Real World Experience of Second-Line Treatment Strategies after Palbociclib and Letrozole: Overall Survival in Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer

Round 1

Reviewer 1 Report

Review of:

Real world experience of second-line treatment strategies after palbociclib and letrozole: Overall survival in metastatic hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer

 

Comments to the Authors

The authors present real world data for the considerations for second line treatments after CDk4/6 aromatase inhibitor treatment.

They conclude that for the first-line treatment most significant factors for OS are visceral mets, elevated CA-15-3, BRCA status and number of metastatic organs.

Second-line treatments OS factors were visceral mets, number of met. Organs, ER-driven, visceral vs bone, treatments.

Capecitabine showed the best OS and PFS even in bone met patients, although Fulvestrant was preferred.

In summary, the authors showed a comprehensive analysis of their patient data.

 

Detailed comments/questions:

What is the treatment in the cohort “clinical trials”?

Where any bone mets observed in the first-line treatment? If yes please include them in supplemental table 1

What are the “other” met sites, besides visceral and bone. Any information?

In Table 4: The number of mets are a significant as well as “visceral” vs “only bone”. Can those factors be stratified in more detailed fashion?

Line 148-149: This sentence does not look complete.  “… was influenced (…).” [by what?]

Minor editing required

Author Response

Reviewer 1.

The authors present real world data for the considerations for second line treatments after CDk4/6 aromatase inhibitor treatment. They conclude that for the first-line treatment most significant factors for OS are visceral mets, elevated CA-15-3, BRCA status and number of metastatic organs. Second-line treatments OS factors were visceral mets, number of met. Organs, ER-driven, visceral vs bone, treatments. Capecitabine showed the best OS and PFS even in bone met patients, although Fulvestrant was preferred. In summary, the authors showed a comprehensive analysis of their patient data.

 

Detailed comments/questions:

What is the treatment in the cohort “clinical trials”?

: Thanks for your comments. In our cohort, 18 patients were enrolled in clinical trial as the second line treatment. Of 18 patients, 10 were enrolled in CAPitello-291, two in PETRA, two in CO23867, two in EMBER, one in C0541001 and one in ACT16105.

The information of each clinical trial is described as below.

Trial Name	NCT nurmber	Title
CAPitello-291	NCT04305496	Capivasertib+Fulvestrant vs Placebo+Fulvestrant as Treatment for Locally Advanced (Inoperable) or Metastatic HR+/HER2- Breast Cancer
PETRA	NCT04644068	Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies (PETRA)
CO42867	NCT04802759	A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Participants With Breast Cancer
EMBER	NCT04188548	A Study of LY3484356 in Participants With Advanced or Metastatic Breast Cancer or Endometrial Cancer
C0541001	NCT03284723	PF-06804103 Dose Escalation in HER2 Positive and Negative (Negative Only in Part 2) Solid Tumors
ACT16105	NCT04059484	Phase 2 Study of Amcenestrant (SAR439859) Versus Physician's Choice in Locally Advanced or Metastatic ER-positive Breast Cancer

 

Where any bone mets observed in the first-line treatment? If yes please include them in supplemental table 1.

: We already presented metastatic lesions at diagnosis in our previous study (DOI: 10.3389/fonc.2021.759150). According to disease progression after palbociclib with letrozole, 57 patients who had initially bone metastasis only have underwent disease progression whereas 46 patients did not undergo disease progression. We added this information in supplementary table 1.

Supplementary Table 1. Baseline patient characteristics (N=305)

Metastatic sites			<.001
Visceral	52 (28.7)	14 (11.3)
Liver	48 (26.5)	12(9.7)
Non-visceral	129 (71.3)	110 (88.7)
Bone only	57 (31.5)	46 (37.1)

 

What are the “other” met sites, besides visceral and bone. Any information?

: Other metastatic sites are vary and therefore we categorized all metastatic lesions into three; visceral, bone only and others. According to your comment, we added the information of disease progression sites in supplementary table 3.

Supplementary Table 3. Disease progression sites after palbociclib with letrozole (N=164)

Organ	N (%)
Visceral	64 (39.0%)
Liver	61 (37.2%)
Central nerve system	4 (2.4%)
Lymphangitic lung metastases	1 (0.6%)
Non-visceral metastasis	53 (32.3%)
Lung	11 (6.7%)
Lymph nodes	27 (16.5%)
Breast	12 (7.3%)
Pleura	8 (4.9%)
Ovary	1 (0.6%)
Stomach	1 (0.6%)
Bone only	47 (28.7%)

 

In Table 4: The number of mets are a significant as well as “visceral” vs “only bone”. Can those factors be stratified in more detailed fashion?

: We also analyzed our data according to your comment. Before analysis, we check the number of metastatic sites.

Number of sites	N(%)
1	74 (45.1%)
2	62 (37.8%)
3	18 (11.0%)
4	5 (3.0%)
5	3 (1.8%)
7	2 (1.2%)

Therefore, we divided the number of sites into 3 categories : one, two, three or metastatic sites. The result of analysis was described as below.

Factors for OS	Ref	N	Hazard ratio	95% CI		P-value
Visceral metastasis	No	120				0.016
Yes		44	2.415	1.181	4.926
Initial CA-15-3	Normal	81				0.239
Elevation		74	1.420	0.831	2.425
Unknown		9	0.525	0.114	2.424
Germline BRCA status	Wild type	54				0.975
Mutation		6	1.065	0.295	3.848
Not tested		104	0.948	0.493	1.926
Number of meta organs	1	74				0.045
2		62	2.101	1.148	3.844
3 or more		28	1.762	0.867	3.584
ER-driven BC	No	66				<0.001
Yes		98	0.155	0.085	0.284
Disease progression site	Other	53				0.022
Visceral organ		64	1.952	0.984	3.875
Bone only		47	0.712	0.343	1.480
Second-line treatment	Capecitabine	47				0.253
Everolimus/exemestane		45	1.255	0.605	2.605
Other cytotoxic chemo		31	1.910	0.953	3.828
Fulvestrant		23	2.014	0.821	4.941
Clinical trials		18	0.514	0.116	2.273

 This table has similar results of previous Table 4. In addition, number of metastatic sites two and three have similar hazard ratio compared to only one metastatic site.

 

Line 148-149: This sentence does not look complete.  “… was influenced (…).” [by what?]

: Thanks for your comment. We revised our manuscript according to your comment.

Lines 152-153 : “The response duration of palbociclib with letrozole did not influence the choice of the second-line treatment strategy (p=0.209).”

 

 

Author Response File: Author Response.docx

Reviewer 2 Report

This manuscript presents an interesting study regarding the second-line treatment strategies after use of palbociclib and letrozole in hormone receptor-positive (HR+), HER2-negative (HER2−) metastatic breast cancer (MBC). The authors used real-world clinical data, and analyzed the second-line treatment regimens and progression-free and overall survival. The study is important. However, there are several points that might be addressed to clarify the findings and improve the manuscript.   Major comments: 1. What percentage of patients with HR+HER2− MBC were treated with palbociclib and letrozole as the first-line treatment? 2. The term “Not progression” would be better changed to “No progression” throughout. 3. Please clearly note the definition of the terms “Progression” and “No progression” in Supplementary Table 1. For how many years were patients with “No progression” followed up? Moreover, adding information on the contents of adjuvant treatments and the median follow-up time is recommended as characteristics in this Table. 4. When considering the treatment strategies and the progression-free and overall survival in the second-line treatment, it may also be important to consider age, ECOG performance status, expression levels of ER/PgR and Ki-67, contents of adjuvant treatments, and disease-free interval, in addition to the information on factors such as metastatic sites and the duration of the first-line therapy. Please provide these factors as clinical factors in Tables 1 to 4, regardless of the influence of these factors. 5. In the part about “Factors for OS2” in Table 2 and in Table 4, please provide PFS2 as a factor. 6. In Table 3, please provide the characteristics that were selected in Supplementary Table 1, information on the duration of the first-line therapy (or ER-driven tumors), and PFS2 as factors. 7. Please show a summary of the second-line treatment strategy, including the factors that the authors recommend should be considered after palbociclib and letrozole, in a figure in the Discussion section.   Minor comments: 1. Line 28 and line 33 in the Abstract; The full names for “PFS2” and “OS2” should be provided. 2. Line 52; “And” should be deleted. 3. Line 289; “…. in patients treated with AI alone as the first-line treatment.” Is the term “alone” necessary?

Author Response

Reviewer 2.

This manuscript presents an interesting study regarding the second-line treatment strategies after use of palbociclib and letrozole in hormone receptor-positive (HR+), HER2-negative (HER2−) metastatic breast cancer (MBC). The authors used real-world clinical data, and analyzed the second-line treatment regimens and progression-free and overall survival. The study is important. However, there are several points that might be addressed to clarify the findings and improve the manuscript.  

Major comments:

1. What percentage of patients with HR+HER2− MBC were treated with palbociclib and letrozole as the first-line treatment?

: In Korea, CDK4/6 inhibitor with aromatase inhibitor can be used as the first line treatment only in metastatic setting and regulated by Ministry of Food and Drug Safety. From July 2016, to December 2021, 465 patients received the first line endocrine treatment of HR+HER2- metastatic breast cancer in Samsung Medical Center. Of 465 patients, 305 patients were treated with palbociclib with letrozole followed by 65 patients with aromatase inhibitor alone, 63 patients with tamoxifen, 15 patients with palbociclib with fulvestrant, nine with abemaciclib with letrozole, five with ribociclib with letrozole and three with GnRH agonist single. This situation depended on the regulation of Ministry of Food and Drug Safety.

1. The term “Not progression” would be better changed to “No progression” throughout.

: Thanks for your consideration. We revised our manuscript according to your comment.

Supplementary Table 1. Baseline patient characteristics (N=305)

Characteristic

Progression (N=181)

No progression (N=124)

P-value

 

2. Please clearly note the definition of the terms “Progression” and “No progression” in Supplementary Table 1. For how many years were patients with “No progression” followed up? Moreover, adding information on the contents of adjuvant treatments and the median follow-up time is recommended as characteristics in this Table.

: Median follow up duration is 41.7 months in all patients; 44.7 months in patients who have not experienced disease progression and 39.8 months in patients. Of 305 patients, 39 patients had been received neoadjuvant chemotherapy and 164 patients had adjuvant chemotherapy. 

According to your comment, we revised our manuscript.

Supplementary Table 1. Baseline patient characteristics (N=305)

Characteristic	Progression (N=181)	No progression (N=124)	P-value
Median FU1 (IQR)2	39.8 (30.7,49.7)	44.7 (36.1, 50.1)
Age			.308
Median (range)	51.5 (31.5, 78.1)	52.0 (33.3, 86.7)
<50 years old	80 (44.2)	50 (40.3)
>50 years old	101 (55.8)	74 (59.7)
ECOG PS3			.465
0	104 (57.5)	73 (58.9)
1	75 (41.4)	47 (37.9)
≥2	2 (1.1)	3 (2.4)
Unknown	0	1 (0.8)
Disease status			.716
De novo	62 (34.3)	45 (36.3)
Recurred	119 (65.7)	79 (63.7)
Adjuvant CTx4	92 (50.8)	71 (57.3)
Neoadjuvant CTx	27 (14.9)	8 (6.4)
Disease-free interval5	(n=198)		.056
<12 months	76 (63.9)	39 (49.4)
≥12 months	43 (36.1)	40 (50.6)
Metastatic sites			<.001
Visceral	52 (28.7)	14 (11.3)
Liver	48 (26.5)	12(9.7)
Non-visceral	129 (71.3)	110 (88.7)
Bone only	57 (31.5)	46 (37.1)
No. of disease sites			.012
1	81 (44.8)	77 (62.1)
2	68 (37.6)	32 (25.8)
3 or more	32 (17.6)	15 (12.1)
Germline BRCA status			.041
Not tested	115 (63.5)	91 (73.4)
BRCA1/2 mutation	6 (3.3)	0
No BRCA mutation	60 (33.2)	33 (26.6)
Initial CA-15-3 status			.001
Normal range	91 (50.3)	85 (68.5)
Elevated	81 (44.8)	30 (24.2)
Unknown	9 (4.9)	9 (7.3)
Initial CEA status			<0.001
Normal range	128 (70.7)	103 (83.1)
Elevated	49 (27.1)	13 (10.5)
Unknown	4 (2.2)	8 (6.4)

1: follow up; 2: Interquartile range; 3: performance status; 4: chemotherapy; 5:defined as breast cancer recurrence within 1 year following adjuvant ET completion

1. When considering the treatment strategies and the progression-free and overall survival in the second-line treatment, it may also be important to consider age, ECOG performance status, expression levels of ER/PgR and Ki-67, contents of adjuvant treatments, and disease-free interval, in addition to the information on factors such as metastatic sites and the duration of the first-line therapy. Please provide these factors as clinical factors in Tables 1 to 4, regardless of the influence of these factors.

: We performed further analysis according to your comment. In this analysis, ECOG performance status, initial visceral metastasis and primary endocrine resistance were affected to choice of 2^nd line treatment after palbociclib with letrozole.

 According to this analysis, we updated Table 1 and result section.

Table 1. Relationships between clinical factors and the second-line treatment regimen (N=164)

	Capecitabine	Eve/Exe	Cytotoxic	Fulvestrant	Clinical trial	P-value
Age						0.292
<50YO (n=74)	19	26	12	8	9
>50YO(n=90)	28	19	19	15	19
ECOG						0.001
0 (n=98)	30	32	23	9	4
1-2 (n=66)	17	13	8	14	14
Initial ER score						0.971
Strong (n=147)	42	40	29	20	16
Weak (n=17)	5	5	2	3	2
Initial PgR score						0.477
Strong (n=64)	17	13	17	6	11
Weak (n=63)	19	19	10	11	4
No (n=37)	11	13	4	6	3
Initial Ki-67 score						0.326
1+ (n=103)	31	28	15	16	13
2+ (n=46)	12	14	13	4	3
3+ (n=12)	3	2	2	3	2
4+ (n=3)	1	1	1	0	0
Initial visceral metastasis						0.006
No (n=120)	26	39	21	20	14
Yes (n=44)	21	6	10	3	4
Number of metastatic sites						0.262
1 (n=74)	16	20	13	15	10
2 (n=88)	18	20	12	5	6
3 or more (n=29)	13	5	6	3	2
Endocrine resistance in adjuvant setting						0.011
De novo (n=70)	22	14	11	12	11
Primary ET resistance (n=28)	14	4	4	5	1
Secondary ET resistance (n=27)	4	12	6	1	4
No ET resistance (n=39)	7	15	10	5	2
Disease progression sites						0.008
Others (n=53)	16	13	9	9	6
Visceral meta (n=64)	20	14	20	4	6
Bone only (n=47)	11	18	2	10	6
PFS of the first line treatment						0.209
ER driven (n=98)	25	28	15	16	14
Not driven(n=66)	22	17	16	7	4

1: years of age; 2: performance status; 3: Estrogen receptor; 4: Progesterone receptor; 5:diseae recurrence before 24 months of adjuvant endocrine therapy; 6: disease recurrence between after 24 months of adjuvant endocrine therapy and after 12 months of the end of endocrine therapy; 7: progression free survival

Lines 153-156 : “Other clinical factors including eastern cooperative oncology group(ECOG) performance status (p=0.001), initial visceral metastasis (p=0.006) and endocrine resistance in adjuvant setting (p=0.011) were associated with second-line treatment strategies.”

 

2. In the part about “Factors for OS2” in Table 2 and in Table 4, please provide PFS2 as a factor.

: PFS2 is continuous factor not numeric factor. So, we made PFS2 to categorical factors according to median PFS2(months). In addition, ECOG performance status, initial visceral metastasis and endocrine resistance state were associated to 2^nd line treatment and therefore we added these factors for revising table 2.

 

Table 2. Clinical characteristics that affected progression-free survival 2 and overall survival 2 (N=164)

Factors for PFS2	Ref	N	Hazard ratio	95% CI		P-value
ECOG PS1	0	98				0.793
1-2		66	1.054	0.710	1.566
Endocrine resistance	De novo	70				0.778
Primary resistance		28	1.000	0.603	1.660
Secondary resistance		27	0.814	0.488	1.358
No resistance		39	0.817	0.511	1.307
Initial visceral metastasis	No	120				0.596
Yes		44	1.166	0.717	1.896
ER2-driven BC3		66				0.078
Yes	No	98	0.725	0.507	1.036
Disease progression site		53				0.039
Visceral organ	Other	64	1.169	0.773	1.768
Bone only		47	0.633	0.397	1.000
Second-line treatment	Capecitabine	47				0.031
Everolimus/exemestane		45	1.665	1.038	2.670
Other cytotoxic chemo		31	1.655	0.995	2.753
Fulvestrant		23	2.383	1.364	4.163
Clinical trials		18	1.713	0.904	3.246
Factors for OS2	Ref	N	Hazard ratio	95% CI		P-value
ECOG PS1	0	98				0.720
1-2		66	0.897	0.494	1.628
Endocrine resistance	De novo	70				0.759
Primary resistance		28	0.770	0.373	1.593
Secondary resistance		27	0.687	0.297	1.590
No resistance		39	0.980	0.465	2.065
Initial visceral metastasis	No	120				0.039
Yes		44	2.097	1.039	4.234
ER2-driven BC3	No	66				0.019
Yes		98	0.525	0.306	0.901
Disease progression site	Other	53				0.026
Visceral organ		64	2.339	1.166	4,234
Bone only		47	0.967	0.461	2.027
Second-line treatment	Capecitabine	47				0.316
Everolimus/exemestane		45	0.890	0.421	1.878
Other cytotoxic chemo		31	1.253	0.600	2.617
Fulvestrant		23	0.669	0.274	1.631
Clinical trials		18	0.292	0.064	1.328
PFS24	≦5.2months	47				<0.001
>5.2 months		76	0.323	0.188	0.589

1: Eastern Cooperative Oncology Group Performance Status; 2: Estrogen receptor; 3: Breast cancer; 4:Progression free survival 2

 

Lines 175-179 : “In terms of OS2, PFS2 was the strongest prognostic factor of OS2 (hazard ratio:0.32, 95%Cis:0.19,0.59; p<0.001). In addition, ER-driven BC was associated with good OS2 (hazard ratio: 0.53, 95%CIs: 0.31, 0.90; p=0.019) whereas initial visceral metastasis and visceral organ disease progression were associated with poor OS2 (hazard ratio: 2.10, 95%CIs: 1.04, 4.23; p=0.039 and hazard ratio: 2.34, 95%CIs: 1.17, 4.23; p=0.026).”

 

For revising Table 4, we added PFS2 for multivariate analysis.

Table 4. Clinical characteristics that affected the OS in patients receiving second-line treatment (N=164)

Factors for OS	Ref	N	Hazard ratio	95% CI		P-value
Visceral metastasis	No	120				0.062
Yes		44	1.935	0.968	3.867
Initial CA-15-3	Normal	81				0.609
Elevation		74	1.295	0.762	2.200
Unknown		9	0.924	0.208	4.095
Germline BRCA status	Wild type	54				0.604
Mutation		6	1.571	0.475	5.199
Not tested		104	0.899	0.482	1.674
Number of meta organs	1	74				0.048
2 or more		90	1.705	1.004	2.894
ER-driven BC	No	66				<0.001
Yes		98	0.180	0.103	0.316
Disease progression site	Other	53				0.034
Visceral organ		64	2.191	1.099	4.368
Bone only		47	0.932	0.444	1.956
Second-line treatment	Capecitabine	47				0.373
Everolimus/exemestane		45	0.984	0.469	2.063
Other cytotoxic chemo		31	1.318	0.624	2.786
Fulvestrant		23	0.829	0.353	1.947
Clinical trials		18	0.292	0.065	1.318
PFS21	≦5.2months	47				<0.001
>5.2 months		76	0.340	0.194	0.598

1: Progression Free Survival 2

In this analysis, PFS2 is significantly associated to OS and OS2. These contents were added in result section and discussion section.

 

3. In Table 3, please provide the characteristics that were selected in Supplementary Table 1, information on the duration of the first-line therapy (or ER-driven tumors), and PFS2 as factors.

: We demonstrated that the impact of baseline characteristics on overall survival in Table 3. Therefore, ER-driven tumor and PFS2 did not exist in Table 3 but in Table 4. According to your comment, we revised table 3 and result section.

Table 3. Clinical characteristics that affected overall survival (N=305)

Factors	Ref	N	Hazard ratio	95% CI		P-value
Age	<50	130				0.131
>50 years old		175	1.493	0.888	2.510
ECOG PS1	0	177				0.658
1		122	0.793	0.483	1.301
2		5	1.543	0.434	5.484
Unknown		1	-	-	-
Visceral metastasis	No	239				0.068
Yes		66	1.599	0.967	2.645
Initial CA-15-3	Normal	272				0.019
Elevation		31	1.922	1.184	3.120
Unknown		2	0.706	0.67	2.986
Initial CEA	Normal	272				0.908
Elevation		31	0.987	0.550	1.771
Unknown		2	1.505	0.231	9.790
Endocrine resistance	De novo	70				0.031
Primary resistance		28	2.250	1.171	4.323
Secondary resistance		27	0.854	0.427	1.705
No resistance		39	0.898	0.499	1.578
Germline BRCA status	Normal	92				0.040
Mutation		6	3.989	1.311	12.139
Not tested		207	1.460	0.867	2.459
Number of meta organs	1	157				0.021
2 or more		148	1.774	1.091	2.886

1: Eastern Cooperative Oncology Group Performance Status

 

Lines 222 – 227 : “The clinical factors that affected the OS were analyzed in all 305 patients (Table 3). In this analysis, visceral metastasis (hazard ratio: 1.60, 95% CIs: 0.97, 2.65; p=0.068), initial CA-15-3 elevation (hazard ratio: 1.92, 95% CIs: 1.18, 3.12), endocrine resistance (hazard ratio for primary resistance: 2.25, 95% CIs: 1.17,4.32), number of metastatic organs (hazard ratio: 1.774, 95% CIs: 1.091, 2.886) and germline BRCA mutation (hazard ratio: 3.99, 95% CIs: 1.31, 12.14) were all associated with a short duration of OS (p<0.05, respectively).

 

7. Please show a summary of the second-line treatment strategy, including the factors that the authors recommend should be considered after palbociclib and letrozole, in a figure in the Discussion section.  

: Thanks for your suggestion. We presented the summary diagram as your comment.

 

 

Minor comments:

1. Line 28 and line 33 in the Abstract; The full names for “PFS2” and “OS2” should be provided.

: Thanks for your comment. We revised our manuscript according to your comment.

Line 26 : “the median progression free survival of 2^nd line treatment in metastatic setting (PFS2)”

Line 31 : “The median overall survival of 2nd line treatment in metastatic setting (OS2)”

 

2. Line 52; “And” should be deleted. 3. Line 289; “…. in patients treated with AI alone as the first-line treatment.” Is the term “alone” necessary?

: Thanks for your kind review. We removed these typos according to your comment.