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The potential benefit of systemic therapy in patients with T1a HER2+ cancers is not well understood, and no consensus guidelines exist. We sought to investigate practice patterns of chemotherapy use in this population.
Methods
From the National Cancer Database (2013-2018), we identified female patients with HER2+ cancers staged as cT1aN0 or pT1aN0 and stratified by receipt of chemotherapy. Using univariate and multivariable analyses we assessed the clinicopathologic features associated with the receipt of chemotherapy. We also compared rates of overall survival (OS).
Results
Of 5176 women with cT1aN0 HER2+ cancers, 88 (2%) received neoadjuvant chemotherapy. Younger age and hormone-receptor (HR) negative tumors were factors independently associated with receipt of neoadjuvant chemotherapy (all P < .001). Of 11,688 women with pT1aN0 HER2+ cancers, 5,588 (48%) received adjuvant chemotherapy. Rates of use increased over the analysis period from 39% in 2013 to 53% in 2018 (P < .001). Factors independently associated with receipt of adjuvant chemotherapy included younger age, having a poorly differentiated tumor, exhibiting lymphovascular invasion, undergoing adjuvant radiation (all P < .001). There were no differences in OS when comparing those who did and did not receive chemotherapy in either group.
Conclusions
The use of chemotherapy in patients with HER2+ T1a cancers is increasing over time and is, as expected, more common among patients with unfavorable clinicopathologic features. Since no prognostic algorithm currently exists, more prospective data is needed to understand which of these patients may derive benefit from systemic therapy and which may safely avoid the morbidity of chemotherapy.
Given the lack of consensus, clinical dilemmas around the appropriate use of systemic therapy in patients with early stage breast cancer persist and are increasing in frequency. With the improvement in technology and increased use of breast imaging for cancer screening, the proportion of patients diagnosed with early stage disease continues to increase.
The diagnosis of tumors <1 cm has seen the largest increase of any invasive tumor size since the advent of widespread screening mammography, constituting 23% of all invasive cancers diagnosed in 2010.
Historically, patients with node-negative T1 breast cancers were treated with surgery alone since they experienced excellent outcomes without systemic therapy; 10-year breast cancer specific survival is reported to be >95%.
Additionally, the prospective studies of systemic therapy in patients with human epidermal growth factor receptor 2 (HER2) overexpressing cancers included only patients with tumors >2 cm, or smaller tumors with high risk clinical features
Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients: BCIRG 006 Study.
Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: Final results of the FinHer trial.
providing little randomized data on which to base the benefit of systemic therapy in patients with T1 tumors without high risk features.
More recently, investigators have identified factors associated with poorer outcomes in patients with early stage tumors for which systemic therapy may be indicated.
Prognosis and management of patients with node-negative invasive breast carcinoma that is 1 cm or smaller in size (stage 1; Tla,bN0M0): a review of the literature.
A risk stratification by hormonal receptors (ER, PgR) and HER-2 status in small (≤1 cm) invasive breast cancer: who might be possible candidates for adjuvant treatment?.
In addition to young age and high tumor grade, these studies highlight differences in receptor subtype, specifically those that are HER2 positive, are associated with a higher risk of recurrence and mortality when systemic therapy is not used. Without clear guidelines, clinicians are left to weigh the morbidity of systemic therapy with a small potential survival benefit in patients with high risk clinicopathologic features.
Since systemic therapy has the most unfavorable risk:benefit ratio in patients with the earliest stage disease, we designed this study to assess the national practice patterns of the use of both neoadjuvant and adjuvant chemotherapy among patients with T1aN0 HER2+ breast cancer. We further sought to identify clinicopathologic features associated with the use of chemotherapy and compare overall survival (OS) between groups.
Materials and Methods
From the National Cancer Database (NCDB), we identified female patients with either cT1aN0 or pT1aN0 HER2+ breast cancer who were treated between 2013 and 2018. The NCDB is a joint collaboration between the American College of Surgeons and the American Cancer Society in which patient-level data are collected from all cancer patients seen at Commission on Cancer accredited programs,
For analysis, we stratified patients by whether they received systemic chemotherapy or not. For patients with cT1aN0 cancer, we selected patients who received NAC, which we defined as systemic chemotherapy initiated at least 30 days prior to first surgery. For patients with pT1aN0 cancer, we selected patients who received adjuvant chemotherapy. We assessed rates of chemotherapy use over time and compared facility, patient and tumor factors of those who received chemotherapy with patients who did not receive chemotherapy. For each group, we performed binary logistic regression to assess the clinicopathologic and demographic features associated with receipt of chemotherapy. We also compared OS between those who did and did not receive chemotherapy.
Statistical Analyses
All statistical analyses were carried out using SPSS statistical software (Version 28.0, IBM Corporation, Armonk, NY, USA). Comparisons of clinicopathologic features were performed using independent T-tests for continuous variables, and Chi square tests for categorical variables. Binary logistic regression models were used to assess factors associated with receipt of chemotherapy. Factors significant on univariate analysis were included in multivariable analysis. Kaplan-Meier survival analyses were used to compare OS between patients who did and did not receive chemotherapy.
Results
Neoadjuvant chemotherapy
We identified 5176 patients with cT1aN0 breast cancer; 2602 (50%) did not receive chemotherapy and 2490 (44%) received chemotherapy (Figure 1A). Among those who received chemotherapy, 88 (4%) received it in the neoadjuvant setting. The rate of NAC use was fairly consistent over time with 1.3% of patients receiving NAC in 2013, a slight increase to over 2% in 2015 and 2016, and a decrease to 1.1% in 2018 (P = .82, Figure 2).
Figure 1Patient selection for analysis of neoadjuvant chemotherapy use among patients with cT1aN0 HER2+ cancer (A) and adjuvant chemotherapy use among patients with pT1aN0 HER2+ cancer (B).
Patients who received neoadjuvant chemotherapy were younger, more likely to have private insurance, poorly differentiated and hormone receptor (HR) negative tumors, and presence of lymphovascular invasion (all P > .05, Table 1). Patients who received neoadjuvant chemotherapy were also more likely to receive adjuvant therapy with radiation, anti-HER2 therapy and endocrine therapy (all P < .001).
Table 1Clinicopathologic Features of Female Patients With cT1aN0 HER2+ Tumors (2013-2018) Stratified by Receipt of Neoadjuvant Chemotherapy.
Of the 85 patients who had clinical and pathologic tumor stages available, 32 (38%) had a breast pathologic complete response (pCR), which was defined as ypT0.
On univariate analysis, younger age, having a Charlson-Deyo score of 0, poorly differentiated and HR-negative tumor were factors associated with receipt of neoadjuvant chemotherapy (all P < .05, Table 2). Younger age (OR 0.97, 95% CI 0.95-0.99, P < .001) and HR-negative status (OR 5.56, 95% CI 3.33-9.09, P < .001) were the only two factors that persisted as independent predictors of receipt of neoadjuvant chemotherapy on multivariable analysis.
Table 2Factors Associated With the Initiation of Chemotherapy in the Neoadjuvant Setting in Patients With cT1aN0 Tumors
Median overall survival (OS) was similar between those who did and did not receive neoadjuvant chemotherapy (76.9 vs. 84.8 months, P = .15, Figure 3A).
Figure 3Kaplan-Meier curves for overall survival among patients with cT1aN0 HER2+ cancer (A) and pT1aN0 HER2+ cancer (B) stratified by receipt of chemotherapy.
We identified 11,831 patients with pT1aN0 breast cancer; 5529 (47%) did not receive chemotherapy and 6159 (53%) received chemotherapy (Figure 1B). Among those who received chemotherapy, 5588 (91%) received it in the adjuvant setting. The rate of adjuvant chemotherapy use increased from 39% in 2013 to 53% in 2018 (P < .001, Figure 2).
Patients who received adjuvant chemotherapy were younger, more likely to have private insurance, a Charlson-Deyo score of 0, poorly-differentiated and hormone receptor negative tumors, and lymphovascular invasion (all P ≤ .05, Table 3). Patients who received adjuvant chemotherapy were also more likely to receive adjuvant therapy with radiation, anti-HER2 therapy and endocrine therapy (all P < .001).
Table 3Clinicopathologic Features of Female Patients With pT1aN0 HER2+ Tumors (2013-2018) Stratified by Receipt of Adjuvant Chemotherapy
On univariate analysis, many clinicopathologic features were associated with the receipt of adjuvant chemotherapy (Table 4). Younger age (OR 0.96, 95% CI 0.95-0.97), poorly differentiated tumors (OR 2.08, 95% CI 1.46-2.98), presence of lymphovascular invasion (OR 2.80, 95% CI 1.91-4.11), and receipt of adjuvant anti-HER2 therapy (OR 143.69, 95% CI 118.63-174.05) were all independent predictors of receipt of adjuvant chemotherapy on multivariable analysis. Unlike in the neoadjuvant setting, HR status was not an independent predictor of adjuvant chemotherapy receipt.
