Loss-of-function mutations in BRCA1 and BRCA2 are detected in at least 5% of unselected patients with breast cancer (BC). These BC susceptibility genes encode proteins critical for DNA homologous recombination repair (HRR). This review provides an update on oral poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of BC. Olaparib and talazoparib are PARP inhibitors approved as monotherapies for deleterious/suspected deleterious germline BRCