Potential effectiveness of combining bevacizumab with paclitaxel for treating HER2-positive metastatic breast cancer

Abstract

Although various first- to third-line HER2-targeted therapies have been established, the optimal sequence after third-line therapy has not been determined yet. Here, we describe seven patients with HER2-positive metastatic breast cancer who underwent bevacizumab (BV) and paclitaxel (PTX) combination therapy after several HER2-targeted therapies. Re-biopsy of metastatic sites was performed on four patients during the treatment prior to BV + PTX; three patients presented the same HER2-positive status as that of the primary tumor and two of whom achieved partial response. Four of seven patients achieved partial response and a 10-month median progression-free survival. Therefore, bevacizumab combined with paclitaxel is potentially effective in the treatment of HER2-positive metastatic breast cancer, if standard HER2-targeted therapy fails.

Introduction

Systemic therapies for HER2-positive metastatic breast cancer (MBC) are evolving rapidly. In 2020, trastuzumab-deruxtecan (T-Dxd) was approved as a third-line HER2-targeted therapy in Japan. Various strategies for first- to third line HER2-targeted therapies have recently been established; however, the optimal sequence after third-line therapy has not yet been determined. Bevacizumab (BV) combined with paclitaxel (BV + PTX) is so effective that it has become a popular treatment for rapidly progressing HER2-negative metastatic breast cancer (MBC) [1]. Additionally, there are several reports on the efficacy of BV in treating HER2-positive MBC. Here, we report the effectiveness of BV + PTX in seven patients with HER2-positive MBC after several HER2-targeted therapies.

Case report

Case 1

A 67-year-old female was diagnosed with advanced breast cancer (ABC) with brain, bone, and lymph node (LN) metastases. Biopsy of the breast tumor revealed a luminal-HER2 type (invasive ductal carcinoma (IDC); ER: 95%, PgR: 80%, HER2: 2 + , HER2-FISH: 2.4, Ki67: 40%). After undergoing stereotactic radiosurgery for two brain metastases, she received trastuzumab (T-mab), pertuzumab (P-mab), and docetaxel (DTX) as systemic therapy. Although a computed tomography scan showed partial response of breast tumor and LN metastasis after four cycles, both lesions had regrown by the eighth cycle. The progression-free survival (PFS) was 5 months. Re-biopsy of the breast tumor revealed no change in the subtype. T-DM1 as second-line therapy and lapatinib with capecitabine as third-line therapy were ineffective and resulted in only 1-month PFS. BV + PTX as fourth-line therapy was so effective that breast tumors and LN metastases were significantly reduced after two cycles as shown in Fig. 1. Subsequently, mastectomy with axillary dissection and latissimus dorsi reconstruction were performed to achieve local control. The pathological finding of surgical specimens was IDC (ER: 90%, PgR: 85%, HER2: 2 + , HER2-FISH: 2.1, Ki67: 60%), revealing the same subtype as the preoperative biopsy. After surgery, BV + PTX followed by letrozole combined with BV was administered. Skin metastasis developed 14 months after surgery.

Fig. 1.

The clinical course before and after BV + PTX therapy in case 1. Because BV + PTX therapy markedly reduced the tumor in the breast, mastectomy could be performed

Case 2

A 62-year-old female was diagnosed with early breast cancer with axillary LN metastases. Biopsy of the breast tumor revealed HER2 type carcinoma (IDC, ER: 0%, PgR: 0%, HER: 3 +). After receiving neoadjuvant chemotherapy (nanoparticle albumin-bound PTX + T-mab followed by 5-fluorouracil, epirubicin, and cyclophosphamide), she underwent breast-conserving surgery with axillary dissection. The pathological finding of the surgical specimens was IDC (pT1c, nuclear grade 3, ly0, v0, pN1 (2/9), ER: 0%, PgR 0%, HER2: 2 + , HER2-FISH: 3.4, Ki67: 40%). After radiation therapy for residual breast tissue, she underwent adjuvant T-mab therapy.

