 Home > Active Ingredient News > Antitumor Therapy > ASCO 2021: Summary Overview and Outlook 10 | Overview of Latest Breast Cancer Research (Triple Negative Breast Cancer Column)

ASCO 2021: Summary Overview and Outlook 10 | Overview of Latest Breast Cancer Research (Triple Negative Breast Cancer Column)

 Last Update: 2021-05-31
 Source: Internet
 Author: User

Tags

age aluminum

1 2 4 trimethylbenzene

Search more information of high quality chemicals, good prices and reliable suppliers, visit www.echemi.com

（ASCO）2021648，。，。，。

（ASCO）2021648，。，。，。（ASCO）2021648，。，。，。

：

：：

ASCO 2021: Summary Overview and Outlook 11 | Breast Cancer Research Overview (Invasive Breast Cancer Column)

Background: Background:

The GeparNuevo trial investigated the effect of adding anti-PD-L1 checkpoint inhibitor (CPI) durvalumab to standard neoadjuvant chemotherapy (NACT) in patients with early-stage TNBC.

Method: Method:

GeparNuevo randomized patients with cT1b-cT4a-d tumors and confirmed that TNBC received durvalumab (D) 1.

Result: Result:

Between June 2016 and September 2017, a total of 174 patients were recruited.

Conclusion: Conclusion:

Despite the small increase in pCR and no continued treatment after surgery, adding Durvalumab to neoadjuvant chemotherapy for TNBC can still significantly improve the long-term prognosis.

For details, see: For details, see: Durvalumab improves long-term outcome in TNBC: results from the phase II randomized GeparNUEVO study investigating neodjuvant durvalumab in addition to an anthracycline/taxane based neoadjuvant chemotherapy in early-negative breast cancer (TNBC).

Background: Background:

TNBC patients with residual invasive disease (RD) after the completion of NAC are at high risk of recurrence, and capecitabine adjuvant (C) can reduce the risk of recurrence.

Method: Method:

Clinical II/III TNBC staging (1:1) after neoadjuvant taxane +/- anthracycline chemotherapy and the RD in the surgical sample is at least 1 cm RD to receive P (carboplatin or cisplatin every 3 weeks) One time, 4 cycles in total) or C (14/7d every 3 weeks, 6 cycles in total).
TNBC subtypes (basic and non-basic) were analyzed in surgical specimens by PAM50.
Assuming that the 4-year iDFS of group C is 67%, a non-inferiority design is selected (the risk [HR] non-inferiority margin [HR] is 1.
154) (the alternative HR is 0.
754).
Non-inferiority complex is tested first.
If it shows non-inferiority, then a formal test of the superiority of P over C will be conducted.

result:

Result: Result:

Between 2015 and 2020, 401 participants were randomly assigned to P or C (recruitment target of 775), of which 310 (77%) had TNBC basic subtype disease (the main analysis population).
The median age of Pts is 52 years, 71% for whites and 19% for blacks.
At the time of diagnosis, most tumors were high grade (78%), T2 (59%), N0 47% and N1 40%.
Residual tumors were 37% ypT1, 44% ypT2 and 47% ypN0.
The overall incidence of any toxicity is similar (83% for P and 80% for C), but P is more common for grade 3 and 4 toxicity (no grade 5) (25% vs.
15%).
After a median follow-up of 18 months, 113 iDFS events occurred (58% of all information).
The 3-year iDFS of group P was 40% (95% CI, 29%-51%), and group C was 44% (95% CI, 32%-55%).
The HR of the weapon P/C is 1.
09 (95% repeat confidence interval is 0.
62-1.
90), and the probability of final rejection of inferiority (ie, conditional power) is 6%.
The Data Security and Surveillance Committee recommended that the trial be stopped in the fifth interim analysis in March 2021, because the trial is unlikely to show the inferiority or disadvantage of the P-arm.

in conclusion:

Conclusion: Conclusion:

Regardless of the treatment, the 3-year iDFS of participants with TNBC and RD after NAC was lower than expected.
The available data indicate that the study is unlikely to determine the non-inferiority of P versus C.
In addition, severe toxicity of P is more common.
In TNBC, especially in patients with basal subtype and RD of at least 1 cm after NAC and high risk of recurrence, the use of adjuvant P does not improve the prognosis.
Correlation analysis of RD tissue (NGS), circulating markers (before and after ctDNA and CTC treatment) and patient report results (PRO) questionnaire will now be carried out.

