a mean age of 52.6 years (SD = 12.2), and 99.5% were females. The majority (71.9%) of patients were classified as overweight or obese, with a mean body mass index (BMI) of 28.7 kg/ m2 (SD = 6.3). There were some differences in patient demographics between the node-positive and node-negative cohorts. The cohorts showed a significant difference in distribution of races (p = 0.0082). Among the differences, the node-positive cohort had a greater proportion of African American patients compared with the node-negative cohort at 11.9% versus 1.0%, respectively, and a lower proportion of White patients at 73.3% versus 84.4%, respectively. Additionally, the node-positive cohort had a larger mean BMI compared with the node-negative cohort at 29.6 kg/ m2 (SD = 6.8) versus 27.1 kg/m2 (SD = 5.1), respectively (p = 0.0072) (Table 1). Overall, 84.3% of patients presented with Eastern Cooperative Oncology Group (ECOG) scores of ≤ 1 at the index date and ECOG values were similar between the node-positive and node-negative cohorts (Table 2).

Clinical characteristics

Overall, patients were primarily classified as Stage IIA or IIB at diagnosis (62.2%). The predominant clinical tumor size overall was > 2 cm (74.7%). T2 represented the largest proportion of clinical tumor stage overall at 54.8%. There was a difference between the cohorts with respect to clinical tumor stage (p = 0.0006). Among the different stages, T2 classification was found among 44.4% in the node-positive cohort compared with 75.3% in the node-negative cohort. More than half of the overall patient study population had grade 3 tumors (59.0%). There was a difference in tumor grade distribution between the cohorts (p = 0.0086). For instance, the node-positive cohort exhibited a larger proportion of grade 3 cancers at 61.5% compared with 57.1% for the node-negative cohort (Table 2).
Overall, 52.1% of patients had ER− and PR− cancers, and the remainder of patients (47.9%) had ER+ or PR+. The proportion of patients with ER− and PR− disease in the node-positive cohort was 58.5%, compared with 39.0% in the node-negative cohort (p = 0.0061) (Table 2).

