A case sharing of domestic trastuzumab combined with pertuzumab neoadjuvant therapy for HER2-positive/HR-positive breast cancer

*For medical professionals only

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HER2-positive breast cancer is a subtype
with a high degree of malignancy and a poor prognosis.
Systemic neoadjuvant therapy prior to surgery or radiotherapy significantly reduces tumor primary and reduces clinical stage, thereby increasing the rate of complete pathological response (pCR) in patients
.
Especially after the emergence of targeted drugs, the application of single-target and dual-target regimens in the neoadjuvant therapy stage greatly improves the long-term prognosis
of patients.
This article shares a case of HER2-positive/HR-positive locally advanced breast cancer in which partial remission (PR) was obtained by neoadjuvant therapy with "domestic trastuzumab* (Hanquyou) + pertuzumab combined with chemotherapy", and clarified the idea of neoadjuvant treatment of triple-positive breast cancer and the efficacy and safety
of trastuzumab biosimilars.

A 61-year-old female patient was hospitalized for "a left breast mass found for more than 4 months
".
The history of "hypertension" is more than 5 years, and the control of oral "amlodipine tablets" is not good; In 2008, he underwent "hysterectomy" for "uterine fibroids"; In 2013, he underwent "bilateral oophorectomy" for "ovarian cyst"; In 2015, he underwent thyroid noduclectomy.

Age of menopause 51 years, G4P1A3
.

At 2 o'clock in the lateral upper quadrant of the left breast gland, a lump of about 40*30mm in size can be palpated at about 20mm from the nipple, with tough texture, clear borders, irregular morphology, poor mobility, and no tenderness
.
The left axilla can be palpated with a mass of about 20*20mm in size, which is tough, the border is clear, the shape is irregular, the range of motion is poor, and there is no tenderness
.
The right breast and right axilla are not palpated with a significant mass
.

• Mammary ultrasound (2021-10-4): A hypoechoic mass can be seen at 12-3 o'clock in the left breast connected to the nipple, the size is about 40*26mm, BI-RADS class
  4.
  Irregular morphology, unclear boundaries, uneven internal echo, irregular liquid dark area and multiple strong light spot echoes visible, CDFI: visible blood flow signal
  .
  

• Pathological examination: ductal papilloma (left breast mass and axillary lymph nodes) ductal papilloma carcinogenesis (invasive carcinoma, non-special type, grade II).
  
  Cancer metastasis
  in axillary lymph nodes.
  Immunohistochemistry: CK5/6 (partial+), P63 (partial+), ER(+), PR(+), E-ca(+), CD34 (vascular+), P120 (membrane+), HER2 (3+), Ki-67 (+25-50%), P53 (+>75%)
  .
  

The patient started neoadjuvant therapy with the "albumin paclitaxel + carboplatin + trastuzumab + pertuzumab" (TCbHP) regimen on 2021-10-16 for a total of 6 cycles
.

2022-2-23Review of breast ultrasound, left breast 12-2A visible range of about 14*5mm low echo, BI-RADS class
6.
Irregular morphology, unclear boundaries, uneven internal echo, punctate strong echo inside, CDFI: visible blood flow signal
.
The structure of the right breast gland is disordered, the internal echo is uneven, and repeated exploration does not show obvious mass sonography
.
Multiple solid nodules in the left axilla (enlarged lymph nodes?).
）； Multiple solid nodules in the right axilla (lymph nodes?).
）； Hypoechoic nodules in the left supraclavicular fossa (lymph nodes?) ）
。 Efficacy was assessed as PR.

Left breast cancer with axillary lymph node metastasis (cT3N1M0, stage III.
A, LuminalB HER2 positive).

Surgery: The patient underwent modified radical resection of left breast cancer on 2022-2-25
.
Postoperative diagnosis: left breast cancer with axillary lymph node metastasis (ypT2N3M0, stage III.
C, Luminal B).

Postoperative pathology: (left) modified radical resection specimen of breast (after neoadjuvant chemotherapy): invasive carcinoma, tumor size of about 25*15*6mm, tissue cells and lymphocyte infiltration can be seen in the surrounding tissue
.
MP is graded at level
3.
There was no cancer
in the nipple and skin tissue.
There was no cancer
at the peripheral and basal margins.
Metastatic carcinoma (4/18, 1/5, respectively) in the axilla and (third level) lymph nodes (left
).
Immunohistochemistry: ER(+), Ki-67 (+<5%), PR(-), HER2 (1+<b15>).

Case summary

In this case, the patient was diagnosed with left breast cancer, positive axillary lymph nodes, and molecular classification as three-positive (HER2-positive, HR-positive) breast cancer
.
According to the 2019 Chinese Society of Clinical Oncology (CSCO) guidelines for the diagnosis and treatment of breast cancer, patients with HER2-positive breast cancer with tumor volume of > 2 cm or lymph node metastasis at the time of initial diagnosis are recommended neoadjuvant therapy, and the preferred regimen is a dual-target regimen of trastuzumab + pertuzumab combined with chemotherapy^[1].