For details, see: asco.
org/record/201516/abstract" target="_blank" rel="noopener">A randomized phase III post-operative trial of platinum-based chemotherapy (P) versus capecitabine (C) in patients (pts) with residual triple-negative breast cancer (TNBC) following neoadjuvant chemotherapy (NAC): ECOG-ACRIN EA1131 For details, please refer to:asco.
org/record/201516/abstract" target="_blank" rel="noopener"> A randomized phase III post-operative trial of platinum-based chemotherapy (P) versus capecitabine (C) in patients (pts) with residual triple-negative breast cancer (TNBC) following neoadjuvant chemotherapy (NAC): ECOG -ACRIN EA1131 A randomized phase III post-operative trial of platinum-based chemotherapy (P) versus capecitabine (C) in patients (pts) with residual triple-negative breast cancer (TNBC) following neoadjuvant chemotherapy (NAC): ECOG-ACRIN EA1131

DOI: 10.
1200/JCO.
2021.
39.
15_suppl.
605

3.
Evaluation of cerebrospinal fluid (CSF) samples circulating tumor DNA (ctDNA) for early detection of brain metastases (BrM) in patients with triple-negative breast cancer (TNBC)

3.
Assessment of circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) samples for early detection of brain metastases (BrM) in patients with triple-negative breast cancer (TNBC) 3.
Assessment of circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) samples to three The practicality of early detection of brain metastases (BrM) in patients with negative breast cancer (TNBC)

background:

Background: Background:

Although treatment has improved, patients diagnosed with TNBC have a poorer prognosis and are more likely to develop BrM.
Identifying patients at high BrM risk, so as to be able to predict who will benefit from appropriate additional treatment, remains a key issue.
ctDNA represents a valuable tool related to breast cancer outcome and aggressiveness, but prognostic and predictive biomarkers have not yet been identified to predict the occurrence of BrM in TNBC.
We studied the usefulness of evaluating CSF-ctDNA for early identification of BrM risk in TNBC.

method:

Method: Method:

Between January 2016 and December 2020, 323 newly diagnosed non-metastatic TNBC patients who underwent neoadjuvant therapy + surgery (NACT) and had complete remission (CR) were prospectively enrolled.
After the operation, samples for CSF measurement of ctDNA were obtained from all patients: CSF-ctDNA was extracted with QIAamp Circulating Nucleic Acid Kit (Qiagen, Valencia, CA, USA), and ctDNA levels were measured.
The Kaplan-Meier method was used to estimate the survival curve and compared with the log-rank test.
Multivariate Cox regression was used to determine the risk of death at 3 years.

result:

Result: Result:

NACT，126/323（39％）CSF-ctDNA，III101/126（80％）。126（98.
4％）ctDNA +124BrM。，2（2/197，1％）ctDNABrM，195CR（p <0.
001，Fisher）。CSF-ctDNAPFSOS：ctDNAPFS（HR 0.
3; p = 0.
002）OS（HR 0.
2; p <0.
01），BrM。3，ctDNA +ctDNA-PFS13vs，p = 0.
004（）。ctDNA +ctDNA-OSNACT16，p = 0.
0016（）。，CSF-ctDNABrM24（HR：3.
62； p <0.
0001）。，，Ki67％。

：

：：

NACT，CSF-ctDNAPFSOS，TNBCBrM。

：asco.
org/record/201550/abstract" target="_blank" rel="noopener">Usefulness of assessment of circulating tumor DNA(ctDNA) of cerebrospinal fluid(CSF) samples for early detection of brain metastasis (BrM) in patients with triple-negative breast cancer (TNBC)：：asco.
org/record/201550/abstract" target="_blank" rel="noopener">Usefulness of assessment of circulating tumor DNA(ctDNA) of cerebrospinal fluid(CSF) samples for early detection of brain metastasis (BrM) in patients with triple-negative breast cancer (TNBC)Usefulness of assessment of circulating tumor DNA(ctDNA) of cerebrospinal fluid(CSF) samples for early detection of brain metastasis (BrM) in patients with triple-negative breast cancer (TNBC)

DOI:10.
1200/JCO.
2021.
39.
15_suppl.
507

4.
4.

