This article reviews the progress of targeted therapy for breast cancer with low | expression of HER2

Author: Su Hua

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preface

For more than 20 years, anti-HER2-targeted therapy has significantly improved outcomes
for patients with HER2-positive (HER2 amplification-positive IHC 3+/FISH detection) breast cancer (BC).
About 40-50% of breast cancer patients have low HER2 expression (IHC 1+ or IHC 2+ and FISH negative), some of which are classified as Luminal type (HR+) and some as triple-negative breast cancer (TNBC).

In clinical practice, these patients are generally treated
as HER2-negative.

Classical anti-HER2-targeted drugs, such as trastuzumab and T-DM1 (trastuzumab emtansine), have shown significant clinical benefits for HER2-positive BC, but have not been able to "play a big role"
in the field of low-HER2 expression BC.
Fortunately, the exploration of targeted therapies has never stopped, and emerging anti-HER2-targeted drugs have demonstrated unique efficacy, lighting up the dawn of low-expression BC-targeted therapies with
HER2.

One

Treatment status and treatment needs of low-expression BC of HER2

Monoclonal antibodies targeting HER2 (tripa-double target), vaccines (nelipepimut-S), and the first antibody-drug conjugate (ADC) T-DM1 have not made actual clinical progress
in the field of low-expression BC of HER2.
Patients with low HER2 expression BC may have closer clinical characteristics than HER2-positive patients
.
Studies ^[1] have shown that HER2 IHC2+ and FISH-negative BC are more likely to present with large cancers, higher pathological grade, higher Ki67, and positive
axillary lymph node metastases.

In traditional treatment strategies, the disease-free survival time (DFS) of patients with low-HER2 expression BC is inferior to HER2 IHC 0, and DFS is inferior to HER2-positive BC
after adjuvant therapy with trastuzumab combination regimen.
The rate of pathological complete response (pCR) is lower with low HER2 expression BC after neoadjuvant therapy ^[2-3].

These findings fully indicate that HER2 low-expression BC is expected to become an independent subpopulation, and more appropriate, personalized and unique treatment strategies
are urgently needed.

Two

Exploration of classic drugs trastuzumab, pertuzumab and T-DM1 in low-expression BC of HER2

01

Trastuzumab was once thought to be effective in early BC with low HER2 expression, because it could mediate antibody-dependent cytotoxicity (ADCC) in addition to blocking the HER2 signaling pathway, which reduced the effect of HER2 expression levels on trastuzumab activity in tumors
.
In the NSABP B-31 study ^[4], 9.
7 percent of patients were HER2-negative, and these patients, like HER2-positive patients, benefited from
adjuvant trastuzumab therapy.
In the NCCTG N9831 study [5], HER2-negative BC, which accounted for ^5.
5%, showed a trend
of benefit from trastuzumab treatment.
However, subsequent NSABP B-47 studies (phase III) ^[6], with the addition of trastuzumab to standard adjuvant therapy, failed to demonstrate a survival benefit for low-HER2-expressing BCs (regardless of IHC 1+/2+) (Table 1).

02

In xenograft models, pertuzumab inhibits the proliferation
of HER2-negative tumors.
However, in phase II clinical studies ^[7], HER2 low-expression metastatic BC received pertuzumab (the first dose of 840mg, followed by A arm maintained with 420mg q3w, B arm with 1050mg q3w), clinical benefit rate (CBR) (complete response + partial response + stable disease ≥ 24 weeks) was 9.
8%, 5.
4%, median time to progression (mTTP) is 6.
1 weeks
.

03

T-DM1 not only blocks the HER2 signaling pathway and exerts the ADCC effect, but also specifically targets HER2-positive cells to exert cytotoxic effects
.
Although T-DM1 has not been formally prospective studied in patients with BC with low HER2 expression, there have been two phase II clinical studies ^[8-9] that have not found the efficacy of
T-DM1 in patients with high non-HER2 expression.

In the Yazaki S, et al study ^[10], T-DM1 achieved a significantly higher objective response rate (ORR) in patients with HER2 IHC 3+BC than in patients with IHC2+/FISH positive (53.
3 vs 0%), and median progression-free survival (mPFS) was better (7.
9 vs 3.
9 months).

The study was small (IHC 3+: n=32; positive IHC 2+/FISH: n=7), so the conclusion needs to be further verified
.