After 6 cycles of "domestic trastuzumab + pertuzumab + albumin paclitaxel + carboplatin" neoadjuvant therapy to achieve PR, followed by "left breast modified radical resection", the postoperative pathology showed that the MP grade was grade 3
.
Once again, the superior efficacy
of domestic trastuzumab in the neoadjuvant treatment stage was verified.

Expert reviews

HER2-positive breast cancer accounts for about 15%-20% of all breast cancers, has a high degree of malignancy, and is prone to recurrence and metastasis^[2].

Hormone receptors (HR) include estrogen receptors (ER) and progesterone receptors (PR), ER and/or PR positive patients collectively referred to as HR-positive patients
.
Studies have shown that 10-15% of patients have both HER2-positive and HR-positive ^[3], that is, "triple-positive breast cancer"
.
Neoadjuvant therapy has become an important part of the current comprehensive treatment of breast cancer, and its emergence has expanded the indications for breast cancer surgery and changed the clinical diagnosis and treatment mode
of breast cancer.
Chemotherapy combined with targeted neoadjuvant therapy is also one of the
main treatment modalities for triple-positive breast cancer.

In the NeoSphere study ^[4], the pCR rate of patients in the HER2-positive/HR-positive subgroup receiving neoadjuvant therapy with dual-target chemotherapy was 26% (63.
2% HER2-positive/HR-negative).

A review of the relevant studies of neoadjuvant therapy for HER2-positive breast cancer found that whether it was NOAH [⁵] in the single-target era or NeoSphere [4], KRISTINE[6], TRYPHAENA ^[7] in the dual-target era, etc.
, it was shown that patients could receive trastuzumab+ in the neoadjuvant treatment stage regardless of HR status Significant benefit
with chemotherapy or trastuzumab plus pertuzumab + chemotherapy.
Therefore, HER2-positive/HR-positive breast cancer is still classified as HER2-positive breast cancer, and domestic and foreign guidelines emphasize that the early and late treatment basis of HER2-positive/HR-positive breast cancer is anti-HER2 therapy, which is combined with chemotherapy or endocrine therapy ^[1,8].

In this case, the patient was treated with neoadjuvant therapy using the first domestic trastuzumab biosimilar combination regimen, with significant
efficacy.

Biosimilars are highly similar to reference products, with strict standards
for quality, safety and efficacy.
The research design and implementation process of domestic trastuzumab follows the regulatory standards of biosimilars in China, the European Union and the United States, and conducts head-to-head clinical studies in many regions of the world, with no clinically significant differences in efficacy, safety and immunogenicity ^[9].

Based on this, domestic trastuzumab has been approved for marketing by the National Medical Products Administration (NMPA) of China and the European Medicines Agency (EMA), becoming the first "Sino-European double batch" of trastuzumab biosimilars
.
It provides new drug options for HER2-positive breast cancer patients, so that more HER2-positive breast cancer patients can enjoy products equivalent to trastuzum antigen research drugs, and improve survival benefits
.

The patient in this case was a three-positive breast cancer, and the neoadjuvant therapy of the "domestic trastuzumab + pertuzumab + chemotherapy" regimen was used, and PR was obtained after 6 cycles, and no special safety problems
occurred.
The results showed that domestic trastuzumab had significant efficacy and good safety in the treatment of HER2-positive HR-positive locally advanced breast cancer patients, and could be used as an alternative clinically in the clinic
.

References:

Chinese Society of Clinical Oncology Guidelines Working Committee.
Guidelines for the diagnosis and treatment of breast cancer by the Chinese Society of Clinical Oncology (CSCO)[M].
Beijing:People's Medical Publishing House,2019.

[2].
Loibl S, Gianni L.
HER2-positive breast cancer.
Lancet.
2017 Jun 17; 389(10087):2415-2429.

[3].
Alataki A, Dowsett M.
Human epidermal growth factor receptor-2 and endocrine resistance in hormone-dependent breast cancer.
Endocr Relat Cancer.
2022 Jun 23; 29(8):R105-R122.

[4].
Gianni L, Pienkowski T, Im YH, et al.
Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, infl ammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.
Lancet Oncol 2012; 13: 25–32.

[5].
Gianni L, Eiermann W, Semiglazov V, et al.
Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort.
Lancet Oncol.
2014 May; 15(6):640-7.

[6].
Hurvitz SA, Martin M, Symmans WF, et al.
Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial.
Lancet Oncol.
2018 Jan; 19(1):115-126.

[7].
Schneeweiss A, Chia S, Hickish T, et al.
Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).
Ann Oncol.
2013 Sep; 24(9):2278-84.

[8].
Cardoso F, Senkus E, Costa A, et al.
4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4)†.
Ann Oncol.
2018 Aug 1; 29(8):1634-1657.

[9].
Xu B, Zhang Q, Sun T, et al.
Efficacy, Safety, and Immunogenicity of HLX02 Compared with Reference Trastuzumab in Patients with Recurrent or Metastatic HER2-Positive Breast Cancer: A Randomized Phase III Equivalence Trial.
BioDrugs.
2021 May; 35(3):337-350.