：

：：

，（（TNBC））。，，，，，。，I-III（TNBC）。

：

：：

，（SEER）-（TCR）-。20082015I-III66。Cox（OS）（BCSS），，，，，，，，，，，，，。BCSS，FineGray。12，。

：

：：

45063I-III，22,518（50.
0％）（）。55.
9％6.
9％（P <.
001>P = .
021），OS（[HR]，0.
96； 95％CI，0.
901.
03；P = 0.
23）。TNBCBCSS（SHR，0.
60; 95％CI，0.
420.
86; P = .
006）OS（HR，0.
76; 95％CI，0.
610.
95; P= .
018）。，TNBC。，。

We identified 45,063 patients with stage I-III breast cancer who met the inclusion criteria, of which 22,518 (50.
0%) received statins (patients using statins) within one year after diagnosis.
The cumulative 5-year cumulative breast cancer-specific deaths of statin users and non-users are estimated to be 5.
9% and 6.
9%, respectively (P <.
001>P = .
021), but have nothing to do with OS (hazard ratio [HR], 0.
96; 95% CI, 0.
90 to 1.
03; P = 0.
23).
BCSS (SHR, 0.
60; 95% CI, 0.
42 to 0.
86; P = .
006) and OS (HR, 0.
76; 95% CI, 0.
61 to 0.
95; P = .
018) in patients with TNBC.
It has been shown in stages that the treatment of statins in TNBC is limited to patients with local diseases.
When using a propensity score matching model and limiting our analysis to statin treatment started after breast cancer diagnosis, our results are consistent.
<.
001>P = .
021), but not related to OS (hazard ratio [HR], 0.
96; 95% CI, 0.
90 to 1.
03; P = 0.
23).
BCSS (SHR, 0.
60; 95% CI, 0.
42 to 0.
86; P = .
006) and OS (HR, 0.
76; 95% CI, 0.
61 to 0.
95; P = .
018) in patients with TNBC.
It has been shown in stages that the treatment of statins in TNBC is limited to patients with local diseases.
When using a propensity score matching model and limiting our analysis to statin treatment started after breast cancer diagnosis, our results are consistent.
P P P

in conclusion:

Conclusion: Conclusion:

，TNBCOSBCSS。，，，TNBC，，。

：asco.
org/record/198419/abstract" target="_blank" rel="noopener">Association of statin use with clinical outcomes in patients with triple-negative breast cancer.

：asco.
org/record/198419/abstract" target="_blank" rel="noopener">Association of statin use with clinical outcomes in patients with triple-negative breast cancer.
：：asco.
org/record/198419/abstract" target="_blank" rel="noopener">Association of statin use with clinical outcomes in patients with triple-negative breast cancer.
Association of statin use with clinical outcomes in patients with triple-negative breast cancer.

DOI:10.
1200/JCO.
2021.
39.
15_suppl.
523

5.
（TNBC）（NACT）

5.
（TNBC）（NACT）5.
（TNBC）（NACT）

：

：：

，。，。，32NACT，。，TNBCNACT。

：

：：

ARTEMIS（NCT02276443）85TNBC。NACT/（AC）；，4AC<70％（VR）NACT，。2x250 bp85ACDNA16S。，MothurSilva138。，，，，，logit，DESeq2。phyloseqα-。α（）。UniFracβ。DESeq2（pCR）（RD）。

：

：：

85AC。，pCR46，RD39。pCRRD，α（p = 0.
8）β（p = 0.
7）。，RD，pCR（p = 0.
03）。RDLachnospiraceae（p = 0.
03）Bacteroides thetaiotaomicron（p = 0.
02）。

：

：：

RD，pCR。，（）TNBC。

：asco.
org/record/198325/abstract" target="_blank" rel="noopener">The impact of gut microbial composition on response to neoadjuvant chemotherapy (NACT) in early-stage triple negative breast cancer (TNBC).
：：asco.
org/record/198325/abstract" target="_blank" rel="noopener">The impact of gut microbial composition on response to neoadjuvant chemotherapy (NACT) in early-stage triple negative breast cancer (TNBC).
The impact of gut microbial composition on response to neoadjuvant chemotherapy (NACT) in early-stage triple negative breast cancer (TNBC).

DOI:10.
1200/JCO.
2021.
39.
15_suppl.
590

6.
6.

：

：：

（LRR）（BC）。

：

：：

04 / 2005-12 / 2013I-III BC，LRR。LRR，/BC120。LRR，（OS）OS，（AdTx）。：Luminal（Lum）A-（ER）（PR），HER212。Bum-BumA3，Aum，ERPR；（TNBC）-ER，PRHER2; HER2（ER，PR）。LRR，AdTx：（a）TNBC：> = 50％（Chx）。

：

：：

492，LRR7.
211.
8。LRR69.
3％（n = 341），+/-30.
7％（n = 151）。，TN，Lum（p <= 0.
01）。LRR82％，32％，：ER3.
8％，6.
1％；PR9.
1％，15.
1％；HER23.
7％，4.
8％。（n = 255，52％）AdTx。AdTx，。LRR（2.
7）。

（OS）（）

：

：：

LRROS。LRROS，TNBC，Lum A。AdTx。，Lum ALRROSB，。，OS，LRR。

：asco.
org/record/198368/abstract" target="_blank" rel="noopener">Survival following locoregional recurrence in breast cancer by clinical subtype.

：asco.
org/record/198368/abstract" target="_blank" rel="noopener">Survival following locoregional recurrence in breast cancer by clinical subtype.
：：asco.
org/record/198368/abstract" target="_blank" rel="noopener">Survival following locoregional recurrence in breast cancer by clinical subtype.
Survival following locoregional recurrence in breast cancer by clinical subtype.

DOI:10.
1200/JCO.
2021.
39.
15_suppl.
543

7.
（AC）（TNBC）（pts）（atezo）-（nab-p）

7.
（AC）（TNBC）（pts）（atezo）-（nab-p）7.
（AC）（TNBC）（pts）（atezo）-（nab-p）

：

：：

PD-（L）1TNBC（pCR）。，（irAE），。（NAT）pCR（2-5％，GeparTrioAberdeen）。，TNBCptsatezonab-pNATII，AC（NCT02530489）。

I-IIITNBC（AC）4，80％。Ptsatezo（1200mg IV，Q3x 4）nab-p（100mg / m2 IV，Q1，x 12）NAT，atezo（1200mg IV，Q3，x 4） 4）。，GehanpCR5％20％，，，II / III。，378pCR。，TIL（n = 29）。

：

：：

2 / 2016-12 / 2020，34。NAT33，pCR30％（10 / 33，95％CI：16-49％），pCR / RCB-142％（14 / 33，95％CI：25） -61％）。。≥20％（）（73％），（55％），（55％），（48％），（42％），ALT（39％），AST（33％），（30％），（24％），（21％），（21％）。irAEs4（12％，[n = 2]；[n = 1]；[n = 1]）；2pCR。

：

：：

，pt（pCR = 30％，5％）。irAEs12％AC。。

：asco.
org/record/198304/abstract" target="_blank" rel="noopener">Neoadjuvant atezolizumab (atezo) and nab-paclitaxel (nab-p) in patients (pts) with triple-negative breast cancer (TNBC) with suboptimal clinical response to doxorubicin and cyclophosphamide (AC)：：asco.
org/record/198304/abstract" target="_blank" rel="noopener">Neoadjuvant atezolizumab (atezo) and nab-paclitaxel (nab-p) in patients (pts) with triple-negative breast cancer (TNBC) with suboptimal clinical response to doxorubicin and cyclophosphamide (AC)Neoadjuvant atezolizumab (atezo) and nab-paclitaxel (nab-p) in patients (pts) with triple-negative breast cancer (TNBC) with suboptimal clinical response to doxorubicin and cyclophosphamide (AC)

DOI:10.
1200/JCO.
2021.
39.
15_suppl.
592

8.
talimogene laherparepvec（TVEC）2

8.
talimogene laherparepvec（TVEC）28.
talimogene laherparepvec（TVEC）2

：

：：

TVEC1（HSV1），FDA。TVEC，GM-CSF，T（TIL）。TIL（NAC），TVECNAC。2-3 TNBCNACTVEC2。

：

：：

II-III TNBC PTS（N = 37），22TVEC（10 ^ 6 PFU 1 ^ST10 ^ 8 PFU×4）1,4-2,6,8,10 +（80mg / m2）x 12，q2AC（/60/600 mg / m2）x 4。0（RCB0）。p1 = 45％vs.
p0 = 30％，I0.
10，70％，37≥15RCB0。

II-III TNBC PTS（N = 37），22TVEC（10 ^ 6 PFU 1 ^ST10 ^ 8 PFU×4）1,4-2,6,8,10 +（80mg / m2）x 12，q2AC（/60/600 mg / m2）x 4。0（RCB0）。p1 = 45％vs.
p0 = 30％，I0.
10，70％，37≥15RCB0。^ST

：

：：：

Moffitt（5/2018 – 4/2020）40，3，，。：49（27-66），67.
5％，10％，15％，II83％III 17％，+ 42％。RCB0= 16/37（43％，95％CI 27-61％）9RCB-1（RCB0 / 168％，95％CI 50-82％）。NAC，G1-2，，。4G2-3（10％），NAC6％。

：

：：

NACTVECRCB0，，TNBC。。

：asco.
org/record/198341/abstract" target="_blank" rel="noopener">A phase 2 trial of talimogene laherparepvec (TVEC) in combination with neoadjuvant chemotherapy for the treatment of nonmetastatic triple-negative breast cancer：：asco.
org/record/198341/abstract" target="_blank" rel="noopener">A phase 2 trial of talimogene laherparepvec (TVEC) in combination with neoadjuvant chemotherapy for the treatment of nonmetastatic triple-negative breast cancerA phase 2 trial of talimogene laherparepvec (TVEC) in combination with neoadjuvant chemotherapy for the treatment of nonmetastatic triple-negative breast cancer

DOI:10.
1200/JCO.
2021.
39.
15_suppl.
578

9.
（AA）（NonAA）（TNBC）

9.
（AA）（NonAA）（TNBC）9.
（AA）（NonAA）（TNBC）

：

：：

NonAA，（AA）（TNBC）（）。。NonAAAATNBC。

：

：：

，，2000- 2017。，。（WES），RNA，PD-L1（SP142）。H＆E（sTIL）。，。（TIDE）。

：

：：

The tumor mutation burden was similar between the two cohorts.
At the genetic level, few genes have significantly different somatic mutation frequencies, or differential mRNA expression between AA and NonAA samples.
Changes in the pathway level showed that somatic mutations in AA samples had a greater impact on inflammation, immunity (adaptability; congenital), antigen presentation, and allograft rejection pathways.
The affected genes vary from cancer to cancer, and there is no recurrence, so they were missed in the gene-level analysis.
Gene set enrichment and co-expression analysis also showed that AA samples had higher expression of immune-related pathways.
Unsupervised co-expression cluster analysis confirmed that genes involved in immunity, inflammation, and cytokine/chemokine signaling in AA patients were cooperatively overexpressed.
Two predictive features of immunotherapy response, immune sample inflammation, IFNG and sTILs score in AA sample, and PD-L1 positive rate are also higher.
These findings increase the possibility that immune checkpoint inhibitors may be particularly effective in AA patients.
In the NonAA samples, EMT transition, angiogenesis, adipogenesis, myogenesis, fatty acid metabolism, TGFβ signaling, ultraviolet response, and hypoxia pathways were overexpressed.
TIDE analysis showed that TAM M2 in NonAA samples had higher overall TIDE scores and immune rejection scores.
Both UV response and hypoxia pathways are overexpressed.
TIDE analysis showed that TAM M2 in NonAA samples had higher overall TIDE scores and immune rejection scores.
Both UV response and hypoxia pathways are overexpressed.
TIDE analysis showed that TAM M2 in NonAA samples had higher overall TIDE scores and immune rejection scores.

in conclusion:

Conclusion: Conclusion:

Compared with NonAA patients, TNBC in AA patients more often has somatic mutations in genes related to immune function and overexpresses immune and inflammatory genes.