Three

Exploring emerging targeted therapies for low-expression BC of HER2: T-Dxd is a blockbuster

Table 1: Clinical studies of HER2 low-expression BC-targeted therapy

01

T-Dxd has been shown to exert anticancer activity in patients with low HER2 expression in previous clinical studies ^[11].

The therapeutic activity may be related
to its bystander effect (T-Dxd can mediate bystander cytotoxic effects on neighboring cells around HER2-expressing target cells, regardless of HER2 status), high drug load ratio (8:1), and high efficiency and high load.
Unlike T-DM1, the payload released by T-Dxd is membrane permeable
.

Although the low expression of HER2 leads to a relatively low level of T-Dxd binding, relying on the above characteristics, T-Dxd accumulates a higher concentration of cytotoxic levels in the lesion, thereby achieving anticancer activity
in tumors with low HER2 expression.
In the Phase I.
b (NCT02564900) study completed by Modi S, et al in 2020 [12^], T-Dxd achieved 37.
0% ORR and a median duration of response (mDOR) of 10.
4 months
in patients with advanced BC with low HER2 expression (IHC 1+ or IHC 2+ and FISH-negative) and standard therapy failure 。 This brings light to the exploration of targeted therapies with low HER2 expression BC! It also confirms that the inference that low-expression BC of HER2 can benefit from targeted therapy is correct!

Subsequently, the DESTINY-Breast04 (phase III) study ^[13], T-Dxd post-line treatment of HER2 low-expression BC, and then transmission (Table 1), confirmed that T-Dxd post-line treatment of HER2 low-expression BC can further improve survival
.
DESTINY-Breast04 study is expected to rewrite guidelines and reshape treatment strategies for HER2 low-expression BC!

02

SYD985 is composed of trastuzumab + decomposable linker + Duocarmycin (DNA alkylating agent) with a drug loading rate of 2.
8:1
.
The cytotoxic part it carries enters the cell, forming an active toxin
under the action of proteases.
In xenograft models, SYD985 exhibits a killing effect that far exceeds that of T-DM1 against tumors with low HER2 expression ^[14].

In the first human trial of SYD985 [15], 47 patients with low HER2 expression, standard treatment failure, and late/metastatic BC received SYD985, and the partial response rate (PR) of HR-negative and HR-positive patients was 40% (6/¹⁵) and 28% (9/32),
respectively.

03

XMT-1522 uses HT-19 as the "guidance" section, which binds to different HER2 epitopes and is linked
to auristatin derivatives (anti-microtubule) via a biodegradable linker, compared to trastuzumab.
XMT-1522 has a high drug load of 12:1, which excites bystander killing effects, and it exhibits killing effects beyond T-DM1 in HER2-positive, HER2-low-expression xenografts ^[16].

Unfortunately, the development of the XMT-1522 has been suspended
.

04

Zenocutuzumab is a bispecific humanized IgG1 antibody, which can dock HER2 domain I, block HER3 domain III.
, prevent the binding of activating ligands, thereby inhibiting HER2/HER3 heterodimer formation and followed intracellular carcinogenic signaling
.
Zenocutuzumab inhibits HER2/HER3 heterodimer than pertuzumab and can also trigger ADCC effects
.
In the phase II study ^[17], BC patients with low ER+/HER2 expression and CDK4/6 inhibitor treatment failure (n=50) received Zenocutuzumab + fulvestrant or aromatase inhibitor (AI) treatment, and eight patients continued to benefit at 24 weeks, and one patient was stable
for a long time after achieving PR.

05

A phase II.
b study conducted by Clifton GT, et al ^[18] randomized trastuzumab ±nelipepimut-S (NPS vaccine)
in 275 BC patients who completed postoperative standard therapy.
A difference between groups in DFS (HR: 0.
62) was not observed, but trastuzumab + NPS successfully improved DFS (HR: 0.
26)
in patients with TNBC.
Further validation
is required in phase III studies.

06

HER2 positive tumors have a higher mutation burden than negative (Luminal) tumors [19], and tumor-invasive lymphocytes (TILs) and PD-L1 expression are higher ^[19-20].

In mouse models, T-Dxd+ anti-PD-1 monoclonal antibodies are more effective than monotherapy ^[21].

A phase I.
b study ^[22] enrolled 16 patients with BC with low-expression of HER2 who failed standard therapy and were given a combination of T-Dxd + nivolumab with a manageable safety profile and an ORR of 38%, similar
to T-Dxd monotherapy.
More emerging anti-HER2 drugs + immune checkpoint inhibitors (ICIs) in combination with the treatment of low-HER2 expression BC ^{are ongoing [23].}

(Table 2)

Table 2: Emerging anti-HER2 drugs + ICIs combined treatment of HER2 low expression BC

07

In the study of Collins et al ^[24], the addition of fulvestrant to anti-HER2 and HER3 drugs to form a combination regimen can significantly improve the anticancer activity
against ER+/HER2 low-expressing BC xenografts.
As mentioned above, the HER2/HER3 bispecific monoclonal antibody Zenocutuzumab + endocrine combination regimen for the treatment of CDK4/6 inhibitors + endocrine therapy resistant refractory BC has shown clinical efficacy
.
From above, targeting both ER and HER2 axes has clinical potential, and phase I.
b studies of T-Dxd + anastrozole/fulvestrant are underway ^[25].

08

As a downstream pathway of HER2, dysregulation of the cyclin D1-CDK4 axis is a common trigger
for anti-HER2 therapy resistance.
The NA-PHER2 study (phase II) ^[26-27] explored the efficacy of tripaz dual target + fulvestrant + pibocicil neoadjuvant therapy for low-expression of HR+/HER2 BC (n=23), with an ORR of 78.
3%, but no pathological complete response (pCR)
was observed.

Four

epilogue

Although many studies have failed in the field of low-expression BC of HER2, T-Dxd has successfully improved the survival of low-expression of HER2 BC with its strong strength, reversing the depressed momentum of HER2 low-expression BC targeted therapy exploration
.
More emerging drugs and therapies are being used in the study of this BC patient population, which is expected to further bring survival benefits
.

References: (Swipe up to view)

[1] Rossi V, Sarotto I, Maggiorotto F, et al.
Moderate Immunohistochemical Expression of HER-2 (2+) Without HER-2 Gene Amplification Is a Negative Prognostic Factor in Early Breast Cancer[J].
Oncologist 2012, 17, 1418–1425.

[2] Eggemann H, Ignatov T, Bürger E, et al.
Moderate HER2 expression as a prognostic factor in hormone receptor positive breast cancer[J].
Endocr.
-Relat.
Cancer 2015, 22, 725–733.

[3] Gilcrease MZ, Woodward WA, Nicolas MM, et al.
Even Low-level HER2 Expression May be Associated with Worse Outcome in Node-positive Breast Cancer[J].
Am.
J.
Surg.
Pathol.
2009, 33, 759–767.

[4] Paik S, Kim C, Wolmark N.
HER2Status and Benefit from Adjuvant Trastuzumab in Breast Cancer[J].
N.
Engl.
J.
Med.
2008, 358, 1409–1411.

[5] Perez EA, Reinholz MM, Hillman DW, et al.
HER2and Chromosome 17 Effect on Patient Outcome in the N9831 Adjuvant Trastuzumab Trial[J].
J.
Clin.
Oncol.
2010, 28, 4307–4315.

[6] Fehrenbacher L, Cecchini RS, Geyer CE, et al.
NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2+[J].
J.
Clin.
Oncol.
2020, 38, 444–453.

[7] Gianni L, Lladó A, Bianchi G, et al.
Open-Label, Phase II, Multicenter, Randomized Study of the Efficacy and Safety of Two Dose Levels of Pertuzumab, a Human Epidermal Growth Factor Receptor 2 Dimerization Inhibitor, in Patients With Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer[J].
J.
Clin.
Oncol.
2010, 28, 1131–1137.

[8] Burris HA, Rugo HS, Vukelja SJ, et al.
Phase II Study of the Antibody Drug Conjugate Trastuzumab-DM1 for the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2) –Positive Breast Cancer After Prior HER2-Directed Therapy[J].
J.
Clin.
Oncol.
2011, 29, 398–405.

[9] Krop IE, Lorusso P, Miller KD, et al.
A Phase II Study of Trastuzumab Emtansine in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer Who Were Previously Treated With Trastuzumab, Lapatinib, an Anthracycline, a Taxane, and Capecitabine[J].
J.
Clin.
Oncol.
2012, 30, 3234–3241.

[10] Yazaki S, Hashimoto J, Ogita S, et al.
Lower response to trastuzumab emtansine in metastatic breast cancer patients with human epidermal growth factor receptor 2 immunohistochemistry score of 2 and fluorescence in situ hybridization positive compared with immunohistochemistry score of 3: a retrospective study[J].
Anticancer Drugs.
2020 Oct; 31(9):973-978.
doi: 10.
1097/CAD.
0000000000000939.

[11] Ogitani Y, Aida T, Hagihara K, et al.
DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1 [J].
Clin Cancer Res 22:5097-5108, 2016.

[12] Modi S, Park H, Murthy RK, et al.
Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study[J].
J Clin Oncol.
2020 Jun 10; 38(17):1887-1896.
doi: 10.
1200/JCO.
19.
02318.

[13] Modi S, Jacot W, Yamashita T, et al.
Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer[J].
N Engl J Med.
2022 Jul 7; 387(1):9-20.
doi: 10.
1056/NEJMoa2203690.

[14] Van Der Lee MM, Groothuis PG, Ubink R, et al.
The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast Cancers[J].
Mol.
Cancer Ther.
2015, 14, 692–703.

[15] Banerji U, Van Herpen CML, Saura C, et al.
Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: A phase 1 dose-escalation and dose-expansion study[J].
Lancet Oncol.
2019, 20, 1124–1135.

[16] Le Joncour V, Martins A, Puhka M, et al.
A Novel Anti-HER2 Antibody–Drug Conjugate XMT-1522 for HER2-Positive Breast and Gastric Cancers Resistant to Trastuzumab Emtansine[J].
Mol.
Cancer Ther.
2019, 18, 1721–1730.

[17] Pistilli B, Wildiers H, Hamilton EP, et al.
Clinical activity of MCLA-128 (zenocutuzumab) in combination with endocrine therapy (ET) in ER+/HER2-low, non-amplified metastatic breast cancer (MBC) patients (pts) with ET-resistant disease who had progressed on a CDK4/6 inhibitor (CDK4/6i) [J].
J.
Clin.
Oncol.
2020, 38, 1037.

[18] Clifton GT, Hale D, Vreeland TJ, et al.
Results of a Randomized Phase IIb Trial of Nelipepimut-S + Trastuzumab versus Trastuzumab to Prevent Recurrences in Patients with High-Risk HER2 Low-Expressing Breast Cancer[J].
Clin Cancer Res.
2020 Jun 1; 26(11):2515-2523.
doi: 10.
1158/1078-0432.
CCR-19-2741.

[19] Pernas S, Tolaney SM.
HER2-positive breast cancer: New therapeutic frontiers and overcoming resistance[J].
Ther.
Adv.
Med Oncol.
2019, 11, 1–16.

[20] Bianchini G, Gianni, L.
The immune system and response to HER2-targeted treatment in breast cancer[J].
Lancet Oncol.
2014, 15, e58–e68.

[21] Iwata TN, Ishii C, Ishida S, et al.
A HER2-Targeting Antibody–Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model[J].
Mol.
Cancer Ther.
2018, 17, 1494–1503.

[22] Hamilton E, Shapiro CL, Petrylak D, et al.
Trastuzumab Deruxtecan (T-DXd; DS-8201) with Nivolumab in Patients with HER2-Expressing, Advanced Breast Cancer: A 2-Part, Phase 1b, Multicenter, Open-Label Study; SABCS: San Antonio, TX, USA, 2020.

[23] Eiger D, Agostinetto E, Saúde-Conde R, et al.
The Exciting New Field of HER2-Low Breast Cancer Treatment[J].
Cancers (Basel).
2021 Mar 1; 13(5):1015.
doi: 10.
3390/cancers13051015.

[24] Collins D, Jacob W, Cejalvo JM, et al.
Direct estrogen receptor (ER) / HER family crosstalk mediating sensitivity to lumretuzumab and pertuzumab in ER+ breast cancer[J].
PLoS ONE 2017, 12, e0177331.

[25] Jhaveri K, Hamilton E, Loi S, et al.
Trastuzumab Deruxtecan (T-DXd; DS-8201) in Combination with Other Anticancer Agents in Patients with HER2-Low Metastatic Breast Cancer: A Phase 1b, Open-label, Multicenter, Dose-Finding and Dose-Expansion Study ( DESTINY-Breast08); SABCS: San Antonio, TX, USA, 2020.

[26] Gianni L, Colleoni M, Bisagni G, et al.
Ki67 during and after neoadjuvant trastuzumab, pertuzumab and palbociclib plus or minus fulvestrant in HER2 and ER-positive breast cancer: The NA-PHER2 Michelangelo study[J].
J.
Clin.
Oncol.
2019, 37, 527.

[27] Gianni L, Bisagni G, Colleoni M, et al.
Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): An exploratory, open-label, phase 2 study[J] .
Lancet Oncol.
2018, 19, 249–256.

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