A guide to HER2-positive breast cancer treatment in Germany: how HER2 testing guides therapy, how antibody-based treatments, antibody-drug conjugates, and oral inhibitors are used before and after surgery and after progression, where European regulatory developments stand, and how international patients can arrange specialist assessment.

HER2-Positive Breast Cancer in Germany: Treatment Decisions, Targeted Therapy and Next Steps

HER2-positive breast cancer is defined by HER2 protein overexpression and/or HER2 (ERBB2) gene amplification identified through standardized pathology testing. It accounts for approximately 15% to 20% of breast cancers, and HER2 status helps determine whether HER2-directed therapies may be appropriate [1]. In Germany, as elsewhere, HER2 status is one part of treatment planning; disease stage, hormone-receptor status, and previous treatment also help guide the choice of therapy.

HER2 Status and Breast Cancer Treatment Choices

HER2 status, together with estrogen and progesterone receptor status, helps guide breast cancer classification and treatment. HER2-positive tumors that are also hormone receptor-positive may receive endocrine therapy in addition to HER2-directed treatment, whereas hormone receptor-negative tumors do not benefit from endocrine therapy. 

Tumor size, lymph node involvement, and overall disease extent guide treatment strategies. In early or locally advanced stages, treatment is given with curative intent and aims to reduce the risk of recurrence, whereas advanced disease is managed to control the cancer, prolong survival, and maintain quality of life [1].

Previous treatment also matters: a patient who has already received trastuzumab and pertuzumab is considered differently from someone starting HER2-targeted therapy for the first time.

• HER2 status together with hormone receptor status.
• Tumor size and lymph node involvement.
• Whether disease is early, locally advanced, or advanced/metastatic.
• Previous HER2-targeted treatment and how the tumor responded.
• Overall health and treatment tolerance.

HER2 Testing and Treatment Eligibility

HER2 status is established through immunohistochemistry (IHC), which scores HER2 protein expression from 0 to 3+. A result of IHC 3+ is classified as HER2-positive.

An IHC 2+ result is equivocal and requires additional in situ hybridization (ISH), such as fluorescence in situ hybridization (FISH), to assess HER2 gene amplification. A tumor with confirmed amplification is generally classified as HER2-positive. Some ISH patterns are less clear-cut, and their interpretation requires integrating the ISH findings with the corresponding IHC result.

Accurate HER2 testing is important because the result helps determine eligibility for HER2-directed treatment, alongside disease setting and treatment history.

HER2-low describes tumors with an IHC score of 1+, or 2+ without HER2 gene amplification on ISH. It is not classified as HER2-positive breast cancer, although this expression level may determine eligibility for certain antibody-drug conjugates in specific disease settings.

HER2 status may need to be reassessed over the course of disease, for example when a metastatic biopsy becomes available, since HER2 expression can occasionally differ between the primary tumor and a later recurrence [1].

HER2-Targeted Therapy for Breast Cancer

HER2-targeted therapies are central to treating HER2-positive breast cancer because they act against HER2 signaling or HER2-expressing cancer cells. Their use and combination with other systemic treatments depend on the disease setting [1].

In previously untreated unresectable or metastatic disease, trastuzumab plus pertuzumab with a taxane (THP) has long been the standard first-line regimen. In the phase III DESTINY-Breast09 trial, trastuzumab deruxtecan plus pertuzumab prolonged median progression-free survival to 40.7 months, compared with 26.9 months with THP [2], and the European Commission authorized the combination on 1 September 2026 [3]. EU authorization does not by itself mean that the regimen is available, reimbursed, or recommended for every patient in Germany; its place in German practice depends on applicable German treatment recommendations and the individual clinical situation.

HER2-directed therapies fall into three broad groups:

• Monoclonal antibodies: including trastuzumab and pertuzumab, which are used across several early-stage and advanced HER2-positive treatment settings.
• Antibody-drug conjugates (ADCs): including trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), used according to disease setting, prior treatment, and authorized indications.
• Oral tyrosine kinase inhibitors (TKIs): including tucatinib, neratinib, and lapatinib, used in selected HER2-positive treatment settings.

