Commercial

Medical Policy

Notification

Pertuzumab (Perjeta®) and related biosimilar pertuzumab-dpzb (Poherdy)

Notification Issue Date:

This version of the policy will become effective 07/01/2019.

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia.

Policy criteria were updated to clarify tumor staging for treatments of breast cancer.

Not medically necessary statement was added for testing results that do not show HER2 protein overexpression

Title:

Pertuzumab (Perjeta®) and related biosimilar pertuzumab-dpzb (Poherdy)

Policy #:

08.01.07l

Policy

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

MEDICALLY NECESSARY

Pertuzumab (Perjeta®) and related biosimilar pertuzumab-dpzb (Poherdy) are considered medically necessary and, therefore, covered for the indication(s) identified below in individuals who meet the applicable criteria, and whose tumors have human epidermal growth factor receptor 2 (HER2) protein overexpression verified as a positive result by one of the US Food and Drug Administration (FDA)–approved diagnostic tests for the following:

BREAST CANCER

Early Breast Cancer (EBC)

For the neoadjuvant treatment of individuals with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either >2 cm in diameter or node-positive) as part of a complete treatment regimen for EBC in combination with trastuzumab and chemotherapy
For the adjuvant treatment of individuals with HER2-positive EBC at high risk of recurrence in combination with trastuzumab and chemotherapy

Inflammatory Breast cancer

As adjuvant systemic therapy** for individuals who had a response to preoperative systemic therapy, followed by surgery, and need to complete planned chemotherapy, for node-positive HER2-positive pT2-3 and pN0 or pN+ tumors only with one of the following regimens:

As a component of TCHP (docetaxel, carboplatin, trastuzumab, and pertuzumab) regimen (National Comprehensive Cancer Network [NCCN] preferred regimen)
In combination with paclitaxel, carboplatin, and trastuzumab
In combination with trastuzumab and paclitaxel following AC (doxorubicin and cyclophosphamide) (dose-dense or every 3 weeks) regimen*
In combination with trastuzumab and docetaxel following AC regimen*
In combination with paclitaxel and trastuzumab
In combination with docetaxel and trastuzumab

As preoperative systemic therapy for HER2-positive disease with one of the following regimens:

As a component of TCHP (docetaxel, carboplatin, trastuzumab, and pertuzumab) regimen (NCCN-preferred regimen)
In combination with paclitaxel, carboplatin, and trastuzumab
In combination with trastuzumab and paclitaxel
In combination with trastuzumab and docetaxel following AC regimen*
In combination with paclitaxel and trastuzumab (useful in certain circumstances)
In combination with docetaxel and trastuzumab

For individuals with no response to preoperative systemic therapy, or recurrent unresectable (local or regional) or stage IV (M1) HER2-positive disease that is either hormone receptor-negative or hormone receptor positive with one of the following regimens:

As NCCN-preferred first-line therapy in combination with trastuzumab with either docetaxel or paclitaxel
As first-line therapy in combination with fam-trastuzumab deruxtecan-nxki
In combination with trastuzumab with or without cytotoxic therapy (e.g., vinorelbine or taxane) for one line of therapy in individuals previously treated with chemotherapy and trastuzumab in the absence of pertuzumab

First-line maintenance therapy in combination with an aromatase inhibitor and trastuzumab with or without palbociclib for postmenopausal women* or for premenopausal women treated with ovarian ablation/suppression with no response to preoperative systemic therapy, or have recurrent unresectable (local or regional) or stage IV (M1) hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive disease if treatment was initiated with chemotherapy, pertuzumab, and trastuzumab, and the chemotherapy was stopped

Invasive Breast Cancer

As preoperative systemic therapy for individuals with HER2-positive tumors and locally advanced c≥T2 or cN+ and M0 disease (NCCN preferred), or cT1c, cN0 disease with one of the following regimens:

As a component of TCHP (docetaxel, carboplatin, trastuzumab, and pertuzumab) regimen (NCCN-preferred regimen)
In combination with paclitaxel, carboplatin, and trastuzumab
In combination with trastuzumab and paclitaxel following AC (doxorubicin and cyclophosphamide) (dose-dense or every 3 weeks) regimen (both useful in certain circumstances)*
In combination with trastuzumab and docetaxel following AC regimen*
In combination with paclitaxel and trastuzumab
In combination with docetaxel and trastuzumab

As adjuvant systemic therapy** for (pT1-3 and pN0 or pN+ tumors) individuals with node-positive HER2-positive tumors only with one of the following regimens:

In combination with paclitaxel, carboplatin, and trastuzumab
In combination with trastuzumab and paclitaxel following AC (doxorubicin and cyclophosphamide) (dose-dense or every 3 weeks) regimen (both useful in certain circumstances)*
As a component of TCHP (docetaxel, carboplatin, trastuzumab, and pertuzumab) regimen (NCCN-preferred regimen)
In combination with trastuzumab and docetaxel following AC regimen*
In combination with paclitaxel and trastuzumab
in combination with docetaxel and trastuzumab

As adjuvant systemic therapy for individuals with HER2-positive tumors and locally advanced disease following completion of planned chemotherapy and following mastectomy or breast-conserving surgery (BCS) with surgical axillary staging, with trastuzumab as NCCN-preferred regimen if one of the following present:

ypT0N0 or pCR (especially if node positive at initial staging)
ypT1-4N0 (if ado-trastuzumab discontinued for toxicity) (especially if node positive at initial staging)
ypN≥1 (if ado-trastuzumab discontinued for toxicity) (especially if node positive at initial staging)

For recurrent unresectable (local or regional) or stage IV (M1) HER2-positive disease that is either hormone receptor-negative or hormone receptor-positive with one of the following regimens:

As NCCN preferred first-line therapy in combination with trastuzumab with either docetaxel or paclitaxel
As first-line therapy in combination with fam-trastuzumab deruxtecan-nxki
In combination with trastuzumab with or without cytotoxic therapy (e.g., vinorelbine or taxane) for one line of therapy in individuals previously treated with chemotherapy and trastuzumab in the absence of pertuzumab

First-line maintenance therapy in combination with an aromatase inhibitor and trastuzumab with or without palbociclib for postmenopausal women* or for premenopausal women treated with ovarian ablation/suppression with recurrent unresectable (local or regional) or stage IV (M1) hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive disease if treatment was initiated with chemotherapy, pertuzumab, and trastuzumab, and the chemotherapy was stopped

*It is acceptable to change the administration sequence to taxane (with or without HER2-targeted therapy) followed by AC.
**If no residual disease after preoperative therapy, complete up to 1 year of HER2-targeted therapy with trastuzumab with or without pertuzumab after completing planned chemotherapy regimen course. If residual disease is present after preoperative therapy and ado-trastuzumab emtansine is discontinued for toxicity, then trastuzumab with or without pertuzumab to complete 1 year of therapy can be used (NCCN-preferred regimen).

Metastatic Breast Cancer (MBC)

For the treatment of individuals with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease in combination with trastuzumab and docetaxel.

BILIARY TRACT CANCERS

Biliary Tract Cancers: Extrahepatic Cholangiocarcinoma/Gallbladder Cancer/Intrahepatic Cholangiocarcinoma

As subsequent treatment in combination with trastuzumab for progression on or after systemic treatment for unresectable or resected gross residual (R2) disease, or metastatic disease that is HER2-positive (IHC3+/ISH+/NGS amplification)

CENTRAL NERVOUS SYSTEM CANCERS

Limited Brain Metastases with HER2 (ERBB2) Positive Breast Cancer

In combination with high-dose trastuzumab for one of the following indications:

As initial treatment in individuals with small asymptomatic brain metastases for newly diagnosed or stable systemic disease or if reasonable systemic treatment options exist
As treatment for recurrent brain metastases

Extensive Brain Metastases with HER2 (ERBB2)-Positive Breast Cancer

In combination with high-dose trastuzumab for one of the following indications:

As primary treatment in individuals with small asymptomatic brain metastases
As treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options

COLON CANCER

Colon Cancer

Initial treatment in combination with trastuzumab in individuals with HER2 (ERBB2) overexpression/amplification and RAS and BRAF wild-type (proficient mismatch repair/microsatellite-stable [pMMR/MSS]; mismatch repair deficient/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb] and individual is not a candidate for immunotherapy) and for individuals with unresectable metachronous metastases and previous FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPEOX (capecitabine and oxaliplatin) within the past 12 months.

Less-intensive therapy in combination with trastuzumab, if not previously given HER2 (ERBB2) overexpression/amplification and RAS and BRAF wild-type (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or ineligible for or progressed on checkpoint inhibitor immunotherapy for mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or polymerase epsilon/delta (POLE/POLD1) mutation with ultra-hypermutated phenotype (e.g., TMB >50 mut/Mb) if no previous treatment with a HER2 inhibitor for one of the following indications:

As primary treatment for locally unresectable or medically inoperable disease
As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction
As primary treatment for synchronous unresectable metastases of other sites
As initial treatment for unresectable metachronous metastases in individuals who have not received previous FOLFOX or CAPEOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy

Appendiceal Adenocarcinoma

Second-line and subsequent therapy (if not previously given) in combination with trastuzumab for individuals with HER2-positive and RAS and BRAF wild type (WT) disease for any of the following:

Recurrence with serial tumor marker elevation or radiographic progression and progressive or positive findings
Biopsy-proven recurrence of high-risk disease if cytoreductive surgery was previously received or not possible
Progressive disease or inadequate response after neoadjuvant systemic therapy for metastatic peritoneal-only disease
Extraperitoneal disease

Preoperative systemic therapy for individuals with human epidermal growth factor receptor 2 (HER2)-positive tumors and locally advanced c≥T2 or cN+ and M0 disease , or cT1c, cN0 disease

as a component of TCHP (docetaxel, carboplatin, trastuzumab and pertuzumab) regimen (preferred regimen)
in combination with paclitaxel, carboplatin and trastuzumab
in combination with trastuzumab and paclitaxel following AC (doxorubicin and cyclophosphamide) (dose-dense or every 3 weeks) regimen* (both useful in certain circumstances)
in combination with trastuzumab and docetaxel following AC regimen*
in combination with paclitaxel and trastuzumab (useful in certain circumstances)
in combination with docetaxel and trastuzumab (useful in certain circumstances)

NCCN note:*It is acceptable to change administration sequence to taxane followed by AC.

HEAD AND NECK

As systemic therapy for HER2-positive recurrent disease in combination with trastuzumab, for one of the following indications:

Treatment of individuals with a performance status (PS) of 0–3 with distant metastases
Treatment of individuals with unresectable locoregional recurrence or second primary with prior radiation therapy

RECTAL CANCER

Initial treatment in combination with trastuzumab for individuals with HER2 (ERBB2) overexpression/amplification and RAS and BRAF wild-type with unresectable metachronous metastases (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or mismatch repair deficient/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb] and are not candidates for immunotherapy) and previous FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPEOX (capecitabine and oxaliplatin) within the past 12 months.
Less-intensive therapy in combination with trastuzumab if not previously given, in individuals with HER2 (ERBB2) overexpression/amplification and RAS and BRAF wild-type (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or ineligible for or progressed on checkpoint inhibitor immunotherapy for mismatch repair deficient/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb]) and no previous treatment with a HER2 inhibitor for one of the following indications:

As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction
As primary treatment for synchronous unresectable metastases of other sites
As primary treatment for unresectable isolated pelvic/anastomotic recurrence
As initial treatment for unresectable metachronous metastases in individuals who have not received previous FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy
As subsequent therapy

Less intensive primary treatment in combination with trastuzumab, if not previously given, for T3, N Any; T1-2, N1-2; T4, N Any; or locally unresectable or medically inoperable disease (HER2 [ERBB2] overexpression/amplification and RAS and BRAF wild-type) if resection is contraindicated following total neoadjuvant therapy (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or ineligible for or progressed on checkpoint inhibitor immunotherapy for mismatch repair deficient/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb]) or neoadjuvant/definitive immunotherapy (dMMR/MSI-H)
Subsequent therapy in combination with trastuzumab, if not previously given, for progression of advanced or metastatic disease (HER2 [ERBB2] overexpression/amplification and RAS and BRAF wild-type) (proficient mismatch repair/microsatellite-stable [pMMR/MSS] or ineligible for or progressed on checkpoint inhibitor immunotherapy for mismatch repair deficient/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta [POLE/POLD1] mutation with ultra-hypermutated phenotype [e.g., TMB >50 mut/Mb]) not previously treated with HER2 inhibitor and if previously treated with oxaliplatin-based and irinotecan-based therapy or beyond second-line therapy.