Treatment patterns: duration of neoadjuvant and adjuvant therapy

The average duration of neoadjuvant pertuzumab–trastuzumab therapy plus chemotherapy was 3.5 months (SD = 0.6), with a mean of 5.8 cycles (SD = 0.9) of therapy received (Table 3). Most patients (95%, n = 206) completed the planned neoadjuvant pertuzumab–trastuzumab treatment and 82% (n = 178) completed all planned neoadjuvant treatment, including chemotherapy. All patients except one received nonanthracycline chemotherapy regimens. Discontinuation due to toxicity of neoadjuvant pertuzumab–trastuzumab therapy occurred in 3.7% (n = 8) of the patients overall. The mean duration of adjuvant trastuzumab therapy overall was 7.2 months (SD = 3.66) with a mean of 10.2 cycles (SD = 2.60) of therapy administered. Most patients completed planned adjuvant treatment with trastuzumab (91.2%, n = 198). Discontinuation of trastuzumab adjuvant therapy due to toxicity occurred in 2.3% (n = 5) of the patients overall. Patients with ER+ or PR+ (hormone receptor positive [HR+]) tumors received adjuvant endocrine therapy per standard of care. Radiation therapy was given per standard of care guidelines postoperatively.
Overall, 172 (79.3%) experienced toxicities related to neoadjuvant pertuzumab or trastuzumab: 4 (1.8%) patients experienced decreased left ventricular ejection fraction (defined as a decrease of at least 10% from baseline to a value of < 50%) and 169 (77.9%) experienced diarrhea. Among patients experiencing diarrhea, most cases were mild: only 5.5% required hospitalization and only 4.2% required emergency department care (Table 3). Clinical outcomes: invasive disease‑free survival The average duration of patient follow-up from start of neoadjuvant treatment was 49.8 months (SD = 13.3) while the average follow-up from the date of surgery was 45.1 months (SD = 13.6) (Table 3). Overall, 21 patients experienced an invasive disease event that occurred during the study observation period between 01 June 2013 and 31 August 2019. In the node-positive cohort (n = 135), 16 (11.9%) patients had an iDFS event while in the node-negative cohort (n = 77), 5 (6.5%) patients experienced an iDFS event. Overall, the invasive disease events were as follows: 4 locoregional recurrences, 13 distant recurrences and 4 deaths. The node-positive cohort experienced 3 locoregional recurrences, 11 distant recurrences and 2 deaths while the node-negative cohort experienced 1 locoregional recurrence, 2 distant recurrences and 2 deaths. At 2 years, the iDFS rate for the overall study sample was 93.8% (95% CI 89.6%, 96.4%). Within the cohorts at 2 years, the iDFS rate for the node-positive cohort was 92.4% (95% CI 86.3%, 95.8%) while for the node-negative cohort, it was 96.0% (95% CI 88.0%, 98.7%). At 4 years, the iDFS rate for the overall study sample was 90.0% (95% CI 84.6%, 93.6%). Within the cohorts at 4 years, the iDFS rate for the node-positive cohort was 86.2% (95% CI 78.1%, 91.4%), while for the node-negative cohort it was 96.0% (95% CI 88.0%, 98.7%). There was no statistical difference (p = 0.1677) in the iDFS probabilities between the nodepositive and node-negative cohorts (Fig. 1, Tables 4, 5). A multivariate Cox regression analysis was performed to better understand the relationship of certain risk factors with iDFS in the HER2+ patients who had a pCR with nPT and then received aT. The analysis examined the relationship of patient age, BMI, ECOG PS, node status at diagnosis, stage and estrogen/progesterone receptor status with the risk of having an iDFS event. The hazard ratios associated with the Cox regression covariates were age = 1.04 per year of age increase (95% CI 0.997, 1.078), BMI = 1.03 per unit increase (95% CI 0.962, 1.096), ECOG PS = 2.08 per unit increase (95% CI 0.676, 6.392), positive nodal status = 1.60 (95% CI 0.534, 4.788), tumor stage T3/T4 = 1.53 (95% CI 0.580, 4.058) and estrogen/ progesterone receptor status ER+ or PR+ = 0.79 (95% CI 0.293, 2.155) (Table 6). Discussion In this retrospective study, we evaluated the demographic and clinical characteristics, treatment patterns, and iDFS rates of patients with HER2+, locally advanced, inflammatory, or high-risk early stage breast cancer (either > 2 cm in diameter or node positive) who received neoadjuvant pertuzumab plus trastuzumab plus chemotherapy, had a pCR in breast and axillary lymph nodes, and then received treatment with adjuvant trastuzumab (with endocrine therapy for HR+ patients) in the US Oncology Network community practices. Between June 1, 2013 and August 31, 2015, a total of 217 patients with HER2+ breast cancer received a mean of 6 cycles of neoadjuvant pertuzumab plus trastuzumab plus chemotherapy, had a pCR and then received treatment with a mean of 10 cycles of adjuvant trastuzumab, completing a total of 1 year of trastuzumab therapy. Patients had a median follow-up duration of 45 months post-surgery. Of those 217 patients, 212 were positively identified as either node positive (n = 135) or node negative (n = 77). At 4 years post-surgery, iDFS probabilities in the overall, node-positive and node-negative cohorts were 90%, 86%, and 96%, respectively.
Data from the 6-year analysis of the APHINITY trial showed that adding 1 year of adjuvant pertuzumab to the previous adjuvant standard of trastuzumab (for 1 year) plus chemotherapy after definitive surgery further reduced the risk of recurrence and death in patients with HER2+ early breast cancer. In this analysis, Piccart and colleagues found that patients whose cancer had metastasized to axillary lymph nodes continued to derive iDFS benefit with the addition of adjuvant pertuzumab to trastuzumab/chemotherapy. The iDFS in patients with node-positive disease was 87.9% with pertuzumab and 83.4% with placebo, representing a 4.5% improvement. The addition of pertuzumab to trastuzumab and chemotherapy after surgery translated to a reduction in the relative risk of recurrence of 28% in this cohort.
Additionally, clinical benefit was observed irrespective of HR status [18]. However, no difference was seen in nodenegative patients, with 95% of patients in both arms being event free at 6 years. Huober et al. evaluated factors predicting recurrence in patients with early breast cancer who had a pCR after neoadjuvant therapy. In an analysis of 5 neoadjuvant studies from the German Breast Group with a median of 59 months of follow up, the authors found that 15% of patients with a pCR still experienced a DFS event and 10% experienced a distant recurrence. Additionally, the authors performed a multivariate Cox regression to assess potential risk factors for recurrence and found that lobular histology, tumor size and lymph node involvement consistently indicated higher risk for recurrence and death after a pCR [16]. Loibl et al. conducted an analysis of patients with HER2+ early breast cancer followed for a median of 61.3 months after neoadjuvant treatment. In the HR+ pCR+ subgroup, 5-year iDFS rates in the T1–2/N−, T3–4/N−, T1–2/N+, and T3–4/N+ subgroups were 91.4%, 87.0%, 83.6%, and 80.4%, respectively. In the HR− pCR+ subgroup, 5-year iDFS rates in the T1–2/N−, T3–4/N−, T1–2/N+, and T3–4/N+ subgroups were 90.3%, 79.3%, 87.5%, and 82.4%, respectively. Their results suggested that tumor size and nodal status remain important prognostic factors for patients who had a pCR [17]. Findings from our study are consistent with results reported to date.
This study focuses on patients with early breast cancer who had a pCR. Attainment of pCR has been previously observed to be associated with improved outcomes (eventfree survival and OS), especially in patients with triple-negative breast cancer or those with HER2+ hormone receptor negative breast cancer [15]. pCR status has been incorporated as a decision node within treatment guidelines for patients with HER2+ breast cancer; NCCN guidelines recommend completion of 1 year of trastuzumab ± pertuzumab in patients who have pCR and 14 cycles of ado-trastuzumab emtansine (T-DM1) in patients who do not have pCR [19]. pCR status is also used as a factor in design of clinical trials in patients with HER2+ breast cancer. The CompassHER2pCR trial aims to assess reduction in chemotherapy use in patients who received neoadjuvant chemotherapy with pertuzumab and trastuzumab stratified by pCR status [20], whereas the CompassHER2 RD [21] and DESTINY- Breast05 [22] trials assess iDFS among patients who did not have a pCR after neoadjuvant therapy, investigating the role of novel agents such as tucatinib and trastuzumab deruxtecan versus the standard of care, TDM-1, in these patients.