Trastuzumab- and Pertuzumab-Based Therapy

Trastuzumab (Herceptin) was the first HER2-targeted antibody in routine use and remains a foundation of treatment across early and advanced HER2-positive breast cancer, usually given with chemotherapy [1]. Trastuzumab can affect cardiac function, so heart function is assessed before treatment and monitored at intervals during treatment, most often by echocardiography, with the schedule guided by the product information and the patient's cardiac risk. Trastuzumab-associated left ventricular dysfunction may improve after treatment interruption or discontinuation, although recovery is not guaranteed. Any decline in cardiac function should be assessed by the treating team, with management guided by its severity and the patient's clinical circumstances.

Pertuzumab (Perjeta) targets a different part of the HER2 receptor and is combined with trastuzumab for dual HER2 blockade. In the final CLEOPATRA analysis, adding pertuzumab to trastuzumab and docetaxel as first-line treatment for HER2-positive metastatic breast cancer improved median overall survival to 57.1 months, compared with 40.8 months for trastuzumab and docetaxel alone [4]. These are trial-level medians and should not be read as a prediction for an individual patient.

In early-stage disease, dual blockade may be used before surgery or, for selected higher-risk patients, after surgery, depending on the individual treatment plan [1].

Antibody-Drug Conjugates for HER2-Positive Breast Cancer

An ADC combines a HER2-targeting antibody with a cytotoxic payload, helping deliver the drug more directly to HER2-expressing cells. Two established ADCs in HER2-positive breast cancer are trastuzumab emtansine (T-DM1, Kadcyla) and trastuzumab deruxtecan (T-DXd, Enhertu).

• T-DM1 after neoadjuvant therapy: In KATHERINE, patients with residual invasive disease after neoadjuvant (pre-operative) chemotherapy and HER2-targeted therapy had a 46% lower risk of invasive disease recurrence or death with adjuvant (post-operative) T-DM1 than with trastuzumab alone (7-year invasive disease-free survival 80.8% versus 67.1%). The final analysis also showed improved overall survival [5].
• T-DXd in metastatic disease: In DESTINY-Breast03, T-DXd produced substantially longer progression-free survival than T-DM1 in previously treated HER2-positive metastatic breast cancer (updated investigator-assessed median 29.0 versus 7.2 months), along with longer median overall survival (52.6 versus 42.7 months) [6].
• T-DXd after neoadjuvant therapy: DESTINY-Breast05 enrolled patients with high-risk HER2-positive early breast cancer and residual invasive disease after neoadjuvant therapy. T-DXd improved invasive disease-free survival compared with T-DM1, with 3-year rates of 92.4% versus 83.7% [7]. Its European regulatory status is covered in the section on treatment after surgery.
• Although T-DXd and T-DM1 use different cytotoxic payloads, both are HER2-directed antibody-drug conjugates, so previous exposure to one can influence how the other is used later.
• T-DXd safety: T-DXd can cause interstitial lung disease (ILD) or pneumonitis, including severe and fatal cases; in DESTINY-Breast09, adjudicated drug-related ILD occurred in 12.1% of patients receiving T-DXd plus pertuzumab . New or worsening cough, breathlessness, or fever should be reported promptly, and suspected ILD requires urgent clinical assessment. T-DXd can also reduce left ventricular function, so cardiac function is assessed before and during treatment according to the product information [2] [3].

Oral HER2-Targeted Therapies

• Tucatinib (Tukysa) is an oral HER2-selective tyrosine kinase inhibitor. Its EU authorization covers use with trastuzumab and capecitabine in locally advanced or metastatic disease after at least two prior anti-HER2 treatment regimens [9]. The pivotal trial included patients with brain metastases. Because tucatinib can interact with other medicines, a full medication review is important before treatment, and liver function is monitored during treatment.
• Neratinib (Nerlynx) is an oral pan-HER tyrosine kinase inhibitor used as extended adjuvant treatment in selected patients with early-stage, hormone receptor-positive, HER2-positive breast cancer after they complete trastuzumab-based therapy [1]. Diarrhea is a common adverse effect, particularly early in treatment, so preventive management is recommended when neratinib is started; liver function is also monitored.
• Lapatinib is an earlier-generation oral HER2/EGFR inhibitor, historically combined with capecitabine or an aromatase inhibitor. Its role has narrowed as newer antibody-drug conjugates and tucatinib-based regimens have become available, and it is now used in more limited circumstances.

HER2 Treatment Before and After Breast Cancer Surgery

For early and locally advanced HER2-positive breast cancer, HER2-targeted therapy may be given before surgery (neoadjuvant), after surgery (adjuvant), or both.

HER2 Treatment Before Surgery

For patients with larger or node-positive HER2-positive early breast cancer (broadly stage II–III), neoadjuvant treatment commonly combines chemotherapy with HER2-directed therapy before surgery. Dual HER2 blockade with trastuzumab and pertuzumab is an established approach for node-positive or otherwise higher-risk tumors. Treatment response can be assessed clinically and with imaging, while the surgical specimen provides the definitive pathological assessment. A pathological complete response (pCR) generally means no residual invasive cancer in the breast or sampled regional lymph nodes and is associated with a more favorable prognosis [1].

Neoadjuvant regimens that include T-DXd have shown higher pathological response rates in high-risk early-stage disease in clinical trials. A higher pathological response rate is an early endpoint and should not be equated with an established long-term survival benefit, and the role of these regimens in Germany depends on European authorization status and German treatment recommendations.

HER2 Treatment After Surgery

After a pathological complete response, HER2-directed therapy generally continues after surgery to complete the planned perioperative course. For many patients with early-stage disease, the total duration is about one year, counting the treatment given before surgery. The specific agent or combination, including whether pertuzumab continues, depends on the neoadjuvant regimen, disease characteristics, and applicable treatment recommendations.

• Residual invasive disease: When invasive cancer remains after neoadjuvant chemotherapy and HER2-targeted therapy, adjuvant T-DM1 remains an established postoperative option, based on the recurrence-risk reduction shown in KATHERINE [5]. HER2 and other tumor markers can also change between the original tumor and residual disease, which supports careful pathological review before further treatment.
• T-DXd for residual disease: Based on DESTINY-Breast05 [7], the EMA's CHMP adopted a positive opinion on 17 September 2026 recommending T-DXd as adjuvant treatment for eligible patients with resected HER2-positive breast cancer and residual invasive disease after neoadjuvant taxane-based and HER2-targeted treatment [8]. A CHMP opinion is a recommendation rather than a final authorization: as of late September 2026, the European Commission's decision is pending, and applicable German recommendations should also be considered. Until authorization is finalized, T-DM1 remains an established postoperative option supported by KATHERINE.
• Extended adjuvant neratinib: For selected patients with hormone receptor-positive disease, neratinib may be considered after completing trastuzumab-based therapy, as described above.

Treatment Options After HER2-Targeted Therapy

When HER2-positive breast cancer no longer responds adequately, usually identified through imaging and clinical review showing progression, the next step is reviewing which HER2-targeted therapies have already been used.

Previous exposure to specific agents, and the time since that exposure, both influence what is considered next [1].

Treatment After Previous HER2 Therapy

There is no single sequence that fits everyone. For patients whose HER2-positive metastatic breast cancer progresses after trastuzumab- and pertuzumab-based treatment, trastuzumab deruxtecan is an established subsequent-line option, based on the DESTINY-Breast03 results described earlier [6]. The next treatment should be individualized according to prior therapy, disease characteristics, brain metastases, treatment tolerance, current authorization, and applicable clinical recommendations. Because T-DXd can now also be used in the first line, some patients will already have received it before progression, and evidence on the best sequence after T-DXd is still developing.

After T-DXd, later-line options may include tucatinib with trastuzumab and capecitabine, including for patients with brain metastases, or other HER2-directed regimens [1].

HER2 Resistance and Treatment Progression

In plain terms, some HER2-positive cancers do not respond well to treatment from the start (primary resistance), while others respond initially but later stop responding (acquired resistance). Because the reasons for resistance vary, the cancer may be reassessed with imaging. When clinically appropriate and feasible, a repeat biopsy may be used to check whether tumor markers such as HER2 have changed before the next treatment is selected; it is not required for every patient [1].

If progression is confirmed, treatment is usually changed to another HER2-directed approach based on previous therapy, disease characteristics, and eligibility. Clinical trials may also be considered.

New and Emerging HER2 Therapies for Breast Cancer

HER2-directed treatment continues to evolve, particularly through next-generation antibody-drug conjugates, bispecific antibodies, and new combination strategies being tested in early-stage and treatment-resistant HER2-positive breast cancer. Therapies that are still in clinical trials are research rather than authorized routine treatment, and their relevance to an individual patient depends on trial results, European authorization, and German treatment recommendations.

Specialist HER2 Breast Cancer Care in Germany

In Germany, treatment recommendations for HER2-positive breast cancer are set out in the national S3 guideline [1], and treatment planning is typically shared across a multidisciplinary team, with the approach adapted to the individual disease setting.

How Is HER2-Positive Breast Cancer Treatment Planned in Germany?

Planning usually starts with the pathology, imaging, and treatment records: HER2 and hormone receptor results are confirmed, the extent of disease is defined, and previous therapies and responses are reviewed. The multidisciplinary team then agrees on the next step, such as neoadjuvant or adjuvant treatment, surgery, or a change of HER2-directed therapy.

International patients seeking specialist assessment or a second opinion for HER2-positive breast cancer in Germany may have their pathology, imaging, medical records, and previous treatment history reviewed by the treating specialists. TIG GmbH (Treatment in Germany) can assist with coordinating specialist appointments, organizing medical documentation, and facilitating communication with German hospitals. Diagnosis, treatment recommendations, and clinical decisions remain the responsibility of the treating medical professionals. Treatment options and timelines depend on the individual clinical circumstances and the services offered by the selected hospital.

The cost of care varies depending on the diagnostic work-up, medications, procedures, treatment setting, and duration of treatment, so an individual estimate generally requires review of the patient's medical situation and proposed treatment plan.

References

1. S3-Leitlinie Mammakarzinom, Version 5.1 (Leitlinienprogramm Onkologie/AWMF, June 2026), AWMF registration no. 032-045OL.

2. Tolaney SM, Jiang Z, Zhang Q, et al. Trastuzumab Deruxtecan plus Pertuzumab for HER2-Positive Metastatic Breast Cancer (DESTINY-Breast09). N Engl J Med. 2026;394(6):551-562. doi:10.1056/NEJMoa2508668.

3. European Medicines Agency. Enhertu (trastuzumab deruxtecan): European Public Assessment Report and product information, including the first-line indication in combination with pertuzumab authorized by the European Commission on 1 September 2026.

4. Swain SM, Miles D, Kim SB, et al. Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer (CLEOPATRA): End-of-Study Results. Lancet Oncol. 2020;21(4):519-530. doi:10.1016/S1470-2045(19)30863-0.

5. Geyer CE Jr, Untch M, Huang CS, et al. Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer (KATHERINE). N Engl J Med. 2025;392(3):249-257. doi:10.1056/NEJMoa2406070.

6. Cortés J, Hurvitz SA, Im SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial. Nat Med. 2024;30(8):2208-2215. doi:10.1038/s41591-024-03021-7.

7. Loibl S, Park YH, Shao Z, et al. Trastuzumab Deruxtecan in Residual HER2-Positive Early Breast Cancer (DESTINY-Breast05). N Engl J Med. 2026;394(9):845-857. doi:10.1056/NEJMoa2514661.

8. European Medicines Agency. Enhertu (trastuzumab deruxtecan): CHMP positive opinion on variation to marketing authorisation, 17 September 2026.

9. European Medicines Agency. Tukysa (tucatinib): European public assessment report and product information.

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