SMALL BOWEL ADENOCARCINOMA

Second-line and subsequent therapy in combination with trastuzumab for advanced or metastatic disease that is HER2 (ERBB2) overexpression/amplification and RAS and BRAF WT (if not previously given)

EXPERIMENTAL/INVESTIGATIONAL

All other uses of pertuzumab (Perjeta®) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

NOT MEDICALLY NECESSARY

When FDA-approved diagnostic tests do not reveal HER2 protein overexpression, pertuzumab (Perjeta®) is considered not medically necessary and, therefore, not covered because the available published peer-reviewed literature does not support its use in the treatment of those diseases.

MANDATES

PENNSYLVANIA MEMBERS

In accordance with the Commonwealth of Pennsylvania's Act 6 of 2020 or Fair Access to Cancer Treatment Act, for members who are enrolled in Pennsylvania commercial products who have Stage 4, advanced metastatic cancer, refer to the Medical Policy titled "Coverage of Anticancer Prescription Oral and Injectable Drugs and Biologics and Supportive Agents" (08.01.08) for additional information regarding the applicable coverage of drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

Guidelines

BLACK BOX WARNINGS

Refer to the specific manufacturer's prescribing information for any applicable Black Box Warnings.

HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 (HER2) PROTEIN OVEREXPRESSION TESTING

Coverage of pertuzumab (Perjeta®) requires that human epidermal growth factor receptor 2 (HER2) protein overexpression is verified as a positive result by one of the following US Food and Drug Administration (FDA)–approved diagnostic tests:

Immunohistochemical (IHC) assay with a result of 3+
Fluorescence in situ hybridization (FISH) test (ratio >2.0)
Single-probe in situ hybridization (ISH) test with average HER2 copy number 6.0 signals/cell or greater
Dual-probe ISH test HER2/CEP17 (chromosome enumeration probe 17) ratio 2.0 or greater; or HER2/CEP17 ratio less than 2.0 AND average HER2 copy number 6.0 signals/cell or greater

Confirmatory tests should be performed for borderline results as follows:

If IHC assay has a result of 2+, confirm with ISH test of the same sample or a new test with IHC or ISH (if new sample available).
If FISH test has a HER2 gene/chromosome 17 ratio of 1.8–2.0, confirm with FISH re-test; additional cell counting and recalculation of the ratio; or IHC assay.
If single-probe ISH assay has an average HER2 copy number result of 4.0 to less than 6.0 signals/cell, confirm with dual-probe ISH or with IHC (if same sample), or with a new ISH or IHC (if new sample available).
If dual-probe ISH assay has a HER2/CEP17 ratio less than 2.0 and an average HER2 copy number result of 4.0 to less than 6.0 signals/cell, confirm with one of the following: IHC (if same sample), alternative ISH chromosome 17 probe, or order a new test with ISH or IHC (if new sample available).

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, pertuzumab (Perjeta®) is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION (FDA)

Pertuzumab (Perjeta®) was approved by the FDA on June 8, 2012, for use in combination with trastuzumab (Herceptin®) and docetaxel (Taxotere®) chemotherapy, for the treatment of individuals with HER2-positive metastatic breast cancer who have not received prior anti-HER2/neu therapy or chemotherapy for metastatic disease.

In September 2013, pertuzumab (Perjeta®) received a subsequent approval by the FDA as a neoadjuvant treatment in combination with trastuzumab and docetaxel for individuals with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either >2 cm in diameter or node positive) as complete breast cancer regimen for early breast cancer.

On November 13, 2025, the Food and Drug Administration approved Poherdy (pertuzumab-dpzb, as an interchangeable biosimilar to Perjeta (pertuzumab, Genentech Inc.). This is the first approval of a biosimilar for Perjeta.

Description

Pertuzumab (Perjeta®) is a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain of the human epidermal growth factor receptor 2 (HER2, previously called HER-2/neu). Amplification of the HER2 gene results in HER2 protein overexpression. Pertuzumab (Perjeta®) is administered intravenously in combination with trastuzumab (Herceptin®) and other chemotherapy agents for the treatment of breast cancer. (Note: Pertuzumab [Perjeta®] is not indicated in breast cancer that does not overexpress the HER2 protein.) Pertuzumab (Perjeta®) is believed to work by targeting a different part of the HER2 receptor than trastuzumab (Herceptin®) and works in a way that is complementary to trastuzumab (Herceptin®), resulting in further reduction in growth and survival of HER2-positive breast cancer cells.

Note: Pertuzumab (Perjeta®) is not indicated in breast cancer that does not overexpress the HER2 protein.

