- Email: [email protected]
Indications for Postmastectomy Radiation After Neoadjuvant Chemotherapy in ypN0 and ypN1-3 Axillary Node-Positive Women
Accepted Manuscript Indications for Post-mastectomy Radiation (PMRT) Following Neoadjuvant Chemotherapy (NAC) in ypN0 and ypN1-3 Axillary Node Positive Women Barbara Fowble, MD, Abhishek Keshav Jairam, BA, Frederick Wang, MD, Anne Peled, MD, Michael Alvarado, MD, Cheryl Ewing, MD, Laura Esserman, MD, MBA, Catherine Park, MD, Ann Lazar, PhD, MS PII:
S1526-8209(17)30225-2
DOI:
10.1016/j.clbc.2017.07.016
Reference:
CLBC 660
To appear in:
Clinical Breast Cancer
Received Date: 20 April 2017 Revised Date:
18 May 2017
Accepted Date: 24 July 2017
Please cite this article as: Fowble B, Jairam AK, Wang F, Peled A, Alvarado M, Ewing C, Esserman L, Park C, Lazar A, Indications for Post-mastectomy Radiation (PMRT) Following Neoadjuvant Chemotherapy (NAC) in ypN0 and ypN1-3 Axillary Node Positive Women, Clinical Breast Cancer (2017), doi: 10.1016/j.clbc.2017.07.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title page Title: Indications for Post-mastectomy Radiation (PMRT) Following Neoadjuvant Chemotherapy (NAC) in ypN0 and ypN1-3 Axillary Node Positive Women
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Shortened title: Neoadjuvant chemotherapy and no PMRT Barbara Fowble MD, Department of Radiation Oncology, University of California, San Francisco; 1600 Divisadero Street, H1031, San Francisco, CA 94115, email: [email protected] Abhishek Keshav Jairam BA, Department of Radiation Oncology, University of California, San Francisco, 1600 Divisadero Street, H1031, San Francisco, CA 94115, email: [email protected]
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Frederick Wang MD, Division of Plastic and Reconstructive Surgery, University of California, San Francisco, Box 0470, 513 Parnassus Ave, 321, San Francisco, CA 94122, email: [email protected]
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Anne Peled MD, Division of Plastic and Reconstructive Surgery, University of California, San Francisco, Box 0470, 513 Parnassus Ave, 321, San Francisco, CA 94122, email: [email protected] Michael Alvarado MD, Carol Frank Buck Breast Care Center, Department of Surgery, University of California, San Francisco, Box 1710, 1600 Divisadero, B6-11, San Francisco, CA 94115, email: [email protected]
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Cheryl Ewing MD, Carol Frank Buck Breast Care Center, Department of Surgery, University of California, San Francisco, Box 1710, 1600 Divisadero, B6-35, San Francisco, CA 94115, email: [email protected], email: [email protected] Laura Esserman MD, MBA, Carol Frank Buck Breast Care Center, Department of Surgery, University of California, San Francisco, Box 1710, 1600 Divisadero, B6-35, San Francisco, CA 94115, email: [email protected]
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Catherine Park MD, Department of Radiation Oncology, University of California, San Francisco, 1600 Divisadero Street, H1031, San Francisco, CA 94115, email: [email protected]
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Ann Lazar PhD, MS, Department of Preventive and Restorative Dental Sciences, Department of Epidemiology and Biostatistics. University of California, San Francisco, Box 1361, 3333 California Street, 495H, San Francisco, CA 94118, email: [email protected] Corresponding author: Barbara Fowble MD, Department of Radiation Oncology, University of California San Francisco, 1600 Divisadero Street, H1031, San Francisco, CA 94115 Phone 415-353-9819, Fax 415353-9883; [email protected] None of the authors have any commercial interest or source of financial or material support for this retrospective study. Keywords: Neoadjuvant chemotherapy, post-mastectomy radiation
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MicroAbstract: This study evaluates local-regional recurrence rates (LRR) in 81 women with stage II-IIIA breast cancer who received neoadjuvant chemotherapy (NAC) followed by mastectomy and no radiation (PMRT). Pathologic complete response resulted in low LRR rates in all subtypes. Residual disease was predictive of high LRR in HR+ Her2+ women despite trastuzumab. This information may guide decisions for PMRT after NAC. Abstract
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Introduction: Downstaging with neoadjuvant chemotherapy (NAC) may obscure indications for PMRT. The degree of downstaging which results in local-regional recurrence (LRR) rates low enough to omit PMRT remains controversial. We examined the rate of LRR in women receiving NAC who underwent mastectomy without PMRT.
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Methods: Between 2004-2013 81 women with stage I-IIIA breast cancer had NAC and mastectomy. 59% were clinical N0 and 41% were clinical N1. Median age 45 years. 43% had HR+ Her2 –, 26% HR+Her2+, 23% HR-Her2- and 9% HR-Her2+ disease. We explored how LRR rates varied with age, BRCA status, grade, receptor status, clinical N status, pathologic response, LVI, and mastectomy margins. Median follow-up was 4.9 yrs.
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Results: Following NAC, 41% had a path CR, 43% were ypN0 and 16% were ypN1-3+. There were 8 LRR (6 chest wall, 1 axillary, 1 supraclavicular node). The 5 year cumulative incidence of LRR was 8% for all patients, 3% for path CR, 16% ypN0, 10% ypN1-3+, 6% HR+Her2-, 25% HR+Her2+, 0% HR-Her2-, and 0% HR-Her2+. LRR was 31% in the ypN0 and 33% in the ypN1-3+ HR+Her2+ women and 12% ypN0 and 0% ypN1-3+ HR+Her2- patients.
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Conclusions: This study is unique. All Her2+ patients received trastuzumab and LRR was analyzed by treatment response, clinicopathologic factors and receptor status. Path CR patients including young women and clinical stage IIIA had low LRR rates. However, ypN0 and ypN1-3+ HR+Her2+ patients had higher rates of LRR compared to other receptor subgroups and based on limited data should be considered for PMRT.
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Clinical Practice Points: Unlike the adjuvant systemic therapy setting, the role of post mastectomy radiation (PMRT) in patients with stage II-IIIA breast cancer receiving neoadjuvant chemotherapy (NAC) has not been established. There are no results from randomized trials. Current recommendations are based on single institution retrospective series or pooled analyses of chemotherapy clinical trials in which receptor status was not always reported and if known, not all Her2+ patients received anti-Her2 therapy. This study is unique in its assessment of local-regional recurrence (LRR) in a select group of women with stage II-IIIA breast cancer who did not receive PMRT and in which all Her2+ women received trastuzumab. New findings include low LRR rates for BRCA+ women, young women with a path CR, and hormone receptor positive (HR) Her2- women who were ypN1-3+. The absence of a path CR in HR+Her2+ women was associated with high LRR rates. Confirmatory findings include low rates of LRR for all subtypes with a path CR and ypN0 women except for those that were HR+Her2+. The study supports 2
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the NSABP B18 and B27 findings of low LRR in stage IIIA disease with a path CR and provides new and additional information that may serve as guide for decisions regarding PMRT. As higher rates of pCR are achieved with more effective systemic therapy, PMRT and its associated morbidity could be avoided in select patients.
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Introduction
Materials and methods Patients
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The use of neoadjuvant chemotherapy (NAC) once reserved for locally advanced breast cancer now includes stage II and IIIA disease. While providing an in vitro response to systemic therapy, it may also allow for a reduction in the extent of surgery (mastectomy and/or axillary dissection) and possibly the avoidance of post-mastectomy radiation (PMRT). Unlike the adjuvant chemotherapy setting(1), the role of PMRT in patients receiving NAC has not been established. There are no published results of randomized trials and the majority of studies have been single institution retrospective series.(2) Pathologic down-staging may include complete eradication of the primary cancer and/or axillary disease and thus obscure conventional indications for PMRT established in the adjuvant chemotherapy setting(3, 4). Debate centers on whether recommendations for PMRT should be based on pathologic response, initial clinical stage or both with proponents of each. An analysis of the NSABP B-18 and B-27 NAC trials identified initial clinical stage and response to therapy as significant predictors for localregional recurrence (LRR) in mastectomy patients, none of whom received PMRT.(5) Receptor status was not reported. A recent analysis of the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) correlated LRR in patients undergoing mastectomy with receptor status, histologic grade and response to treatment but not initial clinical stage.(6) While pathologic complete response (pCR) has been associated with improved survival, the association is strongest in triple negative and HER2+ hormone receptor (HR) negative patients receiving trastuzumab.(7, 8) However, for some subtypes the lack of a pCR is less predictive of clinical outcome.(7) Similarly, LRR rates may be low in all subtypes achieving a pCR but the absence of such a response may not always predict for high LRR rates. Therefore, recommendations for PMRT in some subtypes could result in overtreatment .We undertook a review of patients receiving NAC and mastectomy without PMRT to add to the existing limited literature and serve as a potential guide for treatment decisions until randomized trial data are reported.
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This retrospective review was approved by the [XXXXX] institutional review board. From 2004-2013, 81 of 304 women who received NAC followed by mastectomy did not receive PMRT. Clinical, pathologic and treatment characteristics are presented in Table 1. The median age was 45 years (range 21-75). Clinical stage was determined by a combination of physical examination and imaging (mammogram, ultrasound, breast MRI and computerized tomography +/- PET scans). Seventy-eight percent were clinical stage II (American Joint Committee of Cancer TNM Classification, 7th edition)(9) and 59% were clinically node negative based on imaging (axillary ultrasound and/or MRI or PET-CT). Confirmation of imaging positive axillary nodes was obtained by fine needle aspiration or core biopsy in 64% before NAC. The patients were categorized into 4 groups based on receptor status: HR+ (ER+ and/or PR+) and Her2-, HR+ and HER2+, HR- and Her2 - and HER2 positive and HR-. The majority had HR+ tumors and 38% were HER2+. Seventy-two percent had genetic testing and 26% were BRCA 1/2 positive (BRCA1+ 11 patients, BRCA2+ 4 patients). Four patients had invasive lobular cancers and 77 had invasive ductal cancers. Initial core biopsies identified 41% as grade 3 invasive cancers.
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Treatment
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All patients received NAC consisting of an anthracycline, a taxane or both. All HER2+ patients received neoadjuvant trastuzumab which was continued for a total of one year of treatment. No patient received pertuzumab. Seventeen patients participated in the I-SPY 1 or 2 trials(10, 11) and 10 patients received an investigational agent in addition to a taxane, doxorubicin and cyclophosphamide. All HR+ patients received adjuvant endocrine therapy for a minimum of 5 years.
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No patient had an axillary dissection (AD) or sentinel node (SN) surgery prior to NAC. Seventeen patients had skin sparing mastectomies and 64 had total nipple/areolar skin sparing mastectomies. Immediate reconstruction included expander/implant based reconstruction (72 patients), trans rectus abdominis myocutaneous flap reconstruction (5 patients) and deep inferior epigastric perforator flap reconstruction (4 patients). SN mapping was performed with Tc 99m sulfur colloid. SN surgery alone was performed in 98% of the clinical N0 patients. One clinical N0 patient had an AD. The median number of SN removed was 2 (range 1-6). AD was performed in 94% of the clinical node positive patients. The median number of nodes removed was 12 (range 3-25). Two clinical N1 patients had SN surgery without AD. Both were ypN0. Statistical analysis
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Results
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Follow-up was determined from the date of diagnosis. The median follow-up was 4.9 years (range 1.912.6 years). LRR was defined as recurrence in the ipsilateral chest wall, axilla, or internal mammary or supraclavicular nodes confirmed on imaging or biopsy. Cumulative incidence (CI) of LRR in the presence of a competing risk (distant recurrence) was estimated at 5 years.(12) Patients who did not have a LRR were censored at last follow-up. Survival was defined as time from diagnosis to death. Kaplan-Meier product limit estimator was used to estimate 5 year survival. We explored how LRR rates varied according to age, BRCA status, histologic grade, receptor status, clinical N status, response to treatment, the presence of lymphovascular invasion (LVI) and mastectomy margins. Small numbers in subgroups precluded analysis for statistical significance. Statistical analyses were performed using SAS version 9.4 and R CRAN cmprsk.
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Following NAC 43% of the patients had a pCR (no residual invasive cancer in the breast and negative axillary nodes). Thirteen patients with residual DCIS were included in the pCR group. Forty-one percent had residual disease in the breast with negative axillary nodes (ypN0) and 16% had positive axillary nodes (ypN1-3+). Ten patients had 1 positive node, 2 had 2 positive nodes and 1 patient had 3 positive nodes. No patient had ≥ 4 positive nodes. Micrometastases were identified in 2 women, macrometastases in 10 and isolated tumor cells in one patient. Sixty-seven percent of the clinical N1 patients had negative axillary nodes. A single clinical N0 patient had a positive axillary node (macrometastasis). The median size of residual invasive cancer in the breast was 1.5 cm (range < 1mm to 15.3 cm). None of the 47 patients with residual disease in the breast had a positive mastectomy 5
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margin for invasive cancer or DCIS. Two patients had a margin ≤ 2 mm for DCIS and 3 patients had a margin ≤ 2 mm for invasive cancer. Treatment outcome
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Eight patients developed a LRR (6 chest wall, 1 axillary and 1 supraclavicular node) with a median interval of 2.5 years (range 0.3-5.2). All were isolated without simultaneous distant metastases. Seven of the 8 LRR occurred within 3.1 years. The 5 year CI of a LRR was 8%. Table 2 presents characteristics of patients with LRR. The 2 LRR in ypN1 patients included one clinical N1 patient with 1/8 axillary nodes positive (isolated tumor cells) who had a supraclavicular recurrence at 3 years. The second clinical N1, ypN1 patient had 1/6 nodes positive (3.3 mm metastasis). She developed a chest wall recurrence at 5.2 years while on tamoxifen. Two of 33 patients (6%) with histologic grade 3 tumors developed a LRR compared to 6 of the 45 patients (13%) with grade 1-2 cancers. None of the 6 patients who developed a chest wall recurrence had a final close or positive mastectomy margin. One of six patients with lymphovascular invasion developed a LRR in a supraclavicular node. There was no correlation between LRR and initial clinical stage (12.5% stage IIA, 8.6% IIB, 0% IIIA). LRR developed in 2 of 33 (6%) clinical N1 and 6 of 48 (12.5%) clinical N0 patients.
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Table 3 presents 5 year CI of LRR related to receptor status and pathologic response. LRR was 3% for pCR patients, 16 % for ypN0 and 10% for ypN1. Of note, all LRR were in HR+ women and 5 of 8 were in the HR+Her2+ subgroup. None of the 9 clinical stage IIIA patients who had a path CR had a LRR. Table 4 presents 5 year CI of LRR related to age, receptor status and pathologic response. Seven of 8 LRR were in women < 50 years of age. LRR was 13% for women ≤ 40 years of age (25 patients), 9% for those 41-49 years (32 patients) and 4% for those ≥ 50 years (24 patients). Regardless of age, women who had a path CR had low LRR rates. There were no LRR in 15 BRCA carriers, eleven of whom had a path CR. Distant metastases and survival
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Distant metastases developed in 5 patients with a median interval of 5 years (range 1.2-5.1 yrs. ). One patient developed distant disease 3.9 years after a chest wall recurrence. Distant metastases occurred in 3 HR+Her2- patients, one HR+Her2+ patient and one HR-Her2+ patient. Three of the 5 patients with distant disease have died. The 5 year overall survival was 97%. Discussion
This single institution retrospective study includes a select group of primarily stage II patients who did not receive PMRT. While the study population seems small, the current literature assessing LRR in women receiving contemporary NAC with mastectomy and no PMRT is similarly limited in patient numbers.(2) Mamounas et al(5) reported LRR rates in 1071 mastectomy patients in the NSABP B-18 and B-27 trials. Receptor status was not reported and targeted therapies were not given. The pooled analysis of the CTNeoBC reported LRR in 2041 patients undergoing mastectomy.(6) Specific information on which patients received PMRT was lacking since criteria varied among the trials. Only 38% of Her2+ patients received trastuzumab. In a meta-analysis of 3 Gepar NAC randomized trials, 150 of the 1001 mastectomy patients did not receive PMRT.(13, 14) In the most recently reported series from MD 6
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Anderson(15) 297 of the 1041 (28.5%) mastectomy patients who received NAC did not receive PMRT. None of the Her2+ patients received trastuzumab. Diaz et al(16) reported LRR in 116 clinical stage IIB patients treated with NAC and mastectomy, 15 of whom did not receive PMRT. In a separate review of 142 patients with stage II-III Her2+ breast cancer treated with NAC (including trastuzumab) and mastectomy, 28 patients did not receive PMRT.(17) Therefore, our series appears to be the largest to date in which receptor status was known and all Her2+ patients received trastuzumab.
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Our 8% 5 year CI of LRR is comparable to other reported series (Table 5) (5, 6, 13-20). Similar to the findings of the CTNeoBC, LRR was not related to initial clinical stage or N stage.(6) Our series as well as others confirms the association of pCR with low LRR rates including stage IIIA patients.(5, 13-15, 18) While the magnitude of the risk that prompts a recommendation for PMRT may vary, it is generally accepted that risks < 10%-15% (4, 21-25) do not warrant treatment. Weighing the potential benefit of PMRT is particularly important for patients with implant based reconstruction since the risk of a complication including reconstruction failure may exceed the benefit of treatment.(26-28)
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Similar to the CTNeoBC, we found subtype as approximated by receptor status to predict for LRR.(6) With larger numbers of patients in the CTNeoBC but the receipt of PMRT uncertain and only 38% of Her2+ patients receiving trastuzumab, higher rates of LRR were observed in the ypN0 or N1 HR-Her2and HR-Her2+ patients. However, in our series the highest rates of LRR were observed in the HR+Her2+ women all of whom received trastuzumab and endocrine therapy. This finding suggests that residual disease in this subgroup treated with contemporary systemic therapy may have a greater impact on LRR. In contrast, LRR for the HR+Her2- women was low both for the ypN0 and ypN1-3+ subgroups.
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Age (< 50 vs. ≥50 yrs.) was not an independent predictor for LRR in mastectomy patients in the NSABP B18 and B-27 trials or the CTNeoBC pooled analysis.(5, 6) Garg et al reported a 31% 5 year LRR in 28 women ≤ 40 years of age with stage II disease who did not receive PMRT.(18) In another series of women < 35 yrs. from MD Anderson(29), LRR rates were 35% for 9 ypN0 women and 30% for 11 ypN13+ women who did not receive PMRT. Shim et al(20) identified age ≤ 40 as a significant factor for LRR free survival in 151 clinical stage II-III patients who were ypN0. In the present series the 5 year CI of LRR was 13% for women ≤ 40, 9% for those 41-49 and 4% for those ≥ 50 years (Table 4). The highest rate of LRR was in the HR+Her2+ women ≤ 40 years of age. Ours is the first series to report LRR rates (8.3%) in women ≤ 40 who had a pCR and did not receive PMRT. We did not identify a correlation with histologic grade, lymphovascular invasion or BRCA status and LRR. In the CTNeoBC pooled analysis, grade 3 HR+Her2- ypN1 patients had a higher rate of LRR than those with grade 1-2 tumors.(6) None of the patients in our series had positive mastectomy margins for DCIS or invasive cancer and none of the 6 chest wall recurrences occurred in women with margins ≤2 mm. Vila et al(15) correlated LRR rates in women receiving NAC with initial clinical stage (CS), pathologic stage (PS), estrogen receptor (E) and nuclear grade (G) (CPS+EG score). With a median follow-up of 4.25 years, 8.1% of the 297 patients who had mastectomy without PMRT (82% initial stage II) had a LRR. None of the Her2+ patients received trastuzumab. The authors noted that for clinical stage III or ypN1 patients there was no benefit to PMRT if the CPS+EG score was ≤2. This low score was driven primarily
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by low grade ER+ tumors. The investigators commented that they are revising the score to incorporate Her2 status and trastuzumab use.
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We recognize that the small numbers of patients in our subgroups and those in other series (table 5) preclude definitive conclusions. However, we report some important observations including the predominant pattern of LRR in the chest wall with most occurring within 3 years despite contemporary systemic therapy and negative mastectomy margins; the low rate of axillary recurrence with SNB in clinical N0, ypN0; the low rate of LRR in women who experience a pCR (including women ≤40 and initial stage IIIA) or are ypN0 (all subtypes except HR+Her2+), or are ypN1-3+ in the HR+Her2- subgroup. For HR+Her2+ tumors that are ypN0 or ypN1-3+ LRR rates were >20%. The recent PMRT guideline from the American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology(14) recommends PMRT for any ypN1 patient after NAC. The guideline does not acknowledge the contribution of receptor status, the extent of nodal disease or the CPS+EG score to LRR rates.
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Conclusions
There is a complex relationship between tumor subtype, treatment response and LRR in the setting of increasingly effective systemic therapy and as more patients fall into the pCR category, the opportunity to avoid PMRT may increase. The results of the NRG Oncology Group 9353 trial will provide additional information regarding the role of PMRT in T1-3N1 ypN0 (including pCR) women.
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References
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We acknowledge the significant contributions of our research associate Keith Sharee for data collection and editorial support.