For details, see:asco.
org/record/198464/abstract" target="_blank" rel="noopener"> Characterization of the tumor immune microenvironment of triple negative breast cancer (TNBC) patients who self-identify as African American (AA) or non-African American (NonAA)

For details see: For details see: For details see:asco.
org/record/198464/abstract" target="_blank" rel="noopener"> Characterization of the tumor immune microenvironment of triple negative breast cancer (TNBC) patients who self-identify as African American (AA) or non-African American (NonAA) Characterization of the tumor immune microenvironment of triple negative breast cancer (TNBC) patients who self-identify as African American (AA) or non-African American (NonAA)

DOI: 10.
1200/JCO.
2021.
39.
15_suppl.
564

10.
Predict the benefit of thyroid capecitabine maintenance therapy in early triple-negative breast cancer: the results of the SYSUCC-001 study

10.
Predict the benefits of thyroid capecitabine maintenance therapy in early triple-negative breast cancer: the results of the SYSUCC-001 study 10.
Predict the benefits of thyroid capecitabine maintenance therapy in early triple-negative breast cancer: the results of the SYSUCC-001 study

background:

Background: Background:

Recent clinical trials and meta-analysis have shown the benefits of adding capecitabine to standard chemotherapy for early triple-negative breast cancer (TNBC).
We aim to develop a personalized predictive model to quantify the clinical benefit of maintaining rhythmic capecitabine in TNBC.

method:

Method: Method:

Patients from the SYSUCC-001 trial were pooled and randomly assigned to receive or not receive the standard treatment of rhythmic capecitabine maintenance therapy.
Candidate covariates include age, tumor size, lymph nodes, histological grade, Ki-67 percentage, lymphatic invasion, chemotherapy regimen, and capecitabine medication.
The primary endpoint is disease-free survival (DFS).
The nonlinear effects of continuous covariates are modeled by restricted cubic splines.
We developed a survival prediction model using the Cox proportional hazards model.

result:

Result: Result:

A total of 434 patients were recruited (306 in the development cohort and 128 in the validation cohort).
In the development cohort and validation cohort, the estimated 5-year DFS was 77.
8% (95% CI, 72.
9-82.
7%) and 78.
2% (95% CI, 70.
9-85.
5%), respectively.
Age and lymph nodes have a significant non-linear effect on DFS.
In the final prediction model, the four covariates that were significantly related to DFS were age, lymph nodes, lymphatic invasion and capecitabine medication.
The model has a C index of 0.
722 (95% CI, 0.
662-0.
781) and 0.
764 (95% CI, 0.
668-0.
859) in the development cohort and the validation cohort, respectively, showing suitable calibration and fair discrimination capabilities.
Based on this model, we designed an easy-to-use online calculator that can predict the maintenance benefits of capecitabine.

in conclusion:

Conclusion: Conclusion:

Evidence-based predictive models can identify those patients most in need of maintaining rhythmic capecitabine therapy, thereby helping to make treatment decisions in daily clinical practice.

For details, see:asco.
org/record/198312/abstract" target="_blank" rel="noopener"> Predict the benefit of metronomic capecitabine maintenance in early-stage triple-negative breast cancer: Results from the SYSUCC-001 study

For details see: For details see: For details see:asco.
org/record/198312/abstract" target="_blank" rel="noopener"> Predict the benefit of metronomic capecitabine maintenance in early-stage triple-negative breast cancer: Results from the SYSUCC-001 study Predict the benefit of metronomic capecitabine maintenance in early-stage triple-negative breast cancer: Results from the SYSUCC-001 study

DOI: 10.
1200/JCO.
2021.
39.
15_suppl.
521

This is a column that is being continuously updated, please pay attention to save this column~

This is a column that is being continuously updated, please pay attention to save and bookmark this column~ This is a column that is being continuously updated, please pay attention to save and bookmark this column~

For more information, follow the ASCO special page of Metz Medicine: https://meeting.
medsci.
cn/ASCO2020

https://meeting.
medsci.
cn/ASCO2020

Reference source: https://meetinglibrary.
asco.
org/results?meetingView=2021%20ASCO%20Annual%20Meeting

https://meetinglibrary.
asco.
org/results?meetingView=2021%20ASCO%20Annual%20Meeting

Leave a message here

This article is an English version of an article which is originally in the Chinese language on echemi.com and is provided for information purposes only. This website makes no representation or warranty of any kind, either expressed or implied, as to the accuracy, completeness ownership or reliability of the article or any translations thereof. If you have any concerns or complaints relating to the article, please send an email, providing a detailed description of the concern or complaint, to service@echemi.com. A staff member will contact you within 5 working days. Once verified, infringing content will be removed immediately.