Strengths/limitations

The strengths of this study are the inclusion of recent data, the ability to observe patients longitudinally over time, and the use of community oncology clinic EHR as the source for the data, which include much more detailed information on medication use than the medical claims data often used in studies of this nature. The results provide insights into the real-world recurrence and death rates of patients with high-risk HER2+ breast cancer who received neoadjuvant pertuzumab plus trastuzumab plus chemotherapy, had a pCR, and then received treatment with adjuvant trastuzumab. This study is subject to inherent limitations of retrospective analyses based on electronic medical records in that EHR data are recorded for clinical care, not for research, which may result in data errors of omission and commission. Generalizability may be limited due to the location distribution of US Oncology Network practices and their use of evidence-based guidelines. Further, the sample size in this study was small, with a result that hazard ratios for patient characteristics associated with iDFS did not reach statistical significance. In future, studies with larger sample sizes may definitively assess statistical significance of risk factors for iDFS in real-world HER2+ pCR populations. A final limitation is that owing to a lack of available data, this study did not consider the long-term iDFS of patients receiving the current standard of care for patients who achieve a pCR (continuation of dual antiHER2 therapy with PT in the adjuvant setting, following receipt of nPT). As long-term data become available, future research should assess rates of recurrence for patients treated with this regimen.

Conclusion

In this retrospective study of real-world data, patients with HER2+, high-risk early stage and locally advanced breast cancer who received neoadjuvant pertuzumab plus trastuzumab plus chemotherapy, had a pCR, and then received treatment with adjuvant trastuzumab remain at risk for disease recurrence and death, most notably patients with nodepositive disease at diagnosis. There are potential opportunities to improve outcomes in high-risk patients who have a pCR by continuing pertuzumab as adjuvant therapy as this agent is known to improve iDFS in patients unselected for pCR status in the adjuvant setting.

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