Table 4Factors associated with the initiation of chemotherapy in the adjuvant setting in patients with pT1aN0 tumors
Median overall survival (OS) was similar between those who did and did not receive adjuvant chemotherapy (85.1 vs. 85.7 months, P = .49, Figure 3B).
Discussion
In this study of national practice trends, we demonstrate an increase in the use of chemotherapy in patients with pT1aN0 HER2+ breast cancer, with rates exceeding 50% by the end of the study period.
The use of NAC in patients with locally advanced HER2+ breast cancer is well established as it provides the opportunity to downstage the breast and axilla to increase rates of breast conservation and avoidance of axillary lymph node dissection (ALND).
Petruolo O, Sevilimedu V, Montagna G, Le, Bs T, Morrow M, Barrio A V. How often does modern neoadjuvant chemotherapy downstage patients to breast-conserving surgery?Ann Surg Oncol. 28. doi:10.1245/s10434-020-08593-5
These benefits do not pertain to patients with cT1aN0 cancers. Breast conservation is almost universally an option (except in those for whom radiation is contraindicated and therefore would not require NAC for downstaging), and the rate of pathologic lymph nodes requiring ALND is extremely low.
Additionally, in patients with locally advanced disease, documentation of a pCR not only is prognostic for survival,
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.
Prospective trials of neoadjuvant chemotherapy and anti-HER2 therapy for patients with HER2+ cancers have documented pCR rates ranging from 46% to 52%.
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.
Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).
None of these trials included patients with T1a disease, so the significance of the 38% pCR rate we observed in this study and its impact on survival outcomes in this group remain unclear.
Despite the unclear benefit of NAC, its use continues to increase in patients with cT1 HER2+ cancer.
Based on our study, though, it appears national rates of NAC remain low in patients with the earliest stage of disease.
The use of adjuvant chemotherapy plus anti-HER2 therapy has become standard of care, and its benefit in disease-specific and overall survival for patients with HER2+ node-positive or locally advanced cancers are supported by level 1 evidence.
Importantly, these trials did not include patients with T1 tumors, and so there are currently no consensus guidelines to support the use of any systemic therapy in patients with early stage disease. Our study, however, demonstrates that over half of patients with pT1aN0 HER2+ cancer are currently receiving adjuvant chemotherapy plus anti-HER2 therapy. Importantly, these prospective studies demonstrate that over 60% of patients experience a grade ≥3 adverse event and up to 7% suffer from a decrease in cardiac function due to the synergistic negative effects of these therapies.
Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2–positive breast cancer.
Adjuvant Trastuzumab Emtansine versus Paclitaxel in combination with Trastuzumab for stage I HER2-positive breast cancer (ATEMPT): A Randomized Clinical Trial.
trials could be considered for patients with very early stage disease in order to minimize the potential risks of therapy.
This risk of morbidity must be weighed with an undefined benefit in breast cancer outcomes. Retrospective analyses of both the Surveillance, Epidemiology, and End Results (SEER) database
failed to demonstrate breast-specific and overall survival benefits for patients with HER2+ T1a receiving systemic therapy. We similarly did not find any impact of chemotherapy on overall survival in our study. In a study of the Netherlands Cancer Registry, van Ramshorst et al. analyzed the use of systemic therapy in T1N0 HER2 positive cancers and, similar to our study, found an increase over time.
Additionally, they found that receipt of adjuvant systemic therapy was associated with a significant improvement of 5% in breast cancer specific survival in T1 patients, but the difference, although similar, was not significant in the T1a subgroup likely due to a small sample size. Similarly, a Canadian study of adjuvant chemotherapy and trastuzumab in patients with T1N0 HER2+ cancer by Ali et al. found improvements in disease-free and overall survival, but the results are challenging to interpret when it comes to T1a disease since only 8 patients with T1a tumors received systemic therapy.
In light of the lack of a consistently demonstrable survival benefit, and in the era of de-escalation of many treatment modalities, the increase in the use of systemic therapy in patients with T1a HER2+ breast cancer is curious. One possible reason that the use of adjuvant therapy would increase is a change in the composition of the cancers diagnosed over time in which high risk features become more prevalent. We did not note any significant change over time of the main factors that predicted adjuvant chemotherapy use (analysis not shown). The other factors that could influence the increased use of systemic therapy in this population is an increase in the use of regimens with less toxic chemotherapy backbones, prompting higher rates of recommendation for systemic therapy by medical oncologists, and increase in uptake by patients due to reduced risk for toxicity. We do not have data on the tolerability of the chemotherapy regimens, adverse effects, nor of disease-specific outcomes, which are required to clearly define the risk and benefit in this population. A prospective trial documenting each of these findings would help clarify the risks and benefits of treatment, and may offer additional clinicopathologic factors that should be considered when considering adjuvant treatment in patients with very early stage disease. Given the already-favorable outcomes, and the risk/benefit ratio in the experimental arm, enrollment in such a trial may be challenging. However, several ongoing trials of limited or no chemotherapy with anti-HER2 therapy in Stage 1 HER2+ breast cancer, such as the ADEPT
A single arm phase II study of adjuvant endocrine therapy, Pertuzumab, and Trastuzumab for patients with anatomic stage I hormone receptor-positive, HER2-positive Breast Cancer - Full Text View - ClinicalTrials.gov. Accessed July 6, 2022. https://clinicaltrials.gov/ct2/show/NCT04569747
trials, may help to clarify some of the questions related to benefit while minimizing the risk of systemic therapy. Additionally, as the use of genomic expression profiling for breast cancer increases, identification of patients whose tumor proliferation is actually driven by HER2 stimulation versus another biologic pathway may help to select patients for specific treatment regimens.
Our study has several strengths and limitations. The use of the NCDB allows us to analyze practice patterns across the spectrum of institution types and a diverse group of practitioners and patients. This provides an opportunity to assess trends in the use of systemic therapy over time, and to evaluate a large data set for factors associated with its use. The NCDB, like any large database, does not provide granular data related treatment decisions, so we are unable to assess the reasons for the use of chemotherapy in each instance, which would be helpful in more thoroughly understanding practice patterns. Additionally, the chemotherapeutic and anti-HER2 agents used are not documented individually, so we are not able to assess the specific regimens being used. There are also no data related to discontinuation of therapy, which prevents us from analyzing rates of completion, which may impact outcomes. While OS is documented, the NCDB does not provide data on any disease-specific outcomes which, for early-stage cancer, are important in assessing the benefit of therapy.
Conclusion
The use of chemotherapy in patient with T1aN0 HER2+ breast cancer is increasing over time, mostly in the adjuvant setting. There are currently no genomic assays that predict a benefit of chemotherapy in these patients, and lack of data on the impacts on outcomes in very early stage disease make the risk:benefit analysis challenging. More investigation into clinicopathologic features that can help predict benefit of chemotherapy are needed in order personalize the systemic therapy recommendations for these patients.
Clinical Practice Points
Patients with T1aN0 breast cancer have often been treated without systemic therapy given their excellent survival outcomes. The majority of studies evaluating the effect of chemotherapy and targeted anti-HER2 therapy have been performed in patients with higher stage disease, but there may be evidence to suggest that even patients with the earliest stage HER2+ disease may benefit from systemic therapy. Using the National Cancer Database, we found that the use of adjuvant chemotherapy among patients with T1aN0 HER2+ breast cancer has been increasing, and currently exceeds 50%. We found no overall survival benefit among patients treated with systemic therapy. Since there are currently no genomic assays that can predict which patients with HER2+ disease may benefit from systemic therapy, and so future, large-scale studies to determine which factors predict a higher benefit than risk of chemotherapy in these patients is needed.
Disclosure
All authors report no disclosures.
References
Hanrahan EO
Gonzalez-Angulo AM
Giordano SH
et al.
Overall survival and cause-specific mortality of patients with stage T1a,bN0M0 breast carcinoma.
Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients: BCIRG 006 Study.
Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: Final results of the FinHer trial.
Prognosis and management of patients with node-negative invasive breast carcinoma that is 1 cm or smaller in size (stage 1; Tla,bN0M0): a review of the literature.
A risk stratification by hormonal receptors (ER, PgR) and HER-2 status in small (≤1 cm) invasive breast cancer: who might be possible candidates for adjuvant treatment?.
Petruolo O, Sevilimedu V, Montagna G, Le, Bs T, Morrow M, Barrio A V. How often does modern neoadjuvant chemotherapy downstage patients to breast-conserving surgery?Ann Surg Oncol. 28. doi:10.1245/s10434-020-08593-5
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.
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.
Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).
Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2–positive breast cancer.
Adjuvant Trastuzumab Emtansine versus Paclitaxel in combination with Trastuzumab for stage I HER2-positive breast cancer (ATEMPT): A Randomized Clinical Trial.
A single arm phase II study of adjuvant endocrine therapy, Pertuzumab, and Trastuzumab for patients with anatomic stage I hormone receptor-positive, HER2-positive Breast Cancer - Full Text View - ClinicalTrials.gov. Accessed July 6, 2022. https://clinicaltrials.gov/ct2/show/NCT04569747
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