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Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update. J Clin Oncol. 2016;34(36):4431-42. doi: 10.1200/JCO.2016.69.1188. PubMed PMID: 27646947. 15. Vila J, Teshome M, Tucker SL, Woodward WA, Chavez-MacGregor M, Hunt KK, Mittendorf EA. Combining Clinical and Pathologic Staging Variables Has Prognostic Value in Predicting Local-regional Recurrence Following Neoadjuvant Chemotherapy for Breast Cancer. Ann Surg. 2016. doi: 10.1097/SLA.0000000000001492. PubMed PMID: 27735826. 16. Diaz DA, Hurley J, Reis I, Takita C, Zhao W, Wright J. Locoregional outcomes in clinical stage IIB breast cancer after neoadjuvant therapy and mastectomy with or without radiation. Medicine (Baltimore). 2014;93(29):e230. doi: 10.1097/MD.0000000000000230. PubMed PMID: 25546661; PMCID: PMC4602589. 17. Arsenault D, Hurley J, Takita C, Reis IM, Zhao W, Rodgers S, Wright JL. Predictors of locoregional outcome in HER2-overexpressing breast cancer treated with neoadjuvant chemotherapy. Am J Clin Oncol. 2015;38(4):348-52. doi: 10.1097/COC.0b013e31829d1eb8. PubMed PMID: 23799288. 18. Garg AK, Strom EA, McNeese MD, Buzdar AU, Hortobagyi GN, Kuerer HM, Perkins GH, Singletary SE, Hunt KK, Sahin A, Schechter N, Valero V, Tucker SL, Buchholz TA. T3 disease at presentation or pathologic involvement of four or more lymph nodes predict for locoregional recurrence in stage II breast cancer treated with neoadjuvant chemotherapy and mastectomy without radiotherapy. Int J Radiat Oncol Biol Phys. 2004;59(1):138-45. doi: 10.1016/j.ijrobp.2003.10.037. PubMed PMID: 15093909. 19. Le Scodan R, Selz J, Stevens D, Bollet MA, de la Lande B, Daveau C, Lerebours F, Labib A, Bruant S. Radiotherapy for stage II and stage III breast cancer patients with negative lymph nodes after preoperative chemotherapy and mastectomy. Int J Radiat Oncol Biol Phys. 2012;82(1):e1-7. doi: 10.1016/j.ijrobp.2010.12.054. PubMed PMID: 21377284. 20. Shim SJ, Park W, Huh SJ, Choi DH, Shin KH, Lee NK, Suh CO, Keum KC, Kim YB, Ahn SD, Kim SS, Ha SW, Chie EK, Kim K, Shin HS, Kim JH, Lee HS. The role of postmastectomy radiation therapy after neoadjuvant chemotherapy in clinical stage II-III breast cancer patients with pN0: a multicenter, retrospective study (KROG 12-05). Int J Radiat Oncol Biol Phys. 2014;88(1):65-72. doi: 10.1016/j.ijrobp.2013.09.021. PubMed PMID: 24161425. 21. Taylor ME, Haffty BG, Rabinovitch R, Arthur DW, Halberg FE, Strom EA, White JR, Cobleigh MA, Edge SB. ACR appropriateness criteria on postmastectomy radiotherapy expert panel on radiation oncology-breast. Int J Radiat Oncol Biol Phys. 2009;73(4):997-1002. doi: 10.1016/j.ijrobp.2008.10.080. PubMed PMID: 19251087. 22. Bellon JR, Wong JS, Burstein HJ. Should response to preoperative chemotherapy affect radiotherapy recommendations after mastectomy for stage II breast cancer? J Clin Oncol. 2012;30(32):3916-20. doi: 10.1200/JCO.2012.44.3358. PubMed PMID: 23032626. 23. Beriwal S, Shinde A, Rajagopalan MS, Kannan N, Heron DE, Deutsch M. Recommendations for post-mastectomy radiation therapy after neo-adjuvant chemotherapy: an International Survey of Radiation Oncologists. Breast J. 2013;19(6):683-4. doi: 10.1111/tbj.12193. PubMed PMID: 24118536. 24. Hoffman KE, Mittendorf EA, Buchholz TA. Optimising radiation treatment decisions for patients who receive neoadjuvant chemotherapy and mastectomy. Lancet Oncol. 2012;13(6):e270-6. doi: 10.1016/S1470-2045(12)70038-4. PubMed PMID: 22652235. 25. Garg AK, Buchholz TA. Influence of neoadjuvant chemotherapy on radiotherapy for breast cancer. Ann Surg Oncol. 2015;22(5):1434-40. doi: 10.1245/s10434-015-4402-x. PubMed PMID: 25727554. 26. Fowble B, Park C, Wang F, Peled A, Alvarado M, Ewing C, Esserman L, Foster R, Sbitany H, Hanlon A. Rates of Reconstruction Failure in Patients Undergoing Immediate Reconstruction With Tissue Expanders and/or Implants and Postmastectomy Radiation Therapy. Int J Radiat Oncol Biol Phys. 2015;92(3):634-41. doi: 10.1016/j.ijrobp.2015.02.031. PubMed PMID: 25936815.
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27. Lam TC, Hsieh F, Boyages J. The effects of postmastectomy adjuvant radiotherapy on immediate two-stage prosthetic breast reconstruction: a systematic review. Plast Reconstr Surg. 2013;132(3):511-8. doi: 10.1097/PRS.0b013e31829acc41. PubMed PMID: 23676964. 28. Momoh AO, Ahmed R, Kelley BP, Aliu O, Kidwell KM, Kozlow JH, Chung KC. A systematic review of complications of implant-based breast reconstruction with prereconstruction and postreconstruction radiotherapy. Ann Surg Oncol. 2014;21(1):118-24. doi: 10.1245/s10434-013-3284-z. PubMed PMID: 24081801; PMCID: PMC4153348. 29. Garg AK, Oh JL, Oswald MJ, Huang E, Strom EA, Perkins GH, Woodward WA, Yu TK, Tereffe W, Meric-Bernstam F, Hahn K, Buchholz TA. Effect of postmastectomy radiotherapy in patients <35 years old with stage II-III breast cancer treated with doxorubicin-based neoadjuvant chemotherapy and mastectomy. Int J Radiat Oncol Biol Phys. 2007;69(5):1478-83. doi: 10.1016/j.ijrobp.2007.05.029. PubMed PMID: 17855016; PMCID: PMC4329785.
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Table 1
Patient, Tumor and Treatment Characteristics
No. patients Median follow-up Median age Initial clinical stage T stage N stage Clinical stage Histology
081 4.9 years (range 1.9-12.6) 45 years (range 21-75)
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T1 10% (8 pts,) T2 73% (59 pts), T3 17% (14 pts) N0 59% (48 pts) N1 41% (33 pts) I 7% (6 pts), IIA 49% (40 pts), IIB 28% (23 pts), IIIA 15% (12 pts) Invasive ductal 95% (77 pts), Invasive lobular 5% (4 pts) Grade 1-2 52% (42 pts), Grade 3 48% (39 pts) Lymphovascular invasion 7% (6 pts) HR+Her2- 41% (33 pts), HR+ Her2+ 26% (21 pts), HR-Her2- 23% (19 pts), HR- Her2+ 9% (7 pts) 26% positive (58 patients tested), BRCA1+ 11 patients, BRCA2+ 4 patients
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Receptor status BRCA status Surgery
Skin sparing mastectomy 21% (17 pts) Total skin sparing mastectomy 79% (74 pts) Expander/implant 89% (72 pts) Autologous tissue 11% (9 pts)
Reconstruction Axilla Clinical N0 Clinical N1
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Breast
SN surgery 98% (47 pts), AD 2% (1 patient) SN surgery 6% (2 pts), AD +/- SN surgery 94% (31 pts)
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AD= axillary dissection SN= sentinel node HR= hormone receptor (estrogen receptor and or progesterone receptor)
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Characteristics of Patients with Local-regional Recurrence (LRR)
34
39
42
42
45
48
60
1 0 IDC 2 -
2 0 IDC 3 -
2 0 IDC 2 -
2 0 ILC 1 -
2 1 IDC 2 -
2 0 IDC 3 -
2 0 IDC 2 -
2 1 IDC 2 +
+ + SN
+ + + SN
+ + + SN
+ + SN
+ + AD
+ + + SN
+ + SN
+ + + AD
2 0/3
Tis 0/1
1a 0/3
2 0/3
2 1/6
2 0/2
2 0/6
1a 1/8
Neg. CW 2.9
Neg. CW 2.1
Neg. CW 3.1
Neg. CW .3
Neg. CW 1.2
Neg. SCV 3
Neg. Neg. Axilla CW .6 3.2
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ILC= invasive lobular cancer CW= chest wall SN=sentinel node AD= axillary dissection
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IDC=invasive ductal cancer SCV= supraclavicular node
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31
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Patient age (yrs.) Clinical stage T N Histology Grade LVI Receptors ER PR Her2 Axillary surgery yp Stage T N Mastectomy Margin Location LRR Interval LRR yrs.
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Table 2
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Table 3
Post-mastectomy Local-regional Recurrence Related to Receptor Status and Pathologic Response to Treatment
6% (3/33) 25% (5/21) 0% (0/19) 0% (0/7) 8% (8/80*)
0% (0/8) 14% (1/7) 0% (0/13) 0% (0/7) 3% (1/35*)
12% (2/17) 31% (3/11) 0% (0/5)
0% (1/9) 33% (1/3) 0% (0/1)
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Receptor status HR+Her2HR+Her2+ HR-Her2HR-Her2+ All patients
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5 Year CI Local-regional Recurrence (crude rate) All patients pCR ypN0 ypN1-3+
16% (5/33)
10% (2/13)
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*Single patient unknown HR receptors, Her2- pCR
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Local-regional Recurrence Related to Age, Receptor Status and Pathologic Response to Treatment
Age (yrs.) Receptor status HR+Her2HR+Her2+ HR-Her2HR-Her2+ Pathologic response pCR ypN0 ypN1-3+ All patients
13% (3/16) 14% (1/8) 0% (0/7) 0% (0/1)
8.3% (1/12) 22% (2/10) 0% (0/3) 13% (3/25)
0% (0/12) 23% (3/13) 0% (1/7) 9% (4/32)
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0% (0/8) 42% (3/6) 0% (0/8 ) 0% (0/3)
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5 year CI Local-regional Recurrence (crude rate) ≤ 40 (N=25) 41-49 (N=32) ≥50 (N=24*) 0% (0/10) 16.7% (1/6) 0% (0/4) 0% (0/3)
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Table 4
0% (0/11) 0% (0/10) 33% (1/3) 4% (1/24)
pCR = pathologic complete response CI= cumulative incidence
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*Single patient unknown hormone receptors, Her2- pCR, age 64 yrs.
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LRR Rates Neoadjuvant Chemotherapy and Mastectomy without PMRT Single Institution and Clinical Trials Experience
Interval reported
12.5%
10 year CI
6.5% 6.3% 11.2% 11%
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0% 10.8% 17% 14%
10.4%^
Median follow-up Yrs. 11.75
5 year CI
3.5
Crude
4.2
11% 16% 20%
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NSABP B18+27(5) Stage II-IIIA 1122 Clinical T1-2N0 pCR 46 ypN0 178 ypN1 184 ypN1-3+ NS Clinical T1-2N1 pCR 21 ypN0 37 ypN1 143 NS ypN1-3+ CTNeoBC(6) Clinical stage I-III 2041 Gepar Trials(13, 14) Clinical stage I-III pCR 20 ypN0* 100 ypN1 45 MD Anderson(15, 18) Clinical stage II 132 pCR 25 ypN0 65 ypN1-3+ 42 Clinical stage I-III 297 University of Miami(16, 17) Clinical stage IIB 15 Clinical stage II-III Her2+ 25 René Huguenin(19) ypN0 Clinical stage II 44 Clinical stage III 12 KROG 12-05(20) ypN0 Clinical stage II-III 46
LRR
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No. pts.
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Table 5
10% 4% 5% 5% 8.1%
5 actuarial
3.8
Crude
4.2
0%
Crude
5.2
18%
Crude
3.6 7.6
7% 9%
5 actuarial 5 actuarial
6.5%
Crude
4.8
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81 35 33 13
8% 3% 16% 10%
5 year CI
4.9
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Present series Clinical stage I-III pCR ypN0 ypN1-3+
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CI= cumulative incidence ^ estimated one third of patients received PMRT *includes path CR NS= not stated
S1526-8209(17)30225-2
DOI:
10.1016/j.clbc.2017.07.016
Reference:
CLBC 660
To appear in:
Clinical Breast Cancer
Received Date: 20 April 2017 Revised Date:
18 May 2017
Accepted Date: 24 July 2017
Please cite this article as: Fowble B, Jairam AK, Wang F, Peled A, Alvarado M, Ewing C, Esserman L, Park C, Lazar A, Indications for Post-mastectomy Radiation (PMRT) Following Neoadjuvant Chemotherapy (NAC) in ypN0 and ypN1-3 Axillary Node Positive Women, Clinical Breast Cancer (2017), doi: 10.1016/j.clbc.2017.07.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title page Title: Indications for Post-mastectomy Radiation (PMRT) Following Neoadjuvant Chemotherapy (NAC) in ypN0 and ypN1-3 Axillary Node Positive Women
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Shortened title: Neoadjuvant chemotherapy and no PMRT Barbara Fowble MD, Department of Radiation Oncology, University of California, San Francisco; 1600 Divisadero Street, H1031, San Francisco, CA 94115, email: [email protected] Abhishek Keshav Jairam BA, Department of Radiation Oncology, University of California, San Francisco, 1600 Divisadero Street, H1031, San Francisco, CA 94115, email: [email protected]
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Frederick Wang MD, Division of Plastic and Reconstructive Surgery, University of California, San Francisco, Box 0470, 513 Parnassus Ave, 321, San Francisco, CA 94122, email: [email protected]
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Anne Peled MD, Division of Plastic and Reconstructive Surgery, University of California, San Francisco, Box 0470, 513 Parnassus Ave, 321, San Francisco, CA 94122, email: [email protected] Michael Alvarado MD, Carol Frank Buck Breast Care Center, Department of Surgery, University of California, San Francisco, Box 1710, 1600 Divisadero, B6-11, San Francisco, CA 94115, email: [email protected]
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Cheryl Ewing MD, Carol Frank Buck Breast Care Center, Department of Surgery, University of California, San Francisco, Box 1710, 1600 Divisadero, B6-35, San Francisco, CA 94115, email: [email protected], email: [email protected] Laura Esserman MD, MBA, Carol Frank Buck Breast Care Center, Department of Surgery, University of California, San Francisco, Box 1710, 1600 Divisadero, B6-35, San Francisco, CA 94115, email: [email protected]
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Catherine Park MD, Department of Radiation Oncology, University of California, San Francisco, 1600 Divisadero Street, H1031, San Francisco, CA 94115, email: [email protected]
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Ann Lazar PhD, MS, Department of Preventive and Restorative Dental Sciences, Department of Epidemiology and Biostatistics. University of California, San Francisco, Box 1361, 3333 California Street, 495H, San Francisco, CA 94118, email: [email protected] Corresponding author: Barbara Fowble MD, Department of Radiation Oncology, University of California San Francisco, 1600 Divisadero Street, H1031, San Francisco, CA 94115 Phone 415-353-9819, Fax 415353-9883; [email protected] None of the authors have any commercial interest or source of financial or material support for this retrospective study. Keywords: Neoadjuvant chemotherapy, post-mastectomy radiation
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MicroAbstract: This study evaluates local-regional recurrence rates (LRR) in 81 women with stage II-IIIA breast cancer who received neoadjuvant chemotherapy (NAC) followed by mastectomy and no radiation (PMRT). Pathologic complete response resulted in low LRR rates in all subtypes. Residual disease was predictive of high LRR in HR+ Her2+ women despite trastuzumab. This information may guide decisions for PMRT after NAC. Abstract
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Introduction: Downstaging with neoadjuvant chemotherapy (NAC) may obscure indications for PMRT. The degree of downstaging which results in local-regional recurrence (LRR) rates low enough to omit PMRT remains controversial. We examined the rate of LRR in women receiving NAC who underwent mastectomy without PMRT.
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Methods: Between 2004-2013 81 women with stage I-IIIA breast cancer had NAC and mastectomy. 59% were clinical N0 and 41% were clinical N1. Median age 45 years. 43% had HR+ Her2 –, 26% HR+Her2+, 23% HR-Her2- and 9% HR-Her2+ disease. We explored how LRR rates varied with age, BRCA status, grade, receptor status, clinical N status, pathologic response, LVI, and mastectomy margins. Median follow-up was 4.9 yrs.
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Results: Following NAC, 41% had a path CR, 43% were ypN0 and 16% were ypN1-3+. There were 8 LRR (6 chest wall, 1 axillary, 1 supraclavicular node). The 5 year cumulative incidence of LRR was 8% for all patients, 3% for path CR, 16% ypN0, 10% ypN1-3+, 6% HR+Her2-, 25% HR+Her2+, 0% HR-Her2-, and 0% HR-Her2+. LRR was 31% in the ypN0 and 33% in the ypN1-3+ HR+Her2+ women and 12% ypN0 and 0% ypN1-3+ HR+Her2- patients.
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Conclusions: This study is unique. All Her2+ patients received trastuzumab and LRR was analyzed by treatment response, clinicopathologic factors and receptor status. Path CR patients including young women and clinical stage IIIA had low LRR rates. However, ypN0 and ypN1-3+ HR+Her2+ patients had higher rates of LRR compared to other receptor subgroups and based on limited data should be considered for PMRT.
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Clinical Practice Points: Unlike the adjuvant systemic therapy setting, the role of post mastectomy radiation (PMRT) in patients with stage II-IIIA breast cancer receiving neoadjuvant chemotherapy (NAC) has not been established. There are no results from randomized trials. Current recommendations are based on single institution retrospective series or pooled analyses of chemotherapy clinical trials in which receptor status was not always reported and if known, not all Her2+ patients received anti-Her2 therapy. This study is unique in its assessment of local-regional recurrence (LRR) in a select group of women with stage II-IIIA breast cancer who did not receive PMRT and in which all Her2+ women received trastuzumab. New findings include low LRR rates for BRCA+ women, young women with a path CR, and hormone receptor positive (HR) Her2- women who were ypN1-3+. The absence of a path CR in HR+Her2+ women was associated with high LRR rates. Confirmatory findings include low rates of LRR for all subtypes with a path CR and ypN0 women except for those that were HR+Her2+. The study supports 2
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the NSABP B18 and B27 findings of low LRR in stage IIIA disease with a path CR and provides new and additional information that may serve as guide for decisions regarding PMRT. As higher rates of pCR are achieved with more effective systemic therapy, PMRT and its associated morbidity could be avoided in select patients.
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Introduction
Materials and methods Patients
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The use of neoadjuvant chemotherapy (NAC) once reserved for locally advanced breast cancer now includes stage II and IIIA disease. While providing an in vitro response to systemic therapy, it may also allow for a reduction in the extent of surgery (mastectomy and/or axillary dissection) and possibly the avoidance of post-mastectomy radiation (PMRT). Unlike the adjuvant chemotherapy setting(1), the role of PMRT in patients receiving NAC has not been established. There are no published results of randomized trials and the majority of studies have been single institution retrospective series.(2) Pathologic down-staging may include complete eradication of the primary cancer and/or axillary disease and thus obscure conventional indications for PMRT established in the adjuvant chemotherapy setting(3, 4). Debate centers on whether recommendations for PMRT should be based on pathologic response, initial clinical stage or both with proponents of each. An analysis of the NSABP B-18 and B-27 NAC trials identified initial clinical stage and response to therapy as significant predictors for localregional recurrence (LRR) in mastectomy patients, none of whom received PMRT.(5) Receptor status was not reported. A recent analysis of the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) correlated LRR in patients undergoing mastectomy with receptor status, histologic grade and response to treatment but not initial clinical stage.(6) While pathologic complete response (pCR) has been associated with improved survival, the association is strongest in triple negative and HER2+ hormone receptor (HR) negative patients receiving trastuzumab.(7, 8) However, for some subtypes the lack of a pCR is less predictive of clinical outcome.(7) Similarly, LRR rates may be low in all subtypes achieving a pCR but the absence of such a response may not always predict for high LRR rates. Therefore, recommendations for PMRT in some subtypes could result in overtreatment .We undertook a review of patients receiving NAC and mastectomy without PMRT to add to the existing limited literature and serve as a potential guide for treatment decisions until randomized trial data are reported.
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This retrospective review was approved by the [XXXXX] institutional review board. From 2004-2013, 81 of 304 women who received NAC followed by mastectomy did not receive PMRT. Clinical, pathologic and treatment characteristics are presented in Table 1. The median age was 45 years (range 21-75). Clinical stage was determined by a combination of physical examination and imaging (mammogram, ultrasound, breast MRI and computerized tomography +/- PET scans). Seventy-eight percent were clinical stage II (American Joint Committee of Cancer TNM Classification, 7th edition)(9) and 59% were clinically node negative based on imaging (axillary ultrasound and/or MRI or PET-CT). Confirmation of imaging positive axillary nodes was obtained by fine needle aspiration or core biopsy in 64% before NAC. The patients were categorized into 4 groups based on receptor status: HR+ (ER+ and/or PR+) and Her2-, HR+ and HER2+, HR- and Her2 - and HER2 positive and HR-. The majority had HR+ tumors and 38% were HER2+. Seventy-two percent had genetic testing and 26% were BRCA 1/2 positive (BRCA1+ 11 patients, BRCA2+ 4 patients). Four patients had invasive lobular cancers and 77 had invasive ductal cancers. Initial core biopsies identified 41% as grade 3 invasive cancers.
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Treatment
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All patients received NAC consisting of an anthracycline, a taxane or both. All HER2+ patients received neoadjuvant trastuzumab which was continued for a total of one year of treatment. No patient received pertuzumab. Seventeen patients participated in the I-SPY 1 or 2 trials(10, 11) and 10 patients received an investigational agent in addition to a taxane, doxorubicin and cyclophosphamide. All HR+ patients received adjuvant endocrine therapy for a minimum of 5 years.
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No patient had an axillary dissection (AD) or sentinel node (SN) surgery prior to NAC. Seventeen patients had skin sparing mastectomies and 64 had total nipple/areolar skin sparing mastectomies. Immediate reconstruction included expander/implant based reconstruction (72 patients), trans rectus abdominis myocutaneous flap reconstruction (5 patients) and deep inferior epigastric perforator flap reconstruction (4 patients). SN mapping was performed with Tc 99m sulfur colloid. SN surgery alone was performed in 98% of the clinical N0 patients. One clinical N0 patient had an AD. The median number of SN removed was 2 (range 1-6). AD was performed in 94% of the clinical node positive patients. The median number of nodes removed was 12 (range 3-25). Two clinical N1 patients had SN surgery without AD. Both were ypN0. Statistical analysis
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Follow-up was determined from the date of diagnosis. The median follow-up was 4.9 years (range 1.912.6 years). LRR was defined as recurrence in the ipsilateral chest wall, axilla, or internal mammary or supraclavicular nodes confirmed on imaging or biopsy. Cumulative incidence (CI) of LRR in the presence of a competing risk (distant recurrence) was estimated at 5 years.(12) Patients who did not have a LRR were censored at last follow-up. Survival was defined as time from diagnosis to death. Kaplan-Meier product limit estimator was used to estimate 5 year survival. We explored how LRR rates varied according to age, BRCA status, histologic grade, receptor status, clinical N status, response to treatment, the presence of lymphovascular invasion (LVI) and mastectomy margins. Small numbers in subgroups precluded analysis for statistical significance. Statistical analyses were performed using SAS version 9.4 and R CRAN cmprsk.
NAC response
Following NAC 43% of the patients had a pCR (no residual invasive cancer in the breast and negative axillary nodes). Thirteen patients with residual DCIS were included in the pCR group. Forty-one percent had residual disease in the breast with negative axillary nodes (ypN0) and 16% had positive axillary nodes (ypN1-3+). Ten patients had 1 positive node, 2 had 2 positive nodes and 1 patient had 3 positive nodes. No patient had ≥ 4 positive nodes. Micrometastases were identified in 2 women, macrometastases in 10 and isolated tumor cells in one patient. Sixty-seven percent of the clinical N1 patients had negative axillary nodes. A single clinical N0 patient had a positive axillary node (macrometastasis). The median size of residual invasive cancer in the breast was 1.5 cm (range < 1mm to 15.3 cm). None of the 47 patients with residual disease in the breast had a positive mastectomy 5
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margin for invasive cancer or DCIS. Two patients had a margin ≤ 2 mm for DCIS and 3 patients had a margin ≤ 2 mm for invasive cancer. Treatment outcome
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Eight patients developed a LRR (6 chest wall, 1 axillary and 1 supraclavicular node) with a median interval of 2.5 years (range 0.3-5.2). All were isolated without simultaneous distant metastases. Seven of the 8 LRR occurred within 3.1 years. The 5 year CI of a LRR was 8%. Table 2 presents characteristics of patients with LRR. The 2 LRR in ypN1 patients included one clinical N1 patient with 1/8 axillary nodes positive (isolated tumor cells) who had a supraclavicular recurrence at 3 years. The second clinical N1, ypN1 patient had 1/6 nodes positive (3.3 mm metastasis). She developed a chest wall recurrence at 5.2 years while on tamoxifen. Two of 33 patients (6%) with histologic grade 3 tumors developed a LRR compared to 6 of the 45 patients (13%) with grade 1-2 cancers. None of the 6 patients who developed a chest wall recurrence had a final close or positive mastectomy margin. One of six patients with lymphovascular invasion developed a LRR in a supraclavicular node. There was no correlation between LRR and initial clinical stage (12.5% stage IIA, 8.6% IIB, 0% IIIA). LRR developed in 2 of 33 (6%) clinical N1 and 6 of 48 (12.5%) clinical N0 patients.
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Table 3 presents 5 year CI of LRR related to receptor status and pathologic response. LRR was 3% for pCR patients, 16 % for ypN0 and 10% for ypN1. Of note, all LRR were in HR+ women and 5 of 8 were in the HR+Her2+ subgroup. None of the 9 clinical stage IIIA patients who had a path CR had a LRR. Table 4 presents 5 year CI of LRR related to age, receptor status and pathologic response. Seven of 8 LRR were in women < 50 years of age. LRR was 13% for women ≤ 40 years of age (25 patients), 9% for those 41-49 years (32 patients) and 4% for those ≥ 50 years (24 patients). Regardless of age, women who had a path CR had low LRR rates. There were no LRR in 15 BRCA carriers, eleven of whom had a path CR. Distant metastases and survival
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Distant metastases developed in 5 patients with a median interval of 5 years (range 1.2-5.1 yrs. ). One patient developed distant disease 3.9 years after a chest wall recurrence. Distant metastases occurred in 3 HR+Her2- patients, one HR+Her2+ patient and one HR-Her2+ patient. Three of the 5 patients with distant disease have died. The 5 year overall survival was 97%. Discussion
This single institution retrospective study includes a select group of primarily stage II patients who did not receive PMRT. While the study population seems small, the current literature assessing LRR in women receiving contemporary NAC with mastectomy and no PMRT is similarly limited in patient numbers.(2) Mamounas et al(5) reported LRR rates in 1071 mastectomy patients in the NSABP B-18 and B-27 trials. Receptor status was not reported and targeted therapies were not given. The pooled analysis of the CTNeoBC reported LRR in 2041 patients undergoing mastectomy.(6) Specific information on which patients received PMRT was lacking since criteria varied among the trials. Only 38% of Her2+ patients received trastuzumab. In a meta-analysis of 3 Gepar NAC randomized trials, 150 of the 1001 mastectomy patients did not receive PMRT.(13, 14) In the most recently reported series from MD 6
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Anderson(15) 297 of the 1041 (28.5%) mastectomy patients who received NAC did not receive PMRT. None of the Her2+ patients received trastuzumab. Diaz et al(16) reported LRR in 116 clinical stage IIB patients treated with NAC and mastectomy, 15 of whom did not receive PMRT. In a separate review of 142 patients with stage II-III Her2+ breast cancer treated with NAC (including trastuzumab) and mastectomy, 28 patients did not receive PMRT.(17) Therefore, our series appears to be the largest to date in which receptor status was known and all Her2+ patients received trastuzumab.
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Our 8% 5 year CI of LRR is comparable to other reported series (Table 5) (5, 6, 13-20). Similar to the findings of the CTNeoBC, LRR was not related to initial clinical stage or N stage.(6) Our series as well as others confirms the association of pCR with low LRR rates including stage IIIA patients.(5, 13-15, 18) While the magnitude of the risk that prompts a recommendation for PMRT may vary, it is generally accepted that risks < 10%-15% (4, 21-25) do not warrant treatment. Weighing the potential benefit of PMRT is particularly important for patients with implant based reconstruction since the risk of a complication including reconstruction failure may exceed the benefit of treatment.(26-28)
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Similar to the CTNeoBC, we found subtype as approximated by receptor status to predict for LRR.(6) With larger numbers of patients in the CTNeoBC but the receipt of PMRT uncertain and only 38% of Her2+ patients receiving trastuzumab, higher rates of LRR were observed in the ypN0 or N1 HR-Her2and HR-Her2+ patients. However, in our series the highest rates of LRR were observed in the HR+Her2+ women all of whom received trastuzumab and endocrine therapy. This finding suggests that residual disease in this subgroup treated with contemporary systemic therapy may have a greater impact on LRR. In contrast, LRR for the HR+Her2- women was low both for the ypN0 and ypN1-3+ subgroups.
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Age (< 50 vs. ≥50 yrs.) was not an independent predictor for LRR in mastectomy patients in the NSABP B18 and B-27 trials or the CTNeoBC pooled analysis.(5, 6) Garg et al reported a 31% 5 year LRR in 28 women ≤ 40 years of age with stage II disease who did not receive PMRT.(18) In another series of women < 35 yrs. from MD Anderson(29), LRR rates were 35% for 9 ypN0 women and 30% for 11 ypN13+ women who did not receive PMRT. Shim et al(20) identified age ≤ 40 as a significant factor for LRR free survival in 151 clinical stage II-III patients who were ypN0. In the present series the 5 year CI of LRR was 13% for women ≤ 40, 9% for those 41-49 and 4% for those ≥ 50 years (Table 4). The highest rate of LRR was in the HR+Her2+ women ≤ 40 years of age. Ours is the first series to report LRR rates (8.3%) in women ≤ 40 who had a pCR and did not receive PMRT. We did not identify a correlation with histologic grade, lymphovascular invasion or BRCA status and LRR. In the CTNeoBC pooled analysis, grade 3 HR+Her2- ypN1 patients had a higher rate of LRR than those with grade 1-2 tumors.(6) None of the patients in our series had positive mastectomy margins for DCIS or invasive cancer and none of the 6 chest wall recurrences occurred in women with margins ≤2 mm. Vila et al(15) correlated LRR rates in women receiving NAC with initial clinical stage (CS), pathologic stage (PS), estrogen receptor (E) and nuclear grade (G) (CPS+EG score). With a median follow-up of 4.25 years, 8.1% of the 297 patients who had mastectomy without PMRT (82% initial stage II) had a LRR. None of the Her2+ patients received trastuzumab. The authors noted that for clinical stage III or ypN1 patients there was no benefit to PMRT if the CPS+EG score was ≤2. This low score was driven primarily
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by low grade ER+ tumors. The investigators commented that they are revising the score to incorporate Her2 status and trastuzumab use.
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We recognize that the small numbers of patients in our subgroups and those in other series (table 5) preclude definitive conclusions. However, we report some important observations including the predominant pattern of LRR in the chest wall with most occurring within 3 years despite contemporary systemic therapy and negative mastectomy margins; the low rate of axillary recurrence with SNB in clinical N0, ypN0; the low rate of LRR in women who experience a pCR (including women ≤40 and initial stage IIIA) or are ypN0 (all subtypes except HR+Her2+), or are ypN1-3+ in the HR+Her2- subgroup. For HR+Her2+ tumors that are ypN0 or ypN1-3+ LRR rates were >20%. The recent PMRT guideline from the American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology(14) recommends PMRT for any ypN1 patient after NAC. The guideline does not acknowledge the contribution of receptor status, the extent of nodal disease or the CPS+EG score to LRR rates.
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Conclusions
There is a complex relationship between tumor subtype, treatment response and LRR in the setting of increasingly effective systemic therapy and as more patients fall into the pCR category, the opportunity to avoid PMRT may increase. The results of the NRG Oncology Group 9353 trial will provide additional information regarding the role of PMRT in T1-3N1 ypN0 (including pCR) women.
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References
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We acknowledge the significant contributions of our research associate Keith Sharee for data collection and editorial support.
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27. Lam TC, Hsieh F, Boyages J. The effects of postmastectomy adjuvant radiotherapy on immediate two-stage prosthetic breast reconstruction: a systematic review. Plast Reconstr Surg. 2013;132(3):511-8. doi: 10.1097/PRS.0b013e31829acc41. PubMed PMID: 23676964. 28. Momoh AO, Ahmed R, Kelley BP, Aliu O, Kidwell KM, Kozlow JH, Chung KC. A systematic review of complications of implant-based breast reconstruction with prereconstruction and postreconstruction radiotherapy. Ann Surg Oncol. 2014;21(1):118-24. doi: 10.1245/s10434-013-3284-z. PubMed PMID: 24081801; PMCID: PMC4153348. 29. Garg AK, Oh JL, Oswald MJ, Huang E, Strom EA, Perkins GH, Woodward WA, Yu TK, Tereffe W, Meric-Bernstam F, Hahn K, Buchholz TA. Effect of postmastectomy radiotherapy in patients <35 years old with stage II-III breast cancer treated with doxorubicin-based neoadjuvant chemotherapy and mastectomy. Int J Radiat Oncol Biol Phys. 2007;69(5):1478-83. doi: 10.1016/j.ijrobp.2007.05.029. PubMed PMID: 17855016; PMCID: PMC4329785.
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Table 1
Patient, Tumor and Treatment Characteristics
No. patients Median follow-up Median age Initial clinical stage T stage N stage Clinical stage Histology
081 4.9 years (range 1.9-12.6) 45 years (range 21-75)
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T1 10% (8 pts,) T2 73% (59 pts), T3 17% (14 pts) N0 59% (48 pts) N1 41% (33 pts) I 7% (6 pts), IIA 49% (40 pts), IIB 28% (23 pts), IIIA 15% (12 pts) Invasive ductal 95% (77 pts), Invasive lobular 5% (4 pts) Grade 1-2 52% (42 pts), Grade 3 48% (39 pts) Lymphovascular invasion 7% (6 pts) HR+Her2- 41% (33 pts), HR+ Her2+ 26% (21 pts), HR-Her2- 23% (19 pts), HR- Her2+ 9% (7 pts) 26% positive (58 patients tested), BRCA1+ 11 patients, BRCA2+ 4 patients
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Receptor status BRCA status Surgery
Skin sparing mastectomy 21% (17 pts) Total skin sparing mastectomy 79% (74 pts) Expander/implant 89% (72 pts) Autologous tissue 11% (9 pts)
Reconstruction Axilla Clinical N0 Clinical N1
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Breast
SN surgery 98% (47 pts), AD 2% (1 patient) SN surgery 6% (2 pts), AD +/- SN surgery 94% (31 pts)
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AD= axillary dissection SN= sentinel node HR= hormone receptor (estrogen receptor and or progesterone receptor)
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Characteristics of Patients with Local-regional Recurrence (LRR)
34
39
42
42
45
48
60
1 0 IDC 2 -
2 0 IDC 3 -
2 0 IDC 2 -
2 0 ILC 1 -
2 1 IDC 2 -
2 0 IDC 3 -
2 0 IDC 2 -
2 1 IDC 2 +
+ + SN
+ + + SN
+ + + SN
+ + SN
+ + AD
+ + + SN
+ + SN
+ + + AD
2 0/3
Tis 0/1
1a 0/3
2 0/3
2 1/6
2 0/2
2 0/6
1a 1/8
Neg. CW 2.9
Neg. CW 2.1
Neg. CW 3.1
Neg. CW .3
Neg. CW 1.2
Neg. SCV 3
Neg. Neg. Axilla CW .6 3.2
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ILC= invasive lobular cancer CW= chest wall SN=sentinel node AD= axillary dissection
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IDC=invasive ductal cancer SCV= supraclavicular node
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31
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Patient age (yrs.) Clinical stage T N Histology Grade LVI Receptors ER PR Her2 Axillary surgery yp Stage T N Mastectomy Margin Location LRR Interval LRR yrs.
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Table 2
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Table 3
Post-mastectomy Local-regional Recurrence Related to Receptor Status and Pathologic Response to Treatment
6% (3/33) 25% (5/21) 0% (0/19) 0% (0/7) 8% (8/80*)
0% (0/8) 14% (1/7) 0% (0/13) 0% (0/7) 3% (1/35*)
12% (2/17) 31% (3/11) 0% (0/5)
0% (1/9) 33% (1/3) 0% (0/1)
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Receptor status HR+Her2HR+Her2+ HR-Her2HR-Her2+ All patients
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5 Year CI Local-regional Recurrence (crude rate) All patients pCR ypN0 ypN1-3+
16% (5/33)
10% (2/13)
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HR=Hormone receptor pCR = pathologic complete response CI= cumulative incidence
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*Single patient unknown HR receptors, Her2- pCR
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Local-regional Recurrence Related to Age, Receptor Status and Pathologic Response to Treatment
Age (yrs.) Receptor status HR+Her2HR+Her2+ HR-Her2HR-Her2+ Pathologic response pCR ypN0 ypN1-3+ All patients
13% (3/16) 14% (1/8) 0% (0/7) 0% (0/1)
8.3% (1/12) 22% (2/10) 0% (0/3) 13% (3/25)
0% (0/12) 23% (3/13) 0% (1/7) 9% (4/32)
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HR=Hormone receptor
0% (0/8) 42% (3/6) 0% (0/8 ) 0% (0/3)
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5 year CI Local-regional Recurrence (crude rate) ≤ 40 (N=25) 41-49 (N=32) ≥50 (N=24*) 0% (0/10) 16.7% (1/6) 0% (0/4) 0% (0/3)
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Table 4
0% (0/11) 0% (0/10) 33% (1/3) 4% (1/24)
pCR = pathologic complete response CI= cumulative incidence
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*Single patient unknown hormone receptors, Her2- pCR, age 64 yrs.
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LRR Rates Neoadjuvant Chemotherapy and Mastectomy without PMRT Single Institution and Clinical Trials Experience
Interval reported
12.5%
10 year CI
6.5% 6.3% 11.2% 11%
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0% 10.8% 17% 14%
10.4%^
Median follow-up Yrs. 11.75
5 year CI
3.5
Crude
4.2
11% 16% 20%
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NSABP B18+27(5) Stage II-IIIA 1122 Clinical T1-2N0 pCR 46 ypN0 178 ypN1 184 ypN1-3+ NS Clinical T1-2N1 pCR 21 ypN0 37 ypN1 143 NS ypN1-3+ CTNeoBC(6) Clinical stage I-III 2041 Gepar Trials(13, 14) Clinical stage I-III pCR 20 ypN0* 100 ypN1 45 MD Anderson(15, 18) Clinical stage II 132 pCR 25 ypN0 65 ypN1-3+ 42 Clinical stage I-III 297 University of Miami(16, 17) Clinical stage IIB 15 Clinical stage II-III Her2+ 25 René Huguenin(19) ypN0 Clinical stage II 44 Clinical stage III 12 KROG 12-05(20) ypN0 Clinical stage II-III 46
LRR
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No. pts.
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Table 5
10% 4% 5% 5% 8.1%
5 actuarial
3.8
Crude
4.2
0%
Crude
5.2
18%
Crude
3.6 7.6
7% 9%
5 actuarial 5 actuarial
6.5%
Crude
4.8
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81 35 33 13
8% 3% 16% 10%
5 year CI
4.9
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Present series Clinical stage I-III pCR ypN0 ypN1-3+
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CI= cumulative incidence ^ estimated one third of patients received PMRT *includes path CR NS= not stated