Abstract
Introduction
Receipt of chemotherapy is associated with decreased satisfaction after breast surgery, but whether timing as adjuvant versus neoadjuvant (NAC) affects patient-reported outcomes (PROs) is unclear. We examined associations between chemotherapy timing and PROs after breast-conserving surgery (BCS) and mastectomy with immediate reconstruction (M-IR).
Methods
In this retrospective cohort study of patients with stage I-III breast cancer undergoing chemotherapy between 01/2017-12/2019, we compared satisfaction with breasts (SABTR) and chest physical well-being (PWB-CHEST) between chemotherapy groups in BCS and M-IR cohorts. Median SABTR and PWB-CHEST scores (scale 0-100) were compared between chemotherapy groups at baseline and for 3 years postoperatively. Factors associated with SABTR and PWB-CHEST at 1 and 2 years were assessed with multivariable linear regression.
Results
Overall, 640 patients had BCS and 602 had M-IR; 210 (33%) BCS patients and 294 (49%) M-IR patients had NAC. Following BCS, SABTR was higher than baseline at all postoperative timepoints, whereas 3-year SABTR remained similar to baseline following M-IR, independent of chemotherapy timing. In both surgical cohorts, PWB-CHEST was lowest after NAC at 6 months compared with baseline, but was similar to adjuvant counterparts by 3 years. NAC was not a statistically significant predictor of SABTR or PWB-CHEST in either surgical cohort on multivariable analysis.
Conclusions
For patients with breast cancer who require chemotherapy, neoadjuvant versus adjuvant timing does not impact long-term PROs in this study. These findings may inform shared decision making regarding the sequence of treatment in patients with operable disease.
Keywords: breast cancer, breast-conserving surgery, chemotherapy, patient-reported outcomes, mastectomy, breast reconstruction
Primary surgery has traditionally represented the standard approach for the treatment of early-stage breast cancer, and prospective trials have demonstrated equivalent survival following upfront mastectomy, breast-conserving surgery (BCS), and radiotherapy.1,2 Increasingly, neoadjuvant chemotherapy (NAC) is used to downstage the axilla and facilitate BCS in patients with large tumors relative to breast size.3,4 Additionally, valuable prognostic information can be inferred from the delivery of systemic therapy in the neoadjuvant setting, with improved overall and disease-free survival in patients who achieve a pathologic complete response (pCR) compared with patients who have residual disease.5 As neoadjuvant chemoimmunotherapy is becoming standard of care for most patients with triple negative and HER2+ tumors on the basis of recent landmark clinical trials,6-8 it is increasingly important to understand whether timing of chemotherapy impacts patient-reported outcomes (PROs).
For patients with operable breast cancer who require chemotherapy on the basis of underlying tumor biology, National Comprehensive Cancer Network guidelines recommend NAC consideration based on patient-level factors, including desire for breast conservation,9 thus highlighting an important role for shared decision making in the provision of guideline-concordant care. In this setting, PROs are increasingly used as metrics of meaningful postoperative outcomes and have become important benchmarks for high-value breast cancer care.10,11 The BREAST-Q survey is a widely utilized, validated measure of breast satisfaction and health-related quality of life post-breast surgery that is approved by the Center for Medicare and Medicaid Services as a quality-performance measure.12-14
Prior evidence suggests that satisfaction with breasts (SABTR) measured by the BREAST-Q is superior post-BCS compared with mastectomy and immediate reconstruction (M-IR).15-18 Independent of surgical procedure, associations between chemotherapy, SABTR, and physical well-being of the chest (PWB-CHEST) are less well-defined.15,18,19 Among patients treated with mastectomy and implant-based or autologous reconstruction, NAC receipt has been reported to be an independent predictor of decreased SABTR compared with no chemotherapy20; however, data are lacking regarding the impact of chemotherapy sequencing with respect to surgery on PROs among patients who require systemic therapy. Here we assess relationships between chemotherapy timing and PROs after BCS and M-IR, respectively.
METHODS
Study Population/Design
Upon Memorial Sloan Kettering Cancer Center institutional review board (IRB) approval, we performed a retrospective cohort study to assess PROs in patients with stage I-III primary breast cancer treated with chemotherapy and breast surgery, including BCS and M-IR. Patients who had delayed or no reconstruction after mastectomy, and who did not require systemic chemotherapy were excluded. Consecutive patients who had surgery between 01/01/2017-12/31/2019, and who completed at least 1 BREAST-Q survey through 12/31/2020 were included. Patients undergoing BCS and M-IR were analyzed as separate cohorts.
Data Collection
The BREAST-Q survey was routinely administered electronically to all patients undergoing BCS and M-IR during the study period as part of routine clinical care. We collected data from surveys administered preoperatively, and 6 months, 1 year, 2 years, and 3 years postoperatively. Clinicopathologic and treatment data were collected from an institutional tumor registry and medical records. Complete BREAST-Q data were obtained from an institutional database in 01/2021.
Patient Variables
Demographic and clinicopathologic data, including age at surgery, race/ethnicity, BMI, clinicopathologic tumor/nodal stage, receptor subtype, histology, breast pCR presence (defined as no residual invasive tumor in the breast specimen post-NAC), axillary surgery, and radiotherapy receipt were collected. Among patients who had M-IR, additional information was obtained from operative reports, including performance of contralateral prophylactic mastectomy (CPM), reconstruction laterality, final reconstruction type (permanent implant/autologous) among patients undergoing 2-stage reconstruction with tissue expanders (TEs), and postoperative complication occurrence requiring unplanned reoperation/hospitalization at any postmastectomy timepoint. Complications were determined by review of the treating surgeon’s documentation and operative reports, and included TE infection with/without removal, mastectomy skin flap tissue loss with/without permanent implant loss, breast cellulitis/abscess, hematoma, and autologous vascular anastomosis revision.
Questionnaire and Outcomes
BREAST-Q survey subscales measuring SATBR and PWB-CHEST were assessed separately in BCS and M-IR cohorts as cross-sectional analyses of prospectively collected data. The SABTR subscale measures satisfaction with breast size, bra fit, and appearance clothed and unclothed. The PWB-CHEST subscale measures pain, tightness, and difficulty with mobility including arm lifting. We compared median SATBR and PWB-CHEST scores between patients treated with NAC and adjuvant chemotherapy in BCS and M-IR cohorts, respectively, from preoperative baseline to 3 years postoperatively. Higher scores on a 0-100 scale indicated superior satisfaction. A minimum 3-point and 4-point difference was considered clinically important for PWB-CHEST and SABTR, respectively.21 Median (interquartile range [IQR]) scores were reported for the overall BCS and M-IR cohorts, and for NAC and adjuvant groups within each cohort at baseline, 6 months, 1 year, 2 years, and 3 years postoperatively.
Statistical Analysis
Baseline characteristics were compared between NAC and adjuvant groups in BCS and M-IR cohorts, respectively, using Fisher’s exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables. Available BREAST-Q data at all timepoints were included in the analysis. Factors associated with SABTR and PWB-CHEST at 1 and 2 years were assessed with univariate linear regression in BCS and M-IR cohorts, respectively. Chemotherapy timing and all statistically significant variables in univariable analyses (P<0.05) were included as predictors in multivariable linear regression models to assess SABTR and PWB-CHEST at 1 and 2 years in BCS and M-IR cohorts. To adjust for multiple comparisons, a Bonferroni correction was applied to the results of multivariable analysis (MVA). Type I error rate (α) was set to 0.0125. All statistical analyses were conducted using R software (Version 3.6.3, R Core Development Team, Vienna, Austria).
RESULTS
Patient/Treatment Characteristics
The study included 640 patients who had BCS and 602 who had M-IR; all required systemic chemotherapy as part of their oncologic treatment. Two hundred ten (33%) patients received NAC in the BCS cohort, 294 (49%) received NAC in the M-IR cohort. Patients who received NAC were younger than those who received adjuvant chemotherapy in both BCS (54 versus 57 years; P<0.001) and M-IR (46 versus 48 years; P=0.039) cohorts (Table 1). Most patients identified as White/Hispanic or Non-Hispanic in the BCS (76%) and M-IR (73%) cohorts. In the BCS cohort, patients who received NAC more frequently identified as Black/Hispanic or Non-Hispanic versus the adjuvant group (19% versus 6.8%; P<0.001).
TABLE 1.
Patient and tumor characteristics by chemotherapy group in BCS and M-IR cohorts
BCS breast-conserving surgery, MI-R immediate reconstruction, IQR interquartile range, NAC neoadjuvant chemotherapy, BMI body mass index, IDC invasive ductal carcinoma, ILC invasive lobular carcinoma, HR hormone receptor, pCR pathologic complete response, ALND axillary lymph node dissection, SLNB sentinel lymph node biopsy
| Characteristic | BCS | M-IR | ||||||
|---|---|---|---|---|---|---|---|---|
| Overall (n=640) |
Adjuvant (n=430) |
NAC (n=210) |
P value | Overall (n=602) |
Adjuvant (n=308) |
NAC (n=294) |
P value | |
| Age at surgery, median (IQR) | 56 (47, 64) | 57 (48, 64) | 54 (42, 63) | <0.001 | 47 (40, 54) | 48 (41, 54) | 46 (39, 53) | 0.039 |
| Race/ethnicity, n (%) | <0.001 | 0.7 | ||||||
| White (Hispanic or Non-Hispanic) | 466 (76) | 336 (82) | 130 (64) | 424 (73) | 219 (74) | 205 (72) | ||
| Black Hispanic or Non-Hispanic) | 66 (11) | 28 (6.8) | 38 (19) | 57 (9.8) | 29 (9.8) | 28 (9.9) | ||
| Asian | 54 (8.8) | 34 (8.3) | 20 (9.9) | 68 (12) | 36 (12) | 32 (11) | ||
| Other race | 28 (4.6) | 14 (3.4) | 14 (6.9) | 32 (5.5) | 13 (4.4) | 19 (6.7) | ||
| Unknown | 26 | 18 | 8 | 21 | 11 | 10 | ||
| Marital status, n (%) | 0.012 | 0.4 | ||||||
| Married/partnered | 430 (68) | 298 (70) | 132 (64) | 443 (75) | 230 (75) | 213 (74) | ||
| Divorced/separated | 72 (11) | 51 (12) | 21 (10) | 36 (6.1) | 17 (5.6) | 19 (6.6) | ||
| Single | 106 (17) | 57 (13) | 49 (24) | 109 (18) | 57 (19) | 52 (18) | ||
| Widowed | 22 (3.5) | 17 (4.0) | 5 (2.4) | 6 (1.0) | 1 (0.3) | 5 (1.7) | ||
| Unknown | 10 | 7 | 3 | 8 | 3 | 5 | ||
| BMI, n (%) | 0.061 | 0.6 | ||||||
| <18.5 | 10 (1.6) | 4 (0.9) | 6 (2.9) | 9 (1.5) | 3 (1.0) | 6 (2.0) | ||
| 18.5-24.9 | 220 (34) | 145 (34) | 75 (36) | 267 (44) | 134 (44) | 133 (45) | ||
| 25-29.9 | 185 (29) | 118 (27) | 67 (32) | 192 (32) | 103 (33) | 89 (30) | ||
| ≥30 | 225 (35) | 163 (38) | 62 (30) | 134 (22) | 68 (22) | 66 (22) | ||
| Clinical T, n (%) | <0.001 | <0.001 | ||||||
| Tis | 7 (1.1) | 7 (1.6) | 0 (0) | 21 (3.5) | 20 (6.5) | 1 (0.3) | ||
| T1 | 396 (62) | 347 (81) | 49 (23) | 211 (35) | 157 (51) | 54 (18) | ||
| T2 | 221 (35) | 76 (18) | 145 (69) | 279 (46) | 113 (37) | 166 (56) | ||
| T3 | 14 (2.2) | 0 (0) | 14 (6.7) | 82 (14) | 18 (5.9) | 64 (22) | ||
| T4 | 2 (0.3) | 0 (0) | 2 (1.0) | 9 (1.5) | 0 (0) | 9 (3.1) | ||
| Clinical N, n (%) | <0.001 | <0.001 | ||||||
| N0 | 519 (81) | 420 (98) | 99 (47) | 383 (64) | 294 (95) | 89 (30) | ||
| N1 | 114 (18) | 9 (2.1) | 105 (50) | 210 (35) | 14 (4.6) | 196 (67) | ||
| N2-3 | 7 (1.1) | 1 (0.2) | 6 (2.9) | 9 (1.5) | 0 (0) | 9 (3.1) | ||
| Histology, n (%) | 0.2 | <0.001 | ||||||
| IDC | 553 (86) | 367 (85) | 186 (89) | 502 (83) | 233 (76) | 269 (91) | ||
| ILC | 35 (5.5) | 29 (6.7) | 6 (2.9) | 58 (9.6) | 52 (17) | 6 (2.0) | ||
| Mixed | 33 (5.2) | 23 (5.3) | 10 (4.8) | 30 (5.0) | 17 (5.5) | 13 (4.4) | ||
| Other | 19 (3.0) | 11 (2.6) | 8 (3.8) | 12 (2.0) | 6 (1.9) | 6 (2.0) | ||
| Subtype, n (%) | <0.001 | <0.001 | ||||||
| HR+/HER2− | 320 (50) | 250 (58) | 70 (33) | 337 (56) | 202 (66) | 135 (46) | ||
| HER2+ | 174 (27) | 108 (25) | 66 (31) | 185 (31) | 76 (25) | 109 (37) | ||
| HR−/HER2− | 146 (23) | 72 (17) | 74 (35) | 80 (13) | 30 (9.7) | 50 (17) | ||
| Pathologic T, n (%) | <0.001 | <0.001 | ||||||
| Tis/T0 | 70 (11) | 0 (0) | 70 (33) | 80 (13) | 0 (0) | 80 (27) | ||
| T1 | 401 (63) | 296 (69) | 105 (50) | 303 (50) | 154 (50) | 149 (51) | ||
| T2 | 166 (26) | 133 (31) | 33 (16) | 174 (29) | 122 (40) | 52 (18) | ||
| T3 | 3 (0.5) | 1 (0.2) | 2 (1.0) | 44 (7.3) | 31 (10) | 13 (4.4) | ||
| T4 | 0 (0) | 0 (0) | 0 (0) | 1 (0.2) | 1 (0.3) | 0 (0) | ||
| Pathologic N, n (%) | 0.003 | 0.077 | ||||||
| N0 | 448 (70) | 297 (69) | 151 (72) | 311 (52) | 158 (51) | 153 (52) | ||
| N1 | 168 (26) | 124 (29) | 44 (21) | 194 (32) | 110 (36) | 84 (29) | ||
| N2 | 21 (3.3) | 8 (1.9) | 13 (6.2) | 72 (12) | 28 (9.1) | 44 (15) | ||
| N3 | 3 (0.5) | 1 (0.2) | 2 (1.0) | 25 (4.2) | 12 (3.9) | 13 (4.4) | ||
| pCR, n (%) | 68 (32) | n/a | 68 (32) | n/a | 79 (27) | n/a | 79 (27) | n/a |
| Axillary surgery, n (%) | <0.001 | 0.2 | ||||||
| ALND | 66 (10) | 12 (2.8) | 54 (26) | 273 (45) | 131 (43) | 142 (48) | ||
| SLNB | 574 (90) | 418 (97) | 156 (74) | 329 (55) | 177 (57) | 152 (52) | ||
| Radiotherapy, n (%) | 631 (99) | 425 (99) | 206 (98) | 0.5 | 331 (55) | 129 (42) | 202 (69) | <0.001 |
In both cohorts, patients who received NAC were more likely to have higher clinical T and N stage tumors, and HER2+ or triple negative subtypes. Among patients who received NAC, the pCR rate was 32% (n=68) in the BCS cohort and 27% (n=79) in the M-IR cohort. Most patients (n=631; 99%) in the BCS cohort received radiotherapy independent of chemotherapy timing, whereas in the M-IR cohort, a higher proportion of patients had radiotherapy in the NAC group versus the adjuvant group (69% versus 42%; P<0.001).
In the M-IR cohort, 51% of patients (n=310) had immediate bilateral reconstruction (Table 2); 290 (94%) underwent CPM and the remaining 20 had reconstruction for bilateral breast cancer. Overall, most patients (n=552; 92%) had immediate TEs, 7.3% (n=44) had immediate autologous reconstruction, and 1.0% (n=6) had an immediate permanent implant placed. A higher proportion of patients who received NAC underwent CPM (55% versus 42%; P=0.002). Among M-IR patients, complications occurred in 20% (n=120), with similar frequency between NAC and adjuvant groups (21% versus 19%; P=0.7).
TABLE 2.
Characteristics of postmastectomy reconstruction by chemotherapy group
NAC neoadjuvant chemotherapy, CPM contralateral prophylactic mastectomy
| Overall (n=602) |
Adjuvant (n=308) |
NAC (n=294) |
P value | |
|---|---|---|---|---|
| CPM, n (%) | 290 (48) | 129 (42) | 161 (55) | 0.002 |
| Laterality of reconstruction, n (%) | 0.005 | |||
| Bilateral | 310 (51) | 141 (46) | 169 (57) | |
| Unilateral | 292 (49) | 167 (54) | 125 (43) | |
| Type of immediate reconstruction, n (%) | <0.001 | |||
| Tissue expander | 552 (92) | 271 (88) | 281 (96) | |
| Autologous | 44 (7.3) | 35 (11) | 9 (3.1) | |
| Permanent implant | 6 (1.0) | 2 (0.6) | 4 (1.4) | |
| Second stage reconstruction, n (%) | 0.10 | |||
| Permanent implant | 454 (82) | 231 (85) | 223 (79) | |
| Autologous | 77 (14) | 29 (11) | 48 (17) | |
| None | 21 (3.8) | 11 (4.1) | 10 (3.6) | |
| Reconstruction complications, n (%) | 120 (20) | 59 (19) | 61 (21) | 0.7 |
| Timing of complication, n (%) | <0.001 | |||
| After radiation | 34 (28) | 8 (14) | 26 (43) | |
| Before radiation | 38 (32) | 15 (25) | 23 (38) | |
| Not applicable (no radiation) | 48 (40) | 36 (61) | 12 (20) | |
| Mastectomy skin flap loss, n (%) | 46 (7.6) | 22 (7.1) | 24 (8.2) | 0.8 |
| Breast cellulitis or abscess, n (%) | 38 (6.3) | 20 (6.5) | 18 (6.1) | >0.9 |
| Hematoma, n (%) | 36 (6.0) | 19 (6.2) | 17 (5.8) | >0.9 |
| Tissue expander loss, n (%) | 45 (8.2) | 22 (8.1) | 23 (8.2) | >0.9 |
| Permanent implant loss, n (%) | 16 (3.5) | 7 (3.0) | 9 (4.0) | 0.8 |
| Vascular anastomosis revision, n (%) | 2 (1.6) | 2 (3.1) | 0 (0) | 0.5 |
BREAST-Q Outcomes: BCS
Median (IQR) scores for SABTR and PWB-CHEST in the BCS cohort are shown in Table 3. Survey response rates were highest at 1 year (n=472; 74%) and 2 years (n=353; 55%). Post-BCS, SATBR scores were above baseline at all postoperative timepoints, independent of chemotherapy timing (Figure 1A). At 3 years postoperatively, median (IQR) SATBR was 72 (59, 100) in the adjuvant group and 66 (55, 82) in the NAC group, representing a small but clinically meaningful difference between groups. At 6 months postoperatively, median PWB-CHEST scores were lower following NAC compared with adjuvant chemotherapy relative to baseline (19- and 3-point differences, respectively), but the observed difference in scores between groups was attenuated at 1 year. PWB-CHEST scores remained below baseline at 3 years in both adjuvant and NAC groups (8- and 10-point differences, respectively); but the difference between groups was not clinically meaningful. (Figure 1B). Notably, we did not make direct statistical comparisons between timepoints.
TABLE 3.
Median (IQR) SABTR and PWB-CHEST scores in the BCS and MI-R cohorts
IQR interquartile range, SABTR satisfaction with breasts, PWB-CHEST physical well-being of the chest, BCS breast-conserving surgery, NAC neoadjuvant chemotherapy, M-IR immediate reconstruction
| BCS Cohort | ||||||
|---|---|---|---|---|---|---|
| SABTR | PWB-CHEST | |||||
| Overall (n=640) |
NAC (n=210) |
Adjuvant (n=430) |
Overall (n=640) |
NAC (n=210) |
Adjuvant (n=430) |
|
| Preoperative | 58 (48, 82) | 58 (46, 61) | 58 (48, 82) | 85 (68, 100) | 85 (74, 96) | 85 (68, 100) |
| 6 months | 78 (63, 100) | 75 (61, 97) | 78 (65, 100) | 76 (60, 89) | 66 (52, 80) | 76 (66, 89) |
| 1 year | 75 (63, 100) | 72 (56, 91) | 75 (63, 100) | 71 (60, 82) | 66 (58, 82) | 76 (60, 89) |
| 2 years | 72 (59, 100) | 67 (55, 88) | 75 (59, 100) | 76 (60, 89) | 71 (60, 82) | 76 (60, 89) |
| 3 years | 72 (59, 100) | 69 (55, 82) | 72 (59, 100) | 76 (66, 89) | 74 (60, 89) | 76 (66, 89) |
| M-IR Cohort | ||||||
| SABTR | PWB-CHEST | |||||
| Overall (n=602) |
NAC (n=294) |
Adjuvant (n=308) |
Overall (n=602) |
NAC (n=294) |
Adjuvant (n=308) |
|
| Preoperative | 58 (48, 79) | 58 (48, 71) | 58 (48, 79) | 85 (74, 100) | 91 (77, 100) | 80 (72, 92) |
| 6 months | 58 (48, 71) | 58 (44, 65) | 58 (49, 71) | 68 (56, 80) | 68 (55, 80) | 72 (59, 80) |
| 1 year | 60 (51, 71) | 58 (51, 71) | 62 (52, 71) | 72 (60, 85) | 68 (55, 80) | 72 (60, 85) |
| 2 years | 58 (48, 69) | 57 (48, 66) | 61 (48, 71) | 76 (60, 85) | 72 (55, 85) | 76 (60,92) |
| 3 years | 58 (52, 71) | 57 (49, 71) | 59 (53, 71) | 76 (59, 85) | 72 (55, 84) | 76 (60, 90) |
Fig. 1.
Median (IQR) (A) SABTR Scores and (B) PWB-CHEST Scores in the BCS Cohort; Median (IQR) (C) SABTR Scores and (D) PWB-CHEST Scores in the M-IR
Cohort IQR interquartile range, SABTR satisfaction with breasts, PWB-CHEST physical well-being of the chest, BCS breast-conserving surgery, MI-R immediate reconstruction
On univariate analysis (UVA) of BCS patients, NAC receipt was associated with decreased SABTR at 1 year (β, −4.2; 95% confidence interval [CI] −8.0, −0.27; P=0.036); however, this association was not statistically significant on MVA (Table 4). Increasing age was an independent predictor of higher SABTR at 1 year (β, 0.28; 95% CI 0.11, 0.46; P=0.002) but not at 2 years postoperatively (P=0.2). Race/ethnicity was not associated with SABTR at either postoperative timepoint, nor were clinicopathologic or axillary surgical factors.
TABLE 4.
Multivariable linear regression of factors associated with 1- and 2-year SABTR and PWB-CHEST in the BCS cohort
*Bonferroni p-value correction <0.0125 considered statistically significant
SABTR satisfaction with breasts, PWB-CHEST physical well-being of the chest, BCS breast-conserving surgery, CI confidence interval, NAC neoadjuvant chemotherapy, ILC invasive lobular carcinoma, ALND axillary lymph node dissection, SLNB sentinel lymph node biopsy
| Characteristic | 1 year | 2 years | ||||
|---|---|---|---|---|---|---|
| β | 95% CI | P value* | β | 95% CI | P value* | |
| SABTR | ||||||
| Chemotherapy timing (ref=adjuvant) | ||||||
| NAC | −0.23 | −5.1, 4.6 | >0.9 | — | — | — |
| Age at surgery | 0.28 | 0.11, 0.46 | 0.002 | 0.12 | −0.07, 0.30 | 0.2 |
| Race/ethnicity (ref=White/Hispanic or Non-Hispanic) | ||||||
| Black/Hispanic or Non-Hispanic | −6.9 | −13, −0.62 | 0.032 | −5.8 | −12, 0.75 | 0.083 |
| Asian | 0.80 | −5.5, 7.1 | 0.8 | −0.52 | −8.2, 7.1 | 0.9 |
| Other | 0.62 | −8.8, 10 | 0.9 | −6.6 | −17, 4.2 | 0.2 |
| Clinical T stage (ref=T1) | ||||||
| T2 | −4.0 | −8.6, 0.63 | 0.091 | −0.91 | −5.2, 3.4 | 0.7 |
| T3 | −12 | −25, 1.9 | 0.092 | −10 | −24, 3.7 | 0.2 |
| Tis | 1.4 | −21, 24 | 0.9 | 19 | −4.9, 42 | 0.12 |
| Histology (ref=IDC) | ||||||
| ILC | 9.4 | 1.7, 17 | 0.017 | — | — | — |
| Mixed | −3.6 | −13, 5.7 | 0.5 | — | — | — |
| Other | −0.02 | −9.9, 9.8 | >0.9 | — | — | — |
| Path N stage (ref=N0) | ||||||
| N1 | — | — | — | −2.9 | −7.5, 1.7 | 0.2 |
| N2 | — | — | — | −7.0 | −20, 5.7 | 0.3 |
| N3 | — | — | — | 13 | −18, 43 | 0.4 |
| Axillary surgery (ref=ALND) | ||||||
| SLNB | — | — | — | 4.5 | −3.9, 13 | 0.3 |
| PWB-CHEST | ||||||
| Chemotherapy timing (ref=adjuvant) | ||||||
| NAC | −1.7 | −6.4, 3.0 | 0.5 | — | — | — |
| Age at surgery | 0.25 | 0.09, 0.41 | 0.003 | 0.30 | 0.14, 0.46 | <0.001 |
| Race/ethnicity (ref=White/Hispanic or Non-Hispanic) | ||||||
| Black/ Hispanic or Non-Hispanic | −9.5 | −15, −3.7 | 0.001 | −9.0 | −14, −3.6 | 0.001 |
| Asian | −2.8 | −8.4, 2.7 | 0.3 | −5.6 | −12, 1.0 | 0.10 |
| Other | −7.8 | −17, 1.0 | 0.083 | −12 | −21, −3.0 | 0.009 |
| Marital status (ref=married/partnered) | ||||||
| Divorced/separated | −0.53 | −5.7, 4.6 | 0.8 | — | — | — |
| Single | −4.1 | −9.2, 0.89 | 0.11 | — | — | — |
| Widowed | 3.2 | −6.2, 13 | 0.5 | — | — | — |
| Clinical T stage (ref=T0) | ||||||
| T2 | — | — | — | 2.1 | −1.5, 5.8 | 0.3 |
| T3 | — | — | — | −8.3 | −20, 3.5 | 0.2 |
| Tis | — | — | — | 4.7 | −15, 25 | 0.6 |
| Clinical N stage (ref=N0) | ||||||
| N1 | −0.56 | −6.5, 5.4 | 0.9 | −2.3 | −7.4, 2.7 | 0.4 |
| N2-3 | −1.8 | −18, 14 | 0.8 | 1.5 | −23, 26 | >0.9 |
| Path N stage (ref=N0) | ||||||
| N1 | −3.0 | −7.0, 1.0 | 0.14 | −3.7 | −7.7, 0.23 | 0.066 |
| N2 | −9.8 | −19, 0.43 | 0.041 | −15 | −26, −3.9 | 0.08 |
| N3 | −13 | −37, 11 | 0.3 | −12 | −37, 14 | 0.4 |
| Axillary surgery (ref=ALND) | ||||||
| SLNB | — | — | — | 0.25 | −7.1, 7.6 | >0.9 |
On UVA of BCS patients, NAC receipt was associated with decreased PWB-CHEST at 1 year (β, −3.7 95% CI −7.3, −0.05; P=0.047); however, this association was not statistically significant on MVA (Table 4). Increasing age was associated with higher PWB-CHEST at 1 year (β, 0.25; 95% CI 0.09, 0.41; P=0.003) and 2 years (β, 0.37; 95% CI 0.14, 0.46; P<0.001). Black/Hispanic or Non-Hispanic race/ethnicity was associated with decreased PWB-CHEST at both postoperative timepoints (1 year: β, −9.5; 95% CI −15, −3.7; P=0.001, and 2 years: β, −9.0; 95% CI −14, −3.6; P=0.001), as was identification as other race/ethnicity at 2 years (β, −12; 95% CI −21, −3.0; P=0.009).
BREAST-Q Outcomes: M-IR
Median (IQR) scores for SABTR and PWB-CHEST in the M-IR cohort are shown in Table 3. Survey response rate was highest at 1 year (n=480; 80%) and 2 years (n=313; 52%). In the NAC group, median SABTR scores remained stable compared with baseline at all postoperative timepoints. In the adjuvant group, median SABTR fell 10 points below baseline at 6 months, but surpassed baseline by 3 years. Median PWB-CHEST scores were lower than baseline at all postoperative timepoints in both chemotherapy groups (Figure 1C-D).
Among M-IR patients, NAC receipt was not statistically significantly associated with SABTR at either postoperative timepoint (Table 5). Radiotherapy receipt (β, −13; 95% CI −18, −7.5; P<0.001) was independently associated with decreased SABTR at 2 years. Obesity (BMI≥30) was associated with decreased SABTR at 1 year (β, −24; 95% CI −40, −7.6; P=0.004), but not at 2 years.
TABLE 5.
Multivariable linear regression of factors associated with 1- and 2-year SABTR and PWB-CHEST in the M-IR cohort
*Bonferroni p-value correction <0.0125 considered statistically significant
SABTR satisfaction with breasts, PWB-CHEST physical well-being of the chest, M-IR immediate reconstruction, CI confidence interval, NAC neoadjuvant chemotherapy, BMI body mass index, HR hormone receptor, ALND axillary lymph node dissection, SLNB sentinel lymph node biopsy
| Characteristic | 1 year | 2 years | ||||
|---|---|---|---|---|---|---|
| β | 95% CI | P-value* | β | 95% CI | P-value* | |
| SABTR | ||||||
| BMI (ref ≤18.5) | ||||||
| 18.5-24.9 | −18 | −34, −2.8 | 0.020 | — | — | — |
| 25-29.9 | −19 | −35, −3.0 | 0.020 | — | — | — |
| ≥30 | −24 | −40, −7.6 | 0.004 | — | — | — |
| Subtype (ref=HER2+) | ||||||
| HR+/HER2− | −3.2 | −8.3, 1.8 | 0.2 | — | — | — |
| HR−/HER2− | 0.19 | −6.5, 6.9 | >0.9 | — | — | — |
| Path N stage (ref=N0) | ||||||
| N1 | −2.4 | −9.8, 5.1 | 0.5 | −3.3 | −8.5, 2.0 | 0.2 |
| N2 | 3.7 | −6.6, 14 | 0.5 | 4.9 | −2.0, 12 | 0.2 |
| N3 | 9.7 | −3.5, 23 | 0.2 | 4.1 | −7.2, 15 | 0.5 |
| Axillary surgery (ref=ALND) | ||||||
| SLNB | 1.7 | −4.5, 8.0 | 0.6 | — | — | — |
| Radiotherapy (ref=no) | ||||||
| Yes | −5.0 | −11, 0.62 | 0.082 | −13 | −18, −7.5 | <0.001 |
| Second-stage reconstruction (ref=none) | ||||||
| Autologous | — | — | — | 32 | 6.9, 57 | 0.013 |
| Permanent implant | — | — | — | 28 | 3.4, 53 | 0.027 |
| Complication (ref=no) | ||||||
| Yes | — | — | — | −6.0 | −11, −1.0 | 0.019 |
| PWB-CHEST | ||||||
| Chemotherapy timing (ref=adjuvant) | ||||||
| NAC | −0.49 | −5.4, 4.4 | 0.8 | — | — | — |
| Marital status (ref=married/partnered) | ||||||
| Divorced/separated | −1.5 | −9.0, 6.1 | 0.7 | −0.08 | −7.7, 7.6 | >0.9 |
| Single | −5.2 | −9.8, −0.61 | 0.027 | −3.5 | −8.3, 1.3 | 0.2 |
| Widowed | −16 | −35, 3.0 | 0.10 | −20 | −41, 0.27 | 0.054 |
| Clinical N stage (ref=N0) | ||||||
| N1 | −2.5 | −7.9, 2.9 | 0.4 | −1.7 | −6.1, 2.7 | 0.4 |
| N2-3 | −8.1 | −23, 6.3 | 0.3 | 0.79 | −13, 15 | >0.9 |
| Path N stage (ref=N0) | ||||||
| N1 | −9.0 | −15, −2.8 | 0.005 | −5.3 | −11, −0.02 | 0.050 |
| N2 | −2.2 | −10, 5.9 | 0.6 | −1.4 | −8.5, 5.7 | 0.7 |
| N3 | −3.2 | −15, 8.2 | 0.6 | −5.0 | −15, 5.1 | 0.3 |
| Axillary surgery (ref=ALND) | ||||||
| SLNB | −2.7 | −8.4, 2.9 | 0.3 | — | — | — |
| Radiotherapy (ref=no) | ||||||
| Yes | −6.4 | −11, −1.4 | 0.012 | −5.7 | −11, −0.49 | 0.032 |
| Complication of reconstruction (ref=no) | ||||||
| Yes | −6.0 | −10, −1.5 | 0.009 | −5.0 | −9.6, −0.35 | 0.036 |
On UVA, NAC receipt was significantly associated with reduced PWB-CHEST at 1 year (β, −5.2; 95% CI −8.8, −1.6; P=0.005) in the M-IR cohort. Radiotherapy receipt (β, −6.4; 95% CI −11, −1.4; P=0.012), postoperative complications (β, −6.0; 95% CI −10, −1.5; P=0.009), and pathologic N1 stage (versus N0) were associated with decreased PWB-CHEST at 1 year postoperatively, but not at 2 years.
DISCUSSION
In this study of patients with stage I-III breast cancer who received chemotherapy, SABTR and PWB-CHEST were not different according to the timing of chemotherapy as NAC versus adjuvant after multivariable adjustment. Post-BCS, SABTR was higher than baseline scores, regardless of chemotherapy timing, which persisted for up to 3 years of follow-up. Post-M-IR, satisfaction remained largely unchanged relative to preoperative baseline at 3 years in both chemotherapy groups. Among all patients, PWB-CHEST was lower at all postoperative timepoints versus baseline. In both surgical cohorts, patients treated with NAC experienced a greater reduction in PWB-CHEST from baseline at 6 months versus counterparts who received adjuvant chemotherapy. This finding may be attributed to the cumulative effect of preoperative chemotherapy exposure and associated toxicities, a previously described risk factor for developing persistent postoperative pain,22-24 superimposed with expected discomfort and—in the M-IR cohort—radiotherapy receipt, which was more frequently administered in the NAC group. However, our results suggest that the early observed differences in PWB-CHEST between chemotherapy groups are no longer evident at 3 years. Although we observed early important differences in PROs between chemotherapy groups in the respective surgical cohorts, NAC receipt was not statistically significantly associated with SABTR or PWB-CHEST on MVA. Demographic factors including age, BMI, race/ethnicity and—in the M-IR cohort—radiotherapy and reconstructive factors—were predictors of PROs at 1 and 2 years after breast surgery, independent of chemotherapy timing.
As long-term survival outcomes for breast cancer continue to improve, satisfaction with breast cosmesis is increasingly recognized as a clinically meaningful outcome. Prior studies have demonstrated negative correlations between chemotherapy receipt and health-related quality of life, regardless of breast surgical procedure, particularly in psychosocial and sexual well-being subdomains.12,15,16 To our knowledge, ours is the first study to directly compare chemotherapy timing’s effect on PROs for patients receiving NAC, particularly those who opt for M-IR. Our findings suggest that SABTR at 1 and 2 years is not significantly affected by chemotherapy timing with respect to surgery, after adjusting for clinicopathologic and treatment factors. Although we did not directly compare satisfaction between BCS and M-IR groups, overall raw SABTR scores were higher at all timepoints following BCS compared with the M-IR group, for whom postoperative scores remained largely unchanged from baseline at 3 years. As NAC is increasingly offered to facilitate breast conservation, our results suggest that eligible patients may be counseled regarding the evidence that mastectomy avoidance improves overall SABTR, regardless of chemotherapy sequencing.
Among patients treated with M-IR, radiotherapy receipt was an independent risk factor for decreased SABTR and PWB-CHEST, consistent with prior studies including patients with immediate implant-based and autologous reconstruction.15,19,20,25 Our findings suggest that among patients undergoing M-IR, chest well-being is significantly compromised by receipt of radiotherapy at 1 year postoperatively with improvement in the following year, whereas poorer cosmetic satisfaction may be expected at this later timepoint. When postmastectomy radiotherapy (PMRT) is anticipated, multidisciplinary discussion is recommended to weigh the benefits of immediate reconstruction against risks, including inferior cosmesis and complications requiring reintervention.26 For patients with locally advanced breast cancer, primary radiotherapy as a strategy to mitigate the negative effects of PMRT on immediate reconstruction is under investigation.27 The PRADA study first demonstrated safety and feasibility of primary radiotherapy followed by deep inferior epigastric perforator flap reconstruction in a small cohort of patients requiring mastectomy.28 Prospective trials at Memorial Sloan Kettering Cancer Center (NCT05412225) and the University of Texas MD Anderson Cancer Center (NCT02912312) are currently enrolling patients in neoadjuvant radiotherapy (NART) trials. If results are positive, whether NART will additionally improve PROs—particularly in the cosmesis and physical well-being domains—is highly anticipated. As traditional treatment paradigms are continuously challenged, perhaps best exemplified in the rigorous study of whether surgery is necessary in exceptional responders to NAC,29 patient experience as measured by PROs will become increasingly vital to critically appraise the clinical value of these innovative approaches.
Additionally, pN1 disease was associated with reduced PWB-CHEST at 1 year, but no significant associations were observed between axillary surgery and PROs. Notably, we did not assess the relative impact of additional regional nodal irradiation (RNI) in the context of PMRT. Two prospective trials are currently evaluating the oncologic benefit of comprehensive RNI post-NAC in patients who achieve a nodal pCR and in those with residual nodal disease, and will include cosmetic satisfaction/quality-of-life measures as secondary endpoints.30,31 Indications for comprehensive RNI administration may expand these trials’ pending results; whether prospectively collected PRO data will support our findings is awaited.
Following M-IR, our results suggest that postoperative complications requiring reintervention negatively impact PWB-CHEST at 1 year postoperatively, but these effects were no longer evident at 2 years. Following immediate implant-based and autologous reconstruction, Hart et al. reported a higher risk of complications requiring rehospitalization and/or reoperation among patients treated with chemotherapy compared with no systemic treatment.32 Among patients treated with NAC, the 2-year risk of major complications was 22% and 27% in patients treated with adjuvant chemotherapy, similar to our study. In this high-risk group of patients undergoing chemotherapy, our findings suggest that patients may be reassured that long-term chest well-being is not significantly compromised despite unplanned re-intervention.
This study identified several demographic factors associated with PROs. In the BCS cohort, increasing age was an independent predictor of higher SABTR at 1 year, and of PWB-CHEST at 1 and 2 years, reiterating the known negative impact of young age on these outcomes.15,18,19,33 Young age has been described as a risk factor for persistent pain post-whole-breast radiotherapy—captured by pain-specific questions in the PWB-CHEST subdomain of the BREAST-Q survey.34,35 Lam described higher odds of breast pain in patients age 40-49 (odds ratio [OR] 1.87; P=0.0003) and 50-59 years (OR 1.55; P=0.0004) compared with those age ≥60, respectively, at 6 weeks post-treatment completion.36 Possible correlations between persistent pain and age have been described, including biological factors related to postmenopausal tissue changes, and psychosocial factors pertaining to symptom reporting in the context of medical comorbidities,22 although causality is not fully understood. Nevertheless, young breast cancer patients receiving chemotherapy should be counseled specifically on expectations regarding postoperative quality of life, and may derive benefit from targeted supportive care based on real-time feedback from PRO measurements during and after treatment.11,37
Additionally, identification as Black/Hispanic or Non-Hispanic was an independent predictor of decreased PWB-CHEST for up to 2 years after BCS, but not in the M-IR cohort. Conversely, among patients with early-stage breast cancer treated with BCS and mastectomy, Arabandi reported a negative interaction between race and choice to undergo mastectomy (β, −4.76; P<0.01), indicating lower overall satisfaction with care among Black versus White patients after controlling for demographic and tumor factors.38 Importantly, qualitative assessment is needed to explore existing gaps in shared decision making and treatment planning that may additionally contribute to the observed racial/ethnic disparity in BCS-specific outcomes.39
In the M-IR cohort, obesity (BMI>30) was independently associated with decreased SABTR at 1 year only; however, our findings suggest that obese patients can expect return to baseline satisfaction by 2 years, consistent with prior evidence that these factors are not predictive of long-term satisfaction.40,41
This study is, to our knowledge, the first to assess postoperative SABTR and PWB-CHEST exclusively in patients treated with chemotherapy for invasive breast cancer, and to provide insight into the impact of delivery of NAC versus adjuvant chemotherapy. Study limitations include its retrospective design and potential for selection bias pertaining to which patients completed electronic BREAST-Q surveys. Willingness to complete the survey may have been affected by level of satisfaction and health-related quality of life; however, this would be expected to be similar between patients treated with NAC and adjuvant chemotherapy, evidenced by similar response rates between groups across all postoperative timepoints. Additionally, we performed a fixed timepoint analysis and included all available observed data, but the retrospective design limited our ability to perform a longitudinal analysis adjusted for baseline scores/time. Further, in our contemporary cohort, long-term outcomes could not be assessed. Additionally, the minimal clinically important difference (MCID) utilized for this study has been defined for reconstructive patients (M-IR), but not yet for BCS patients; we used it as a proxy for the MCID in this cohort. Finally, we did not include patients treated with mastectomy without reconstruction. As more patients are choosing to “go flat,” and with prior data suggesting high satisfaction among patients who receive adequate information regarding surgical options,42 further data are needed to understand differences in PROs with respect to M-IR and the impact of chemotherapy timing.
Conclusions
In patients with invasive breast cancer treated with surgery and chemotherapy, timing of NAC versus adjuvant did not predict SABTR or PWB-CHEST at 1 or 2 years after controlling for patient and tumor factors. In BCS patients, young age and Black race were associated with decreased PROs regardless of chemotherapy timing, as well as high BMI and receipt of radiotherapy in M-IR patients. Qualitative assessment to explore existing gaps in shared decision making and treatment planning that may contribute to these disparities is important.
Synopsis:
Here we investigate whether chemotherapy timing as neoadjuvant versus adjuvant affects patient-reported outcomes after BCS and mastectomy with immediate reconstruction. We find that chemotherapy timing does not significantly affect breast satisfaction or chest well-being at 3 years postoperatively.
ACKNOWLEDGEMENTS
The preparation of this study was supported in part by NIH/NCI Cancer Center Support Grant No. P30CA008748 to Memorial Sloan Kettering Cancer Center, and this study was presented in virtual poster format at the 2021 American Society of Clinical Oncology Annual Meeting, June 4-8, 2021. All authors have no conflict of interest disclosures to report.
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