Pertuzumab-dpzb (Poherdy) injection as an interchangeable biosimilar biological product to Perjeta (pertuzumab). Poherdy (pertuzumab-dpzb) is the first biosimilar approved for Perjeta (pertuzumab).

METASTATIC BREAST CANCER TREATMENT

In June 2012, pertuzumab (Perjeta®) was approved by the US Food and Drug Administration (FDA) for the treatment of individuals with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease in combination with trastuzumab (Herceptin®) and docetaxel (Taxotere®) chemotherapy.

PEER-REVIEWED LITERATURE
Summary

The approval of pertuzumab (Perjeta®) is based on a randomized, double-blind, placebo-controlled, phase III clinical trial involving 808 individuals with HER2-positive metastatic breast cancer who were tested prior to treatment to determine whether the HER2 protein was increased. Individuals were randomly assigned to receive pertuzumab (Perjeta®), trastuzumab (Herceptin®), and docetaxel (Taxotere®), or trastuzumab (Herceptin®), and docetaxel (Taxotere®) with a placebo. The primary endpoint of the randomized trial was progression-free survival (PFS) as assessed by an independent review facility. Pertuzumab (Perjeta®) in combination with trastuzumab (Herceptin®) and docetaxel (Taxotere®) significantly extended PFS by 6.1 months compared with placebo plus trastuzumab (Herceptin®) and docetaxel (Taxotere®) in the first-line treatment of individuals with HER2-positive metastatic breast cancer.

NEOADJUVANT TREATMENT OF BREAST CANCER

In September 2013, the FDA granted accelerated approval of pertuzumab (Perjeta®) as part of a complete treatment regimen, in combination with trastuzumab (Herceptin®) and docetaxel (Taxotere®), before surgery (neoadjuvant setting) in women with locally advanced, inflammatory, or early-stage breast cancer greater than 2 cm. This makes pertuzumab (Perjeta®) the first FDA-approved drug for the neoadjuvant treatment of breast cancer. This indication was based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival.

PEER-REVIEWED LITERATURE
Summary

The accelerated approval for pertuzumab (Perjeta®), for neoadjuvant treatment, was based on an international, randomized, open-label, phase II trial (NeoSpare; n=417), which was designed to measure pathologic complete response (pCR). Women with primary tumor greater than 2 cm in diameter were randomly assigned to one of four neoadjuvant treatment regimens: trastuzumab (Herceptin®) plus docetaxel (Taxotere®); pertuzumab (Perjeta®) plus trastuzumab (Herceptin®) and docetaxel (Taxotere®); pertuzumab (Perjeta®) plus trastuzumab (Herceptin®); or pertuzumab (Perjeta®) plus docetaxel (Taxotere®). Neoadjuvant treatment with pertuzumab (Perjeta®) plus trastuzumab (Herceptin®) and docetaxel (Taxotere®) resulted in statistically significantly greater pCR compared with docetaxel (Taxotere®) plus either trastuzumab (Herceptin®) or pertuzumab (Perjeta®) (45.8% vs. 29%; 45.8% vs. 24%).

OTHER INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

DIAGNOSTIC TESTS FOR HER2 PROTEIN OVEREXPRESSION

HER2 protein overexpression is detected either by immunohistochemical (IHC) assay or with a type of in situ hybridization (ISH) test for gene amplification (e.g., fluorescence in situ hybridization [FISH], chromogenic in situ hybridization [CISH], dual in situ hybridization [DISH]). The FDA has approved several commercially available tests to aid in the selection of breast cancer patients for pertuzumab (Perjeta®) therapy. The NCCN and American Society of Clinical Oncology (ASCO) guidelines further recommend that IHC assay and ISH testing should only be done at laboratories that are accredited to perform HER2 testing.

An IHC test result is reported as 0 or 1+ (negative), 2+ (borderline), or 3+ (positive).
A FISH test result is reported as a HER2 gene/chromosome 17 ratio less than 1.8 (negative), a ratio of 1.8 to less than 2.0 (borderline), or a ratio of 2.0 or greater (positive).
A single-probe ISH test result is reported as average HER2 copy number less than 4.0 signals/cell (negative); 4.0 to less than 6.0 signals/cell (borderline); 6.0 or greater signals/cell (positive).
A dual-probe ISH test result is reported as HER2/CEP17 (chromosome enumeration probe 17) ratio 2.0 or greater (positive); HER2/CEP17 ratio less than 2.0 AND average HER2 copy number less than 4.0 signals/cell (negative); HER2/CEP17 ratio less than 2.0 AND average HER2 copy number 4.0 to less than 6.0 signals/cell (borderline); HER2/CEP17 ratio less than 2.0 AND average HER2 copy number 6.0 signals/cell or greater (positive).

The NCCN and ASCO both have issued guidelines for HER2 testing in invasive breast cancer that call for confirming a borderline or equivocal result:

IHC assay result of 2+: confirm with ISH test (if same sample), or with a new IHC or ISH test (if new sample available).
FISH assay: confirm with either a repeat FISH test or an additional cell counting and recalculation of the ratio. If a repeat FISH test remains equivocal, then an IHC assay is recommended for confirmation.
Single-probe ISH assay: confirm with dual-probe ISH or with IHC (if same sample), or with a new ISH or IHC (if new sample available).
Dual-probe ISH assay: confirm with one of the following: IHC (if same sample), alternative ISH chromosome 17 probe, or order a new test with ISH or IHC (if new sample available).

ERBB2 is a receptor tyrosine kinase within the EGFR/ERBB/HER kinase family. Among the four ERBB receptors, ERBB2 (HER2) has no identified ligand, while ERBB3 (HER3) lacks intrinsic kinase activity. Notably, ERBB3 serves as the preferred dimerization partner for ERBB2, and this pairing generates the most potent signaling complex within the ERBB family. Members of the ERBB receptor family can form both homodimers and heterodimers, which activate key cellular signaling pathways, including the PI3K–AKT pathway.

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Fayanju OM, Ren Y, Thomas SM, et al. The clinical significance of breast-only and node-only pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT): a review of 20,000 breast cancer patients in the National Cancer Data Base (NCDB). Ann Surg. 2018;268(4):591-601.

Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25-32.

Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014;32(19):2078-2099.

Hammond MEH, Hayes DF, Dowsett M, et al. ASCO-CAP guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28(16):2784-2795.

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National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Breast Cancer. V3.2026. [NCCN Web site]. 05/08/2026. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf [via free subscription]. Accessed May 08, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Colon Cancer. V2.2026. [NCCN Web site]. 04/07/2026. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf [via free subscription]. Accessed May 08, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Central Nervous System Cancer. V1.2026. [NCCN Web site]. 04/24/2026. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf [via free subscription]. Accessed May 08, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Head and Neck Cancers. V1.2026. [NCCN Web site]. 08/12/2025. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf [via free subscription]. Accessed May 08, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Biliary Tract Cancers. V1.2026. [NCCN Web site]. 03/10/2026. Available at: at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf [via free subscription]. Accessed May 08, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Appendiceal Neoplasms and Cancers. V2.2026. [NCCN Web site]. 04/10/2026. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf [via free subscription]. Accessed May 08, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Small Bowel Adenocarcinoma. V2.2026. [NCCN Web site]. 04/07/2026. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf [via free subscription]. Accessed May 08, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Rectal Cancer. V2.2026. [NCCN Web site]. 04/07/2026. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf [via free subscription]. Accessed May 08, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium. Pertuzumab (Perjeta®). 2026 [NCCN Web site]. Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=383. [via subscription only]. Accessed May 08, 2026.

Perjeta® (pertuzumab). [prescribing information] South San Francisco, CA: Genentech, Inc.; 2017. 01/2020. Available at: https://www.gene.com/download/pdf/perjeta_prescribing.pdf. Accessed May 08, 2026.

Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365:1273-1283.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Pertuzumab (Perjeta®). [Micromedex® Solutions Web site]. 05/05/2026. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed May 08, 2026.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Pertuzumab (Perjeta®). prescribing information. [FDA Web site]. April 2026. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed May 08, 2026.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Pertuzumab (Perjeta®). Biologics license approval letter. [FDA Web site]. 06/08/2012. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/125409Orig1s000ltr.pdf. Accessed May 08, 2026.

von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30(15):1796-804.

Wolff AC, Hammond MEH, Hicks DG, et al. Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol.2013;31(31):3997-4013.

Yamauchi H, Hayes D. HER2 and predicting response to therapy in breast cancer. [UpToDate Web site]. 09/05/2018. Available at: http://www.uptodate.com/contents/her2-and-predicting-response-to-therapy-in-breast-cancer. Accessed May 08, 2026.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.

HCPCS Level II Code Number(s)

J9306 Injection, pertuzumab, 1 mg

THE FOLLOWING CODES ARE USED TO REPRESENT POHERDY® (pertuzumab-dpzb):

C9399 Unclassified drugs or biologicals

J3590 Unclassified biologics

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

If there is no specific HCPCS code available for the drug administered, then the drug must be reported with the most appropriate unlisted code along with the corresponding National Drug Code (NDC).

Cross Reference

Policy History

Revisions From 08.01.07l:

07/27/2026

This version of the policy will become effective 07/27/2026.

The title of this policy has changed from Pertuzumab (Perjeta®) to Pertuzumab (Perjeta®) and related biosimilar pertuzumab-dpzb (Poherdy)

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and National Comprehensive Cancer Network (NCCN) compendia.

Policy criteria were updated for the treatment of breast cancer, central nervous system (CNS), colon cancer, appendiceal adenocarcinoma, biliary and rectal cancers.

The following HCPCS codes were ADDED to the policy TO REPRESENT POHERDY® (pertuzumab-dpzb):

C9399 Unclassified drugs or biologicals

J3590 Unclassified biologics

Revisions From 08.01.07k:

12/29/2025

This version of the policy will become effective 12/29/2025.

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia.
Policy criteria were updated for the treatment of breast cancer, colon cancer, biliary and rectal cancers.

All of the ICD-10 CM codes will be removed from this policy, since they are informational. ICD 10 code attachment A is removed. Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.

Revisions From 08.01.07j:

04/08/2024

This version of the policy will become effective 04/08/2024.

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia.
Policy criteria were updated for the treatment of breast cancer, colon cancer, head and neck, biliary and rectal cancers.

The following ICD-10 codes were removed from the policy:

C17.0 Malignant neoplasm of duodenum
C17.1 Malignant neoplasm of jejunum
C17.2 Malignant neoplasm of ileum
C17.3 Meckel's diverticulum, malignant
C17.8 Malignant neoplasm of overlapping sites of small intestine
C17.9 Malignant neoplasm of small intestine, unspecified
C78.4 Secondary malignant neoplasm of small intestine

Revisions From 08.01.07i:

01/02/2023

This version of the policy will become effective 01/02/2023

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia.

Policy criteria were updated for the treatment of breast cancer, colon cancer, head and neck, hepatobiliary and rectal cancers.

The following ICD-10 codes were added to the policy:

C23 Malignant neoplasm of gallbladder
C24.8 Malignant neoplasm of overlapping sites of biliary tract
C24.9 Malignant neoplasm of biliary tract, unspecified
C22.1 Intrahepatic bile duct carcinoma
C24.0 Malignant neoplasm of extrahepatic bile duct
C79.31 Secondary malignant neoplasm of brain

The following ICD-10 code was removed from the policy:
C78.7 Secondary malignant neoplasm of liver and intrahepatic bile duct

Revisions From 08.01.07h:

12/20/2021

This version of the policy will become effective 12/20/2021

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia.

Policy criteria were updated for the treatment of breast cancer, colon cancer, head and neck and rectal cancers.

The following ICD-10 codes were added to the policy:

C78.00 Secondary malignant neoplasm of unspecified lung

C78.01 Secondary malignant neoplasm of right lung

C78.02 Secondary malignant neoplasm of left lung

C78.6 Secondary malignant neoplasm of retroperitoneum and peritoneum

C78.7 Secondary malignant neoplasm of liver and intrahepatic bile duct

C79.81 Secondary malignant neoplasm of breast

The following ICD-10 codes were removed from the policy:

C21.0 Malignant neoplasm of anus, unspecified

C21.1 Malignant neoplasm of anal canal

C21.2 Malignant neoplasm of cloacogenic zone

Revisions From 08.01.07g:

01/18/2021

This version of the policy will become effective 01/18/2021.

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia.

Policy criteria were updated for the treatment of breast cancer. New indications were added to the policy for colon cancer, head and neck and rectal cancers.

Revisions From 08.01.07f:

07/01/2019

Revisions From 08.01.07e:

11/01/2017

This version of the policy will become effective 11/01/2017.

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia.
Policy criteria were updated to clarify tumor staging for the treatment of breast cancer.

Version Effective Date:

7/27/2026

Version Issued Date:

7/27/2026

Version Reissued Date: