The Breast 70 (2023) 63–69

Contents lists available at ScienceDirect

The Breast
journal homepage: www.journals.elsevier.com/the-breast

Prognostic factors and clinical outcomes of breast cancer patients with

disease progression during neoadjuvant systemic therapy
Yun-xiao Ling a, b, 1, Yi-fan Xie a, b, 1, Huai-liang Wu a, b, 1, Xiao-fang Wang b, c, Jin-li Ma b, c,
Lei Fan a, b, Guang-yu Liu a, b, *
a
Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China
b
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, PR China
c
Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, PR China

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Disease progression during neoadjuvant systemic therapy for breast cancer indicates poor prognosis,
Breast cancer while predictors of the clinical outcomes of these patients remain unclear. By comparing the clinical outcomes of
Disease progression patients with different patterns of salvage treatment strategies, we try to evaluate the factors predicting distant
Neoadjuvant systemic therapy
failure and explore the favourable treatment for them.
Prognostic factors
Methods: Patients with disease progression during neoadjuvant systemic therapy for stage I–III breast cancer
diagnosed between January 1, 2008 and July 31, 2021 in Fudan University Shanghai Cancer Center were
enrolled. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions or
the appearance of new breast or nodal lesions. Kaplan-Meier, univariate and multivariate Cox proportional
hazard regressions were utilized to compare survival outcomes between different salvage treatment strategies.
Results: Among 3775 patients treated with NST, 60 (1.6%) patients encountered disease progression. A significant
difference between the outcomes of patients receiving direct surgery and other salvage modalities was found (p
= 0.007). Triple-negative breast cancer (p = 0.010) and not receiving direct surgery (p = 0.016) were inde­
pendently associated with distant disease-free survival on multivariate analysis.
Conclusions: Predictors of distant failure in patients with disease progression include triple-negative breast cancer
and not receiving direct surgery. Direct surgery seems to be more favourable than other treatments for patients
with disease progression. For inoperable patients, neoadjuvant radiation can increase their operability but not
improve their prognosis.

1. Introduction [8]. The response to neoadjuvant chemotherapy in breast cancer varies

depending on the tumour subtype. The pCR rate of dual HER2 blockade
The incidence of breast cancer has long ranked first among female can reach 80% in patients with HER2-positive breast cancer [9,10],
malignant tumours worldwide [1]. Due to the advances of various sys­ while only one third of HR-/HER2-patients achieve pCR with standard
tematic therapies, breast cancer treatment has evolved from a anthracycline- and taxane-based regimens in NST [11,12]. In
surgery-based model to multidisciplinary synthetic treatment HR+/HER2-breast cancer patients, pCR rate was much lower which was
comprising surgery, chemotherapy, endocrine therapy, radiation ther­ less than 20%. Regarding the limited benefit, it is desirable to identify
apy, targeted therapy and immunotherapy [2–5]. Neoadjuvant systemic and predict as early as possible patients who will not benefit from
therapy (NST) has been proven to improve the clinical outcomes of neoadjuvant treatments [13]. Actually, there are still a small number of
patients and has become the standard therapy to downstage the tumour patients showing hyposensitivity to NST or even experiencing disease
burden of locally advanced breast cancer [6,7]. Neoadjuvant therapy is progression during NST. Previous studies have evaluated the outcomes
able to provide achievement of pathological complete response (pCR) of patients with disease progression (PD) and found that it was a nega­
associated with improved disease-free and overall survival of patients tive predictor of distant disease-free survival and overall survival [14,

* Corresponding author. Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dongan Road, Xuhui District, Shanghai, 200032, PR China.
E-mail address: [email protected] (G.-y. Liu).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.breast.2023.06.004
Received 16 February 2023; Received in revised form 7 June 2023; Accepted 9 June 2023
Available online 19 June 2023
0960-9776/© 2023 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Y.-x. Ling et al. The Breast 70 (2023) 63–69

15]. Considering the poor outcomes of these patients, different salvage survival (DDFS), and overall survival (OS). Events were measured from
treatment strategies will be utilized, including switching to other the time of initial diagnosis of breast cancer to any documented event or
chemotherapy, concurrent neoadjuvant radiation therapy, and surgery the time of the last follow-up. DDFS was defined as the time from
[16,17]. In China, statistical results concerning the predictive factors of diagnosis to distant metastasis or death, whichever occurred first. OS
distant failure and the outcomes of different salvage treatment strategies was defined as the time from diagnosis to death. The Kaplan–Meier
in patients with PD are rarely studied [18,19]. Considering their poor method was utilized to estimate DDFS for all patients. Different survival
survival outcomes, the identification of favourable features to identify outcomes between groups were evaluated using the log-rank test. To
patients in this subgroup warrants further attention. As such, the determine factors independently associated with DDFS, univariate and
objective of our study was to summarize the characteristics and out­ multivariate Cox proportional hazard regression models were utilized,
comes of breast cancer patients who experienced disease progression and hazard ratios with 95% confidence intervals (CIs) were computed. A
during NST, report the patterns of salvage treatment strategies, and two-tailed p value of <0.05 was considered statistically significant in
evaluate the factors predicting distant failure. this study. Statistical analyses were performed using R Statistical Soft­
ware (v4.1.1; R Core Team) [21] using R packages survival, survminer,
2. Methods rms, readxl, and ggplot2.

2.1. Patients 3. Results

We reviewed all the medical records of patients receiving NST at 3.1. Clinicopathologic and treatment characteristics
Fudan University Shanghai Cancer Center (FUSCC, Shanghai, China)
between January 1, 2008 and July 31, 2021. Detailed inclusion criteria Among 3775 patients treated with NST, 60 (1.6%) patients
included (1) untreated breast cancer with histologically confirmed encountered disease progression during NST. Their clinicopathologic
tumour, (2) age between 18 and 80 years old, (3) assessable tumour in features at the time of diagnosis are presented in Table 1. Of note, 53.3%
the breast without evidence of distant metastasis, (4) no history of other of patients with PD had triple-negative breast cancer (TNBC), 18.3% had
cancer, and (5) all patients received two or more cycles of NST before inflammatory breast cancer (IBC), and one patient with occult breast
PD. The exclusion criteria included (1) male patients, (2) patients who cancer (OBC) was also enrolled. Most manifestations of disease pro­
had bilateral primary breast cancer, (3) patients who received neo­ gression in these 60 patients were a 20% increase in tumour diameters
adjuvant endocrine therapy alone, (4) patients with insufficient evalu­ by clinical exam and imaging. Other patterns were listed in Table_S1. In
ated information, or (5) severe adverse events (including cardiac our cohort, 46 patients were regarded to be “operable” (38 patients with
adverse events, grade 4 haematologic toxicity and grade 3/4 gastroin­ increase in tumour diameters and 8 patients with new breast and axil­
testinal toxicity) for treatment discontinuation. lary lesions), among whom 17 patients received direct surgery and 29
patients received other salvage treatment. Only 14 patients (7 patients
2.2. Assessment and treatment consideration with breast erythema and edema; 2 patients with tumour ulceration; 2
patients with new breast satellite nodule; 1 with supraclavicular aden­
In this study, hormone receptor (HR)-negative was defined as both opathy and 2 patients with distant metastasis) were regarded to be
oestrogen receptor (ER) and progesterone receptor (PR) < 1% and HR- “inoperable” at the time of PD and received other salvage treatment.
positive was defined as ER or PR ≥ 1%. The ER, PR, Ki-67 and human Regarding their treatment characteristics, all patients received conven­
epidermal growth factor receptor 2 (HER2) status were determined tional chemotherapy regimens before PD, while various treatments were
using immunohistochemistry (IHC). HER2 positivity was determined by arranged flexibly according to their response later. Once they pro­
HER2 3+ on IHC or a positive result on fluorescence in situ hybridiza­ gressed, different types of salvage treatment were chosen by the multi-
tion (FISH). According to the Revised Response Evaluation Criteria in disciplinary team. The treatment features, including NST and salvage
Solid Tumours (RECIST) guideline (version 1.1) [20], PD was defined as treatment, are summarized in Table 2. Among 17 HER2-positive pa­
at least a 20% increase in the sum of diameters of target lesions or the tients, 94.1% (16/17) received only trastuzumab as their HER2-
appearance of new breast or nodal lesions. Except for the initial sys­ targeting approach while only one patient received both trastuzumab
tematic evaluation consisting of physical and radiologic examinations, and pertuzumab. A total of 17 (28.3%) patients received direct surgery
patients underwent ultrasound and magnetic resonance imaging (MRI) as their first salvage treatment, while 43 (71.7%) patients switched to
every two cycles during NST and before surgery. The initial chemo­ other chemotherapy regimens when PD occurred during NST. Among
therapy regimen is based on the current guidelines. In general, TNBC these 43 patients, 25 (58.1%) of them received neoadjuvant radiation,
and HR-positive patients received a combination of anthracyclines, among which 56% (14/25) subsequently underwent surgery. As for the
taxanes, and cyclophosphamide. All HER2-positive patients received remaining 18 patients, 94.4% (17/18) proceeded to surgery, and 1
HER2-targeted therapy. Dual anti-HER2 blockade was applied after (5.6%) patient was lost to follow-up. Among all the 48 patients receiving
August 2019, when pertuzumab was approved by National Medical surgery, 46 (95.8%) patients were treated with mastectomy, 1 (2.1%)
Products Administration for the neoadjuvant treatment of received breast-conserving surgery, and 1 patient with OBC only un­
HER2-positive breast cancer. Any salvage treatment such as change of derwent axillary lymph node dissection (ALND). Three patients only
chemotherapy, addition of neoadjuvant radiation, or surgical manage­ received sentinel lymph node biopsy (SLNB), and the other 45 patients
ment was recorded. All salvage treatment strategies were discussed by received ALND. None of them reached pCR based on the surgical spec­
the multi-disciplinary team composed of breast surgical, medical, pa­ imens. Fig. 1A illustrates a schematic diagram of the clinical manage­
thology, and radiation oncology department in Fudan University ment of breast cancer patients with PD during NST.
Shanghai Cancer Center.
3.2. Outcomes after salvage therapy
2.3. Statistical analysis
The median follow-up time for all 60 patients was 25.4 months
The clinical and pathological characteristics of the patients were (range 6–114). Until the last follow-up, a total of 32 (53.3%) patients
summarized by descriptive statistics. The minimum and maximum were alive without disease, and 22 (36.7%) patients developed distant
ranges, together with percentages, median values, and standard de­ metastasis, among whom four patients died. The median DDFS was 20.1
viations of continuous variables, were recorded. The endpoints of our months (range 5–114) (Fig. 1B). The OS ranged between 5 and 114
study included the rate of distant metastasis, distant disease-free months, and the median OS was unknown. Distant metastasis occurred

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Table 1 Overall, a significant difference was found compared to other regimens

Clinicopathologic features of patients with PD while receiving NST. both in all patients (p = 0.007) and in operable patients (p = 0.0045)
Patient and tumour characteristics N = 60 (Fig. 2). When disease progression was assessed, 17 patients received
direct surgery as their first salvage treatment. Distant metastasis
Age, years
Range 25–76 occurred in 2 (11.8%) patients who received direct surgery compared
Median 50.5 with 20 (46.5%) patients who received other salvage modalities. The
Menopausal status median DDFS of the former was 38.2 months, compared with 14.4
Premenopausal 23 (38.3%) months for the rest. Meanwhile, delayed surgeries were conducted in 31
Peri/postmenopausal 37 (61.7%)
BMI (kg/m2)
patients after some non-surgical salvage treatment modalities and
Range 18.2–33.3 48.4% of them developed distant failure with a median DDFS of 19.5
Median 23.7 months. Interestingly, receiving direct surgery also showed an advan­
Inflammatory breast cancer tage over delayed surgery after non-surgical salvage treatment (Fig. S1).
Yes 11 (18.3%)
Radiation therapy also plays an important role in local therapeutics.
No 49 (81.7%)
Clinical T stage In our institution, 83.3% of patients with PD received radiation therapy
Tx 1 (1.7%) including neoadjuvant radiation and adjuvant radiation. Distant
T1 6 (10.0%) metastasis occurred in 21 (42.0%) patients who received radiation
T2 26 (43.3%) therapy compared with 1 (10.0%) patient who did not receive radiation
T3 6 (10.0%)
T4 21 (35.0%)
therapy. However, the median DDFS of the former was 25.3 months,
Clinical N stage while that of the latter was 19.7 months. There was no difference in
N0 6 (10.0%) survival outcomes based on radiation therapy probably because there
N1 32 (53.3%) were few events (p = 0.15) (Fig. 3A). A total of 56.0% (14/25) of our
N2 5 (8.3%)
patients who received neoadjuvant radiation successfully downstaged
N3 17 (28.3%)
AJCC stage their tumour and underwent delayed surgery. Our preliminary data did
IA/IIA 7 (11.7%) not show any significant difference in the survival outcomes of patients
IIB/IIIA 24 (40.0%) who whether successfully underwent surgery after neoadjuvant radia­
IIIB/IIIC 29 (48.3%) tion. Their median DDFS was 13.5 months and 13.1 months, respec­
Histology
tively (p = 0.82) (Fig. 3B).
Ductal carcinoma in situ with areas of micro-invasion 3 (5.0%)
Invasive ductal carcinomas 56 (93.3%)
Unknown 1 (1.7%) 3.3. Predictive factors of distant failure
ER status
Negative 47 (78.3%)
Factors that might influence DDFS were added to univariate and
Positive 13 (21.7%)
PR status multivariate analyses. TNBC (p = 0.025), clinical N3 stage (p = 0.021)
Negative 50 (83.3%) and not receiving direct surgery (p = 0.016) were initially significantly
Positive 10 (16.7%) associated with DDFS in the univariate analysis. After adjusting for some
HER-2 factors (age, clinical N3 disease, IBC, TNBC, direct surgery, radiation
Negative 44 (73.3%)
Positive 16 (26.7%)
and clinical TNM stage at the time of PD) in the multivariate analysis,
Ki-67 score there were still significant differences in patients with TNBC (HR 3.886,
Range 10–90 95% CI 1.393–10.843, p = 0.010) or who received direct surgery (HR
Median 60 0.148, 95% CI 0.031–0.695, p = 0.016) (Table 3).
Receptor status
It was noted that patients with TNBC had worse survival outcomes
HR+, HER2- 11 (18.3%)
HR+, HER2+ 5 (8.3%) than patients with HR-positive or HER2-positive disease. In this study,
HR-, HER2+ 12 (20.0%) 46.9% (15/32) of patients with TNBC developed distant metastasis.
HR− , HER2− 32 (53.3%) Their median DDFS was 16.5 months compared with 22.5 months in
FUSCC TNBC subtypes other patients (p = 0.018) (Fig. S2).
luminal androgen receptor (LAR) subtype 8
Immunomodulatory (IM) subtype 1
Basal-like and immune-suppressed (BLIS) subtype 3 4. Discussion
Mesenchymal-like (MES) subtype 2
Unknow 18 Although most patients with breast cancer show partial or complete
a
PD: progressive disease; NST: neoadjuvant systemic therapy; BMI: body mass response to NST, there is still a fraction of patients running into PD. The
index; AJCC: American Joint Committee on Cancer; ER: oestrogen receptor; PR: rate of PD in our center was 1.6%, in accordance with the study by
progesterone receptor; HR: hormone receptor; HER2: human epidermal growth Leisha (1.9%) but lower than the previous data (3%–7%) [15,16,18,22].
factor receptor 2; FUSCC TNBC subtypes: four transcriptome-based triple- Due to emerging treatment options such as targeted therapy and
negative breast cancer subtypes classified by Fudan University Shanghai Cancer immunotherapy, the survival outcomes of patients receiving neo­
Center. adjuvant systematic therapy are constantly improving. However,
considering the poor outcomes of PD, it is essential to identify these
in 17 (35.4%) patients who received surgery compared with 5 (41.7%) patients promptly and generate appropriate salvage treatment strate­
patients who didn’t receive surgery. The proportion of local recurrence gies. To our knowledge, this study represents the largest contemporary
of the non-surgery group was twice as much as the surgery group dataset of patients with PD in China, focusing on the survival outcomes
(16.67% vs 8.33%). The median DDFS was 23.2 months in patients who and value of predictive factors.
received surgery, compared with 12.5 months in patients who did not Considering the limited clinical studies concerning PD and subse­
receive surgery. The median follow-up, survival outcomes, and vital quent treatments, no standard salvage treatment protocol was estab­
status of all patients with PD are listed in Table_S2. lished. Despite emerging new therapies, surgery has always played a
To determine whether any specific salvage treatment would lead to vital role in treating breast cancer [23,24]. Overall, 80% (48/60) of
better outcomes, we also conducted subgroup survival analyses. We patients received surgical management during this study, among whom
used receiving direct surgery as a standard comparator to all the other 17 received direct surgery and 31 received delayed surgery in our cen­
salvage modalities because of our specific interest in this regimen. ter. According to the univariate and multivariate analyses, not receiving

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Y.-x. Ling et al. The Breast 70 (2023) 63–69

Table 2
Treatment features of neoadjuvant systemic therapy and salvage therapy in patients with progressive disease.
HR+,HER2- cohort N = 11 (%) HER2+,HR+/HER2+,HR- cohort N = 17 HR-,HER2 – cohort N = 32 (%) Total
(%) N = 60
(%)

Neoadjuvant chemo Taxane plus 7 Trastuzumab plus taxane and 16 Taxane plus 13 /
regimens cyclophosphamide (63.6%) carboplatin (94.1%) cyclophosphamide (40.6%)
Anthracycline plus 4 Trastuzumab and pertuzumab plus 1 (5.9%) Anthracycline plus 13
cyclophosphamide (36.4%) taxane and carboplatin cyclophosphamide (40.6%)
Others 6
(18.8%)
Salvage therapy
Direct surgery 3 (27.3%) 4 (23.5%) 10 (31.3%) 17
(28.3%)
Switching to other chemotherapy
Delayed surgery 8 (72.7%) 11 (64.7%) 12 (37.5%) 31
(51.7%)
Non-surgery 0 (0.0%) 2 (11.8%) 10 (31.3%) 12
(20.0%)
Neoadjuvant radiotherapy
Yes 0 (0.0%) 6 (35.3%) 19 (59.4%) 25
(41.7%)
No 11 (100.0%) 11 (64.7%) 13 (40.6%) 35
(58.3%)
Adjuvant radiotherapy
Yes 8 (72.7%) 7 (41.2%) 10 (31.3%) 25
(41.7%)
No 3 (27.3%) 10 (58.8%) 22 (68.7%) 35
(58.3%)

Fig. 1. Clinical management (A) and Kaplan–Meier curve of distant disease-free survival (B) of all 60 patients with PD during NST.

Fig. 2. Subgroup analyses. (A)Kaplan–Meier curve of distant disease-free survival in all patients receiving direct surgery compared with other salvage treatment
modalities. (B) Kaplan–Meier curve of distant disease-free survival in operable patients receiving direct surgery compared with other salvage treatment modalities.

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Y.-x. Ling et al. The Breast 70 (2023) 63–69

Fig. 3. Subgroup analyses. (A)Kaplan–Meier curve of distant disease-free survival in patients receiving radiation therapy compared with patients not receiving
radiation therapy. (B) Kaplan–Meier curve of distant disease-free survival in patients receiving surgery compared with patients not receiving surgery after neo­
adjuvant radiation.

Table 3
Predictors of distant failure in patients with PD while receiving neoadjuvant systemic therapy.
Factor Univariate analysis Multivariate analysis

Hazard ratio 95% CI P Hazard ratio 95% CI P

Age 1.005 0.973–1.038 0.779 0.987 0.955–1.020 0.446

Menopausal status
Premenopausal 1.000 – –
Postmenopausal 1.635 0.666–4.016 0.283
Subtype
Non-TNBC 1.000 – – 1.000 – –
TNBC 2.812 1.14–6.939 0.025* 3.886 1.393–10.843 0.010*
Ki-67 score 0.811 0.011–61.591 0.924
Clinical N stage
N0–N2 1.000 – – 1.000 – –
N3 2.695 1.157–6.276 0.021* 8.04 0.995–20.255 0.052
IBC
No 1.000 – – 1.000 – –
Yes 1.053 0.356–3.12 0.925 0.520 0.126–2.139 0.365
Direct surgery
No 1.000 – – 1.000 – –
Yes 0.168 0.039–0.722 0.016* 0.148 0.031–0.695 0.016*
Radiation
No 1.000 – – 1.000 – –
Yes 3.887 0.521–29 0.185 1.565 0.187–13.120 0.680
Clinical T stage at the time of PD
T0-T1 1.000 – – 1.000 – –
T2-T4 7.517e+07 0 - Inf 0.998 2.950e+07 0.000 - Inf 0.997
Clinical N stage at the time of PD
N0–N2 1.000 – – 1.000 – –
N3 1.944 0.812–4.653 0.136 0.210 0.031–1.441 0.112
Clinical M stage at the time of PD
M0 1.000 – – 1.000 – –
M1 3.757 0.845–16.71 0.082 0.945 0.147–6.071 0.952

a PD: progressive disease; TNBC: triple-negative breast cancer; non-TNBC: patients with hormone receptor (HR)-positive or HER2-positive disease.
b Radiation includes neoadjuvant radiation and adjuvant radiation.
c Signif. codes: ‘***’: 0.001; ‘**’: 0.01, ‘*’:0.05; ‘Inf’: Infinity.

direct surgery was statistically a predictor of poor clinical outcomes in of lesions [27]. Hence, we suggest that once PD occurs, direct surgery
our study (p = 0.013). Furthermore, patients who received delayed should be considered first instead of other regimens.
surgery after other nonsurgical salvage treatment modalities were noted Concurrent radiation is one area of investigation that may hold
to have worse survival outcomes than those who received surgery promise for patients with PD. However, no difference in survival out­
directly. Other neoadjuvant studies also suggested that switching to comes was detected between receiving radiation therapy or not from a
different chemotherapy regimens when PD occurred before surgery did statistical perspective due to the low number of events. Judging from our
not result in any improvement in pCR [25,26]. Similar suggestions were results, neoadjuvant radiation could in part convert a previously unre­
drawn in the study by Abigail S who concluded that early surgical sectable tumour to an operable tumour, thus leading to an increase in
referral is warranted when progression might jeopardize the operability the number of surgeries in patients with PD. Numerically, 56.0% (14/

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25) of our patients receiving neoadjuvant radiation successfully down­ to detecting the significant difference between survival outcomes of
staged their tumours and underwent delayed surgery. Interestingly, we each subgroup and the predicting factors. Therefore, our study can only
did not find any survival difference in those undergoing surgery put forward suggestions according to the outcomes of our patients with
compared with those not undergoing surgery (p = 0.82). Hence, for PD during NST. This result is insufficient to determine the standard
inoperable patients, neoadjuvant radiation may partly show signs of salvage treatment for patients with PD. Prospective studies should be
tumour downstaging but no improvement in survival outcomes. His­ conducted to define the clinical utility of various salvage treatment
torically, neoadjuvant radiation is known as a local therapeutic method strategies.
to increase the rate of breast-conserving surgery by tumour down­
staging. However, the increase in the overall treatment time (OTT) and 5. Conclusions
the higher risk of surgical morbidity caused by neoadjuvant radiation
cannot be neglected [28,29]. Recent studies have found that adjusting Although the prevalence of PD while receiving NST has decreased,
the frequency of neoadjuvant radiation could provide a solution. A we still ought to attach great importance to the features and optimum
randomized pilot trial reported that accelerated neoadjuvant radiation salvage treatment management of these patients, considering their poor
in 5 fractions with a simultaneously integrated boost is feasible and clinical outcomes. Direct surgery seems to be more favourable than
results in a shorter OTT without excess acute toxicity [30]. Other studies other treatments for patients with PD. For those inoperable patients,
have also explored the role of radiation as a supplement to systemic neoadjuvant radiation can increase their operability but not improve
therapy in this population, but there is still no consensus [17,31]. In their prognosis. Predictors of distant failure of patients with PD include
general, the association between neoadjuvant radiation and better sur­ TNBC and not receiving direct surgery. To identify these patients earlier
vival outcomes remains uncertain, and further studies are needed. and ultimately change our treatment strategies and improve survival
As a clinically heterogeneous disease, different subsets of breast outcomes, new biomarkers need to be studied and validated in well-
cancer show variable sensitivity to NST [32,33]. It is notable that in our designed prospective studies.
study, a total of 53.5% of patients were diagnosed with TNBC, while the
rate of TNBC for all breast cancer diagnoses was only 15–20% [34,35]. Authors’ contributions
Compared with patients with HR-positive or HER2-positive disease,
patients with TNBC were noted to have a poorer prognosis. TNBC was Yun-xiao Ling, Yi-fan Xie and Huai-liang Wu participated in the
also proven to be independently associated with distant failure in our conceptualization and carried out the investigation, data collection,
multivariate analysis. TNBC generally has a more aggressive biology, statistical analysis and drafted the manuscript. Xiao-fang Wang partic­
with earlier onset of metastatic disease, visceral metastases, and inferior ipated in the data collection and statistical analysis. Jin-li Ma, Lei Fan
survival outcomes, which could, in part, provide a biological explana­ and Guang-yu Liu conceived of the study and participated in its design
tion for the poor prognosis among this group of patients with PD, and supervision. All authors contributed to the article and approved the
regardless of whether they receive NST [36–38]. The high proportion of submitted version.
TNBC (68.2%) of all patients with PD who developed distant metastasis
suggested that more contemporary treatment of patients with TNBC Funding
should be utilized to improve their outcomes. Previous studies have
demonstrated that triple-negative breast cancer cells are more likely to The authors declare that no funds, grants, or other support were
express proteins of programmed death ligand-1 (PD–L1) than other received during the preparation of this manuscript.
breast cancer subtypes. Several clinical trials of immune checkpoint
inhibitors such as atezolizumab and avelumab have been conducted in Ethics approval and consent to participate
neoadjuvant therapy for patients with TNBC (NeoTRIPaPDL1 Michel­
angelo study, KEYNOTE–173, KEYNOTE–522, etc.). Preliminary results Ethical approval was not provided for this study on human partici­
have shown that immune checkpoint inhibitors combined with chemo­ pants because as a retrospective cohort study, all the procedures per­
therapy can improve the survival of patients with TNBC [39–43]. The formed in studies involving human participants were in accordance with
results of studies concerning other supplementary therapies targeting the ethical standards of the institutional and/or national research
the VEGF and PI3K pathways are also encouraging for improving the committee and with the 1964 Helsinki declaration and its later
pCR rate [44–46]. Taken together, the results of these landmark trials amendments or comparable ethical standards. Written informed consent
demonstrate that other supplementary systemic therapies will play an for participation was not required for this study in accordance with the
important role in the treatment of patients with TNBC and may decrease national legislation and the institutional requirements.
the number of patients with PD while receiving NST.
Given the variability of salvage therapies for patients progressing on Consent for publication
NST and the paucity of studies on predictors of distant failure after PD, it
is necessary to identify these patients in a timely manner in order to Not applicable.
optimize their subsequent treatments and outcomes. Approximately
36.7% of patients in the study population developed distant failure. Declaration of competing interest
Considering their poor prognosis, the identification of favourable fea­
tures to identify patients in this subgroup warrants further attention. The authors declare that the research was conducted in the absence
Thus, we summarized the characteristics of breast cancer patients of any commercial or financial relationships that could be construed as
treated with NST in our own center who progressed and compared potential competing interests.
outcomes of patients using different ST strategies. The ultimate aim is to
identify the best salvage treatment strategy to use and the clinical fea­ Acknowledgements
tures of the patients with the highest risk of distant failure.
Our study had several potential limitations. First, as a retrospective The authors thank all the staff from the department of Breast Sur­
study, selection bias was inevitable. Second, changes in systemic therapy gery, Fudan University Shanghai Cancer Center, for their support in
and the emergence of biological therapies were dismissed in our anal­ collecting the clinical data.
ysis. Third, owing to some loss of follow-up data, it was difficult to
collect all the events accurately which has underpowered our analysis.
Finally, the low prevalence of PD and events may contribute negatively

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Appendix A. Supplementary data [22] Myller S, Ipatti P, Jääskeläinen A, Haapasaari KM, Jukkola A, Karihtala P. Early
progression of breast cancer during neoadjuvant chemotherapy may predict poorer
prognoses. Acta Oncol 2020 Sep 1;59(9):1036–42.
Supplementary data to this article can be found online at https://doi. [23] Al-Hilli Z, Wilkerson A. Breast surgery: management of postoperative
org/10.1016/j.breast.2023.06.004. complications following operations for breast cancer. Surg Clin North Am 2021 Oct
1;101(5):845–63.
[24] Jones C, Lancaster R. Evolution of operative technique for mastectomy. Surg Clin
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