Left lung metastases was diagnosed 13 months after the surgery. The subtype of lung metastasis revealed by excisional biopsy was found to be the same subtype (ER 0%, PgR 0%, HER2: 3 + , Ki67: 60%) as that revealed by preoperative biopsy on the surgical specimen. The patient received T-mab + P-mab + DTX as the first-line therapy. The PFS was 7 months until the occurrence of new hilar lymph node metastases and left plural dissemination. Subsequently, she participated in a clinical trial (UMIN000012232) and received T-mab + P-mab + eribulin as second-line therapy, which resulted in a short PFS of 4 months. Neither T-DM1 nor lapatinib + capecitabine therapy was successful, and the PFS after each line was only 2 months. Metastases was exacerbated with multiple lymph nodes in the left axilla and mediastinum. BV + PTX was then administered as the fifth-line therapy and was so effective that LN metastases and plural dissemination were significantly reduced after three cycles (Fig. 2). Partial response was maintained for 13 months until two new brain metastases were detected. Because grade 3 proteinuria occurred as an adverse event of BV after 10 months, BV + PTX was followed by PTX without BV for 3 months.

Fig. 2.

Changes in the therapeutic effect of BV + PTX over time in case 2. BV + PTX was so effective that the cervical and mediastinal LN metastases and nodules of pleural dissemination were significantly reduced after three cycles

Including the above two patients, seven patients diagnosed with HER2-positive MBC underwent BV + PTX after HER2-targeted therapies between 2014 and 2020 (Table 1). Three patients had MBC, whereas the others had unresectable ABC. Re-biopsy of the metastatic sites or primary breast tumor was performed on four patients during the treatment prior to BV + PTX. Three of them had the same HER2-positive status as that of the primary tumor (cases 1, 2, and 4), and another patient revealed a conversion to HER2-negative status (case 3). Re-biopsy was not performed on the remaining three patients (cases 5, 6, and 7) because the metastatic sites were unsuitable for biopsy. Four patients underwent three HER2-targeted therapies (T-mab + P-mab, T-DM1, lapatinib) prior to BV + PTX therapy. All the patients were not treated with T-Dxd, although it was approved as a third-line therapy in Japan. Case 7 was treated without P-mab and T-DM1 and case 3 without T-DM1 because P-mab and T-DM1 had not been approved in Japan at the time. Although six patients had visceral metastases including lung, liver, and brain metastases, BV + PTX achieved a good response (partial response: 4, stable disease: 2, progressive disease: 1) and 10-month median PFS.

Table 1.

Patient characteristics

Case no.		1		2		3		4		5		6		7
Agea		68		65		73		40		59		42		37
Performance status		1		1		1		2		1		2		2
MBC or de novo		De novo		MBC		MBC		De novo		MBC		De novo		De novo
DFI (months)		–		13		25		–		50		–		–
ER status		Positive		Negative		Negative		Positive		Positive		Positive		Positive
Menopausal status		Post		Post		Post		Pre		Pre		Pre		Pre
Metastatic sites		Brain		Lung		Lymph Nodes		Lung		Lung		Lung		Brain
		Lymph nodes		Lymph nodes		Skin		Lymph nodes		Bone		Liver		Lung
		Bone						Skin				Bone		Liver
														Bone
														Ovary
Re-biopsy	Organ	Breast		Lung		LN		skin		–		–		–
	HER2	Positive		Positive		Negative		positive		–		–		–
Number of previous regimens		3		4		7		8		11		2		3
Previous HER2-targeted therapies and PFS (months)	1st	P-mab + DTX	5.5	P-mab + DTXb	7.5	T-mab + PTX	31.4	P-mab + DTX	13.2	T-mab + DTX	50.4	P-mab + DTX	21.7	T-mab + CBDCA	10.9
	2nd	T-DM1c	1.3	P-mab + ERI	4.4	LAP	8.3	T-DM1	5.3	T-mab + AI	34.2	T-DM1	4.2	LAP	2.9
	3rd	LAP	1.1	T-DM1	1.6	T-mab + VNR	6.9	LAPb	17.9	T-mab + SERM	3.7			T-mab + DTX	7.7
	4th			LAP	2.7	T-mab + ERI	1.8	P-mab + SERMc	3.5	T-mab + AI	9.9
	5th					T-mab + S-1b	114.3	P-mab + LH + AI	6.3	P-mab + DTX	3.3
	6th					T-mab + GEM	9.9	T-DM1	6.4	LAP	2.1
	7th					P-mab + DTXd	1.3	T-mab + ERI	1.8	T-DM1	4.5
	8th							P-mab + LH + SERD	2.1
Best response of BV + PTX		PR		PR		SD		SD		PD		PR		PR
PFS (months)		14		13.6		23		5.6		2.5		9.2		2.8
OS (months)		49.7		75.9		138.2		74		158.9		60.7		28.8

T-mab trastuzumab, P-mab pertuzumab $+$ trastuzumab, T-DM1 trastuzumab emtansine, LAP lapatinib $+$ capcitabine, PTX paclitaxel, DTX docetaxel, CBDCA carboplatin, VNB vinorelbine, ERI eribulin, GEM gemcitabine, LH LH-RH agonist, AI aromatase inhibitor, SERM selective estrogen receptor modulator, SERD selective estrogen receptor down-regulator, DFI disease-free survival, PFS progression-free survival, OS overall survival

^aAge was at the starting date of BV + PTX therapy

^bSurgery was performed and HER2 status was confirmed before the regimen

^cRe-biopsy was performed before the regimen

^dRe-biopsy was performed after finishing the regimen

Discussion

In this case series, we demonstrated that BV + PTX is potentially efficacious in treating HER2-positive MBC after failure of several HER2-targeted therapies. Four out of seven patients achieved partial response with this treatment.

After the approval of T-Dxd, the strategy for administering first- to third-line HER2-targeted therapies was established. All guidelines such as the National Comprehensive Cancer Network recommend HER2-targeted therapy for treating HER2-positive MBCs, even in later lines of therapies. However, in three patients (cases 3, 4, and 5) who received HER2-targeted therapies for more than seven regimens, the PFS after each regimen gradually shortened, suggesting a reduced response to HER2 therapy [2]. Moreover, despite receiving P-mab and T-DM1 as first- to third-line treatment, two (cases 1 and 2) out of four patients (cases 1, 2, 4, and 6) exhibited short PFS after each regimen, thus suggesting that even HER2-targeted therapies have limited efficacy in some cases.

As BV is considered effective for patients with high tumor burden, rapidly progressing disease, or visceral crisis, the 2020 NCCN guideline proposes that BV is a useful treatment option for HER2-negative MBC [2]. Several investigators have reported the efficacy of BV with T-mab-based therapy as first- or second-line treatment for HER2-positive MBC in clinical trials. The response rate was good at 71–74.3% and median PFS was 7.4–16.5 months [3–5]. In contrast, a phase 2 study has demonstrated the efficacy of BV combined with chemotherapy without HER2-targeted agents for brain metastases in HER2-positive MBC [6]. Several case reports also demonstrated the efficacy of BV combined with chemotherapy after the failure of HER2-targeted therapy in HER2-positive MBC. BV-containing regimens without HER2-target agents were reported to be effective for visceral metastases such as those of the brain and pleura from HER2-positive breast cancer [7–9].

Based on all guidelines, several HER2-targeted agents should be used for HER2-positive MBC [2]. Re-biopsy of metastatic sites before the treatment of MBC is often important for the treatment choice based on subtype. It was performed on four patients during the treatment prior to BV + PTX in our case series. Three patients (cases 1, 2, and 4) responded well to BV + PTX despite their HER2-positive status, resulting in 5.6–14-month PFS. Therefore, BV + PTX is also effective in treating HER2-positive MBC, consistent with the results of previous reports. Another patient (case 3) with HER2-negative conversion upon re-biopsy had prolonged PFS (13 months). This indicated the importance of re-biopsy in strategizing the treatment and confirmed the effectiveness of BV + PTX against HER2-negative MBC. Consistent with previous reports, our case series suggests that BV + PTX is effective in some HER2-positive MBC cases with poor response to standard HER2-targeted therapies, even if HER2-positive status of metastatic sites is confirmed through re-biopsy.

Although further accumulation of cases is required to confirm our findings, BV + PTX may be effective against HER2-positive MBCs when standard HER2-targeted therapies have failed.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.