Abstract
Background:
Response to neoadjuvant systemic therapy (NST) for breast cancer enables tailoring of subsequent therapies. Image-guided breast biopsy after NST can accurately predict a pathologic complete response (pCR). The feasibility phase of the clinical trial reported here assesses omission of breast surgery followed by radiotherapy in terms of local recurrence prior to trial expansion.
Study Design:
Women with unicentric, cT1–2 N0–1 M0 triple-negative (TNBC) or HER2-positive (HER2+BC) cancer with <2cm residual disease on post-NST imaging were eligible to enroll. If no residual invasive or in-situ disease was identified by image-guided, vacuum-assisted core biopsy (VACB), breast surgery was omitted, and radiotherapy delivered. The primary endpoint for the feasibility phase was ipsilateral breast tumor recurrence (IBTR) at 6 months. If any recurrence occurred during the feasibility phase the trial would halt.
Results:
Thirteen patients were enrolled from March 2017 to October 2018. The mean age was 60.8 years (range 51–75) and most patients were white (69.2%), non-Hispanic/Latino (84.6%). All patients had invasive ductal carcinoma (6 TNBC, 7 HER2+B). Mean tumor size was 2.4 centimeters (range 0.9–5.0 cm) before NST and 0.7cm (range 0–1.8cm) post-NST. Seven patients (53.8%) had residual disease identified on VACB; the remaining six (46.2%) comprised the feasibility cohort. At a median follow-up of 44.3 (range 41.3–51.3) months, there were no IBTR in this cohort.
Conclusions:
These early data suggest that omission of breast surgery in patients with invasive TNBC and HER2+BC with no evidence of residual disease on standardized VACB following NST is potentially feasible. Results from the expansion phase of this clinical trial will be reported per protocol pre-specified analyses.
Keywords: breast cancer, breast surgery, neoadjuvant systemic therapy, radiotherapy, pathologic complete response
Précis
This prospective, multicenter clinical trial suggests feasibility of omission of breast surgery for invasive triple-negative and HER2-positive cancers with exceptional response to neoadjuvant systemic therapy. No ipsilateral breast tumor recurrences were identified in the feasibility cohort (n=6) at a median follow-up of 44.3 months.
Introduction
Neoadjuvant systemic therapy (NST) is frequently utilized in the multimodality treatment of early-stage triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2-positive breast cancer (HER2+BC).(1) NST facilitates less extensive breast and axillary surgery in cases of substantive tumor downstaging and enables tailoring of adjuvant therapies in cases of residual disease.(2)
Pathologic complete response (pCR) to NST is associated with improved overall survival, event-free survival, and distant recurrence-free survival for TNBC and HER2+BC.(3, 4) With modern systemic therapies for these subtypes, pCR occurs in 46–68% of cases.(5–8)
Image-guided, vacuum-assisted core biopsy (VACB) of the tumor bed following NST can accurately identify residual disease and predict pCR, with a false-negative rate of ~3% when standardized techniques are applied to highly selected patients.(9, 10) The ability to predict, in the preoperative setting, which breast cancers demonstrate pCR to NST calls into question the relative benefit of local therapy for these patients. This prospective multicenter clinical trial aims to evaluate the safety of omitting breast surgery in women with invasive TNBC or HER2+BC with exceptional response to NST.
The feasibility phase of the trial was designed to evaluate the safety of this new approach. If a local recurrence occurred during the first 6 months following radiotherapy among the six patients demonstrated to have a breast pCR on image-guided VACB, the data safety monitoring committee would halt the protocol. In the absence of recurrences, the accrual would continue to 50 total patients in the expansion phase of the trial with protocol specified subsequent planned outcome analyses. This manuscript reports on the feasibility phase of this prospective multicenter clinical trial testing the safety of eliminating breast surgery among patients with VACB proven cases of pCR.
Methods
Cohort Selection
This prospective, multicenter, single-arm, phase 2 clinical trial was registered with the National Cancer Institute (NCT02945579) and approved by the institutional review boards of all participating centers. All patients provided informed consent. Women ≥40 years of age with pathologically confirmed invasive, unicentric, cT1–2 N0–1 M0 TNBC or HER2+BC with <2 centimeters (cm) residual disease (mass, density, suspicious calcifications, or enhancement) on post-NST imaging were eligible to enroll. HER2+BC was defined as immunohistochemistry (IHC) score of 3+ and/or fluorescence in-situ hybridization (FISH) amplified. TNBC was defined as estrogen receptor <10%, progesterone receptor <10%, HER2 IHC 1+ or 2+ or FISH non-amplified. Clinical stage was defined by mammography and breast ultrasound (US) including axillary nodal US, with N1 defined as 1–3 abnormal-appearing nodes on US and pathologic confirmation of metastatic disease on biopsy. MRI was performed per physician discretion. Any NST regimen considered standard for TNBC or HER2+BC was permissible. The primary tumor was localized with image-guided clip marker placement prior to the initiation of NST. Exclusion criteria included prior history of ipsilateral invasive breast cancer or ductal carcinoma in situ (DCIS), pregnancy, and progression of disease during NST.
Trial Design
The trial opened to accrual in March 2017. Patients were eligible to enroll before, during, or after NST. At enrollment, all patients were evaluated with a history and physical examination. After completion of standard NST, patients underwent mammography, breast US, and US of the axilla. Optimal modality for image-guided biopsy of the breast tumor bed was determined by the operating radiologist. Image-guided VACB was performed 2–6 weeks after completion of NST. A minimum of twelve 9-gauge (9G) cores were required. Biopsies were performed of the previously placed clip, which was removed along with >90% of residual radiologic abnormality if present in the tumor bed. A new clip was placed at the biopsy site to facilitate localization in cases of residual disease and for ongoing imaging surveillance. If residual invasive cancer or DCIS was identified on VACB pathology, patients were taken off study and proceeded to standard breast surgical therapy. If no residual disease was identified, participants were eligible to omit breast surgery and proceed to standard whole-breast radiotherapy. Patients with cN1 disease were eligible to participate if they demonstrated a breast pCR on VACB. They were required to undergo targeted axillary dissection, and completion axillary lymph node dissection in the setting of residual nodal disease). Axillary surgery was not required for patients with cN0 disease.
External beam radiotherapy was initiated within 12 weeks of completion of NST. For cN0 patients, whole-breast radiotherapy at a dose of 40.05 Gray (Gy) in 15 fractions was delivered, followed by a tumor bed boost at a dose of 14 Gy in 7 fractions. For cN1 patients, the radiation oncologist had the option to deliver whole-breast and regional nodal radiation at a dose of 50 Gy in 25 fractions, followed by the same boost. Patients were evaluated on a weekly basis during radiotherapy. In the event of severe radiation toxicity, the treating physician had the option to hold therapy for up to 3 days, with substitution of tumor bed boost for whole-breast therapy during this time, provided that the total final doses met the above criteria. Patients with HER2+BC completed adjuvant anti-HER2 targeted therapy, and hormone receptor-positive patients also received adjuvant endocrine therapy.
Following completion of radiotherapy, patients were evaluated with a history and physical examination and mammogram at 6-month intervals for 5 years. Abnormal radiologic findings underwent additional imaging work-up and/or biopsy to evaluate for tumor recurrence. Progression of patients through the trial is illustrated in Figure 1.
Figure 1.
Flow diagram depicting progression of patients through the trial.
Feasibility Endpoint
The feasibility phase of the trial was designed to evaluate six patients with no residual disease following NST, with a primary endpoint of ipsilateral breast tumor recurrence (IBTR). If any of the 6 patients in the feasibility cohort experienced an IBTR within 6 months of post-NST biopsy demonstrating no residual disease, the study would be halted, reviewed by principal investigators and the data monitoring group, and either closed or modified. If no IBTR were observed with this timeframe, patients in the feasibility cohort would be rolled over into the expansion cohort and continue in the second phase of the trial, with continued prespecified monitoring and outcome analyses through five years of follow-up.
We chose a sample size of six patients for the feasibility cohort under both practical consideration and statistical justification. We intended to minimize the number of patients exposed to a new treatment strategy with unknown outcome in the event that IBTR rates may be higher than with standard of care treatment. On the other hand, we wanted to ensure the opportunity to progress to the expansion phase of the study should IBTR rates prove similar to those seen with standard breast surgical therapy. With a cohort size of six patients, if the true IBTR rate at 6 months is 2%, the probability of observing zero IBTR is 89% and the probability of observing at least one IBTR is 11%. Alternatively, if the true IBTR rate at 6 months is 15%, these probabilities are 38% and 62%, respectively.
Results
From March 2017 to October 2018, 13 patients were enrolled leading to 6 patients with pCR by VACB for the feasibility cohort. Patient characteristics are shown in Table 1. Overall, the median age was 62 years (range 51–75). Most patients were white (69%) and/or non-Hispanic/Latino (84%). All patients had invasive ductal carcinoma of either intermediate (38.5%) or high (61.5%) grade. Six patients had TNBC and 7 had HER2+BC 7. All patients with TNBC were treated with Adriamycin and cyclophosphamide followed by paclitaxel (AC+T). All patients with HER2+BC were treated with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) except for one patient whose primary tumor was 0.9 centimeters (cm) and was treated with paclitaxel and trastuzumab (TH).
Table 1.
Patient characteristics overall and by presence or absence of residual disease identified on post-neoadjuvant systemic therapy (NST), image-guided vacuum-assisted core biopsy (VACB).
| Overall (n=13) | Residual disease identified on VACB (n=7) |
No residual disease identified on VACB (n=6) | |
|---|---|---|---|
| Age | Mean 60.8 Range 51–75 |
Mean 59.7 Range 52–67 |
Mean 62.2 Range 51–75 |
| Race White Black Asian |
9 (69.2%) 3 (23.0%) 1 ( 7.7%) |
4 (57.1%) 2 (28.6%) 1 (14.3%) |
5 (83.3%) 1 (16.7%) 0 |
| Ethnicity Hispanic/Latino Non-Hispanic/Latino |
2 (15.4%) 11 (84.6%) |
1 (14.3%) 6 (85.7%) |
1 (16.7%) 5 (83.3%) |
| Breast cancer subtype Triple-negative HER2-positive Hormone-receptor-positive Hormone-receptor negative |
6 (46.2%) 7 (53.8%) 4 (30.8%) 3 (23.0%) |
3 (42.9%) 4 (57.1%) 3 (42.9%) 1 (14.3%) |
3 (50%) 3 (50%) 1 (16.7%) 2 (33.3%) |
| Histology: invasive ductal carcinoma | 13 (100%) | 7 (100%) | 6 (100%) |
| Grade 1 2 3 |
0 5 (38.5%) 8 (61.5%) |
0 2 (28.6%) 5 (71.4%) |
0 3 (50%) 3 (50%) |
| Tumor size, initial (centimeters) | Mean 2.4 Range 0.9–5.0 |
Mean 2.2 Range 0.9–3.1 |
Mean 2.5 Range 1.2–5.0 |
| Tumor size, post-NST (centimeters) | Mean 0.7 Range 0–1.8 |
Mean 1.1 Range 0.5–1.5 |
Mean 0.3 Range 0–1.8 |
| Radiologic complete response | 5 (38.5%) | 0 | 5 (83.3%) |
| Number of VACB cores | Mean 17.3 Range 12–30 |
Mean 18.4 Range 12–30 |
Mean 16 Range 12–24 |
Median initial tumor size was 2.1 centimeters (range 0.9–5.0 cm) which deceased to a median of 0.8cm (range 0–1.8cm) post-NST. Median number of VACB cores was 18 (range 12–30). Seven patients had residual disease identified on VACB (4 with invasive cancer and 3 with DCIS only). The remaining six patients comprised the feasibility cohort.
Among the feasibility cohort, the median age was 62 years (range 51–75) and most women were white (83%) and/or non-Hispanic/Latino (83%). Half had TNBC and were treated with AC+T while the other half had HER2+BC and were treated with TCHP. Median initial tumor size was 2.1cm (range 1.2–5.0). Five patients (83.3%) had a radiologic complete response; the sixth had a residual mass measuring 1.8cm on post-NST imaging. Median number of VACB cores was 15 (range 12–24).
Two patients with initial biopsy proved N1 disease in the feasibility cohort underwent planned targeted axillary dissection per protocol, and no lymph node metastases were identified. These patients with initial N1 disease were treated with whole-breast and regional nodal radiotherapy at a dose of 50 Gy in 25 fractions, whereas the other four patients who did not present with N1 disease received 40 Gy in 15 fractions. All radiotherapy included a tumor bed boost per protocol criteria.
At a median follow-up of 44.3 months (range 41.3–51.3 months), there were no IBTR in the feasibility cohort. At 6 months of follow up, three patients had mammograms with abnormal results which were further evaluated with additional breast imaging. In one case, the mammogram noted focal asymmetry in proximity to the biopsy clip which was further evaluated by ultrasound which showed scarring and shadowing consistent with post-biopsy changes. Contralateral breast ultrasound was recommended for another patient due to a subcentimeter oval mass visualized on mammogram, which had ultrasonographic appearance of fibrocystic changes classified as BI-RADS 2. A third patient’s mammogram report noted post-radiation changes at the site of the clip, with recommendation for ultrasound which was read as “post-radiation changes limiting sonographic evaluation of the breast” with note of a stable benign mass in a different quadrant. An MRI was performed which demonstrated suspicious nonmass enhancement in the region of the benign-appearing mass seen on ultrasound, for which biopsy was recommended. Ultrasound-guided biopsy was performed and pathology demonstrated fibroadenoma with focal atypical lobular hyperplasia.
At 12 months, four patients had benign mammographic findings, including the patient who underwent 6-month biopsy. One patient underwent stereotactic biopsy of a 0.9cm irregular mass associated with the biopsy clip due to interval increase in size, with pathology demonstrating dense nodular stromal fibrosis. Another patient underwent additional breast imaging due to mammographic findings of focal asymmetry with indistinct margins precluding accurate size measurement. Ultrasound showed post-biopsy changes classified as BI-RADS 4A and MRI demonstrated a correlative 1.5cm irregular, non-enhancing mass with spiculated margins classified as BI-RADS 4 with recommendation for biopsy. Stereotactic biopsy was performed and pathology demonstrated stromal fibrosis and therapy related changes. This patient underwent an additional stereotactic biopsy at 24 months for suspicious calcifications located in a different quadrant than the tumor bed, with pathology demonstrating fibroadenoma with stromal calcifications.
Of note, two patients underwent surveillance ultrasound in addition to mammogram in the absence of mammographic abnormalities per radiologist’s preference. One of these patients was found to have three indeterminate, subcentimeter level 2 and 3 axillary lymph nodes at 48 months post-radiation and underwent ultrasound-guided biopsy which confirmed lymphoid tissue and was negative for malignancy.
Discussion
The results of the feasibility phase of this prospective, multicenter clinical trial suggest the potential safety of omitting breast surgery in patients with invasive TNBC and HER2+BC with no evidence of residual disease using standardized, image-guided VACB following NST. The feasibility phase was planned as this was a high-risk and high-potential impact trial where standard surgical therapy has been shown to be effective. As none of the patients in the feasibility cohort experienced an IBTR, the trial was not halted and allowed to reach accrual of 50 patients. Further, none of the patients in the feasibility cohort have experienced an IBTR at a median follow-up of 44.3 months (at the time of writing), demonstrating the potential very early oncologic safety results of de-escalating local therapy for tumors with exceptional response to NST demonstrated on image-guided-VACB to have a breast pCR. This concept is supported by the fact that definitive radiotherapy without surgical resection, with or without systemic therapy, has been shown to be effective for selected patients with esophageal, anal, laryngeal, prostate, cervical, and lung carcinoma.(11) However, until recently, it has not been possible to accurately predict which patients with breast cancer are free of residual disease following NST and thus might safely forego surgery.(12)
NST is increasingly utilized for TNBC and HER2+BC. In 2017, the St. Gallen International Expert Consensus panel strongly endorsed NST for stage II-III TNBC and HER2+BC, especially for cases in which NST may facilitate de-escalation of local therapies.(1) Similarly, current National Comprehensive Cancer Network (NCCN) guidelines recommend NST for patients with operable TNBC and HER2+BC in cases of cT2+ disease, cN1+ disease, or other cases for which NST would enable breast conservation therapy or less extensive axillary surgery, and consideration for NST for cT1cN0 disease.(13) With advances in NST resulting in higher rates of pCR, the next logical step in the push for de-escalation of surgical therapy is omission of breast surgery for tumors with exceptional response to NST.
Higher rates of pCR may be expected in the future as NST continues to be refined and new targeted therapies, immunotherapies, and other novel agents are developed. Indeed, since the initiation of this trial, practice-changing trials such as KEYNOTE-522 have been published, demonstrating improvements in pCR for TNBC from 55% to 69% with the addition of pembrolizumab to a standard chemotherapy backbone of NST.(14) Studies are ongoing to determine optimal NST and adjuvant systemic therapy regimens for different stages of HER2+BC, including possible de-escalation of standard cytotoxic chemotherapy, with attention to pCR rates.(2) As pCR rates continue to improve, if longer term IBTR results from the expansion phase of this trial support omission of breast surgery in TNBC and HER2+BC with pCR to NST, this concept will be tested in subsequent other prospective trials and this option can potentially be offered to greater numbers of patients in the future.
Meticulous multidisciplinary patient selection is essential for the oncologic safety of omitting breast surgery. Preoperative identification of patients predicted to have a pCR can be achieved with high accuracy by adhering to standardized biopsy techniques. A false negative rate of <5% can be achieved through stringent patient selection criteria, thorough sampling of the tumor bed (including removal of the previously placed clip), use of a larger-gauge VACB device with removal of multiple cores, and meticulous specimen processing. (9, 10) The higher false negative rates reported in other studies (37–40%) can be attributed to differences in selection criteria and biopsy techniques. (15, 16) In this clinical trial, pCR was predicted by examining a minimum of twelve cores with a single biopsy procedure using a 9G VACB device. This design was informed by results of a prior trial demonstrating reduction in false negative rate utilizing these measures to ensure adequate tumor bed sampling.(12) The precision of this approach is further illustrated by the ability to discern both residual invasive disease and DCIS among the seven patients who were enrolled and did not meet criteria for inclusion in the feasibility cohort, consistent with prior reports of 95% sensitivity for residual disease.(12) It is interesting to note that one of the patients in the feasibility cohort did not have a radiologic complete response to NST, with a residual 1.8cm on imaging, yet had a pCR predicted by VACB. This is congruent with the known variability in sensitivity and specificity of breast imaging modalities in the detection of residual disease after NST which often overestimates disease as well.(11)
This study is limited by several factors. First, the sample size of the initial feasibility cohort is very small. Given the excellent locoregional recurrence-free survival rates of patients with TNBC and HER2+BC who undergo NST with pCR followed by breast-conservation therapy (98.6% and 97.4% at 5-years, respectively)(17), we anticipate that similar rates would be expected for our feasibility cohort. As such, both a larger number of patients and a longer median follow-up would be necessary to observe a single event of locoregional recurrence. 5-year IBTR results from the expansion cohort will provide key information. Early results from the expansion cohort are very promising demonstrating no detectable IBTR at an approximate 2-year median follow-up for the entire group of patients.(18) Second, given a non-zero false negative rate for predicting pCR by image-guided VACB, it is possible that we failed to identify residual disease in some patients. While whole-breast radiotherapy would be expected to effectively treat a low volume of residual disease, it is possible that IBTR events could be observed with longer follow-up or in a larger cohort. Based on reported 5-year locoregional recurrence-free survival rates of 86.7% and 89.9% for patients with HER2+BC and TNBC whose tumors did not demonstrate pCR following NST and breast-conservation therapy(17), and assuming that lower rates would be observed if surgery were omitted, we would anticipate observing at least one IBTR in the expansion cohort at a future report with a median follow-up of 5 years if the non-zero false negative rate of VACB is clinically meaningful.
Conclusions
In this high-risk and high-potential prospective clinical trial, the feasibility cohort did not demonstrate any local recurrences per the planned safety data monitoring at 6 months and none of these patients have had a recurrence at a median follow-up of 44.3 months. The trial has reached accrual of 50 patients and subsequent outcomes will be reported per protocol specified time-points. If these early limited results pan out, several other prospective trials testing this novel approach will be warranted in multiple medical settings.
Acknowledgment
Exceptional Responders Study Group Participating Investigators:
Emilia J Diego MD FACSi Judy C Boughey MD FACSg, Richard L White MD FACSh,Tanya W Moseley MDc, Jessica WT Leung MDc, Monica Huang MDc, Rosalind P Candelaria MDc, Beatriz E Adrada MDc, Elsa Arribas MDc, Raquel FD van la Parra MD PhDa, Kelly K Hunt MD FACSa, Isabelle Bedrosian MD FACSa, Mediget Teshome MD MPH FACSa, Susie X Sun MD MS FACSa, Rosa F Hwang MD FACSa, Makesha V Miggins MD FACSa, Matthew J Piotrowski MD FACSa, Anna P Refinetti MD FACSa, Richard A Ehlers MD FACSa, Jessica Suarez Colen MD MPHa, Catherine E Loveland-Jones MD MS FACSj, Beth Ann Lesnikowski MD FACSk, Laila Samiian MD FACSl, Clayton D Chong MDm, Simona F Shaitelman MD EdMb, Melissa P Mitchell MD PhDb;
a Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
b Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
c Department of Breast Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas
d Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
e Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
f Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
g Division of Breast and Melanoma Surgical Oncology, Department of Surgery, Mayo Clinic, Rochester, Minnesota
h Division of Surgical Oncology, Department of Surgery, Carolinas Medical Center, Levine Cancer Institute, Atrium Health, Charlotte, North Carolina
i Division of Breast Surgery, University of Pittsburgh Medical Center Magee-Womens Hospital, Pittsburgh, Pennsylvanias
j Division of Breast Surgery, MD Anderson Cancer Center at Cooper University Health Care, Camden, New Jersey
k The Breast Institute at JFK Medical Center, Atlantis, Florida
l Section of Breast Surgical Oncology, Baptist MD Anderson Cancer Center, Jacksonville, Florida
m Medical Oncology, The Queen’s Health System, Honolulu, Hawaii
Support:
This work was supported by the PH and Fay Etta Robinson Distinguished Professorship in Cancer research (HMK), a Cancer Center Support Grant from the National Institutes of Health (NIH) (CA016672), which supports the Clinical Trials Support Unit and Biostatistics Shared Resource, a Clinical and Translational Science Award (grant number UL1 RR024148) to MD Anderson Cancer Center and funding from the MD Anderson Clinical Research Funding Award Program (HMK).
Abbreviations
- DCIS
ductal carcinoma in situ
- HER2+BC
human epidermal growth factor receptor 2-positive breast cancer
- IBTR
ipsilateral breast tumor recurrence
- NST
neoadjuvant systemic therapy
- pCR
pathologic complete response
- TNBC
triple-negative breast cancer
- US
ultrasound
- VACB
vacuum-assisted core biopsy
Footnotes
Clinical Trial identifier NCT02945579
Meeting presentation: Western Surgical Association 130th Scientific Session, Santa Barbara, California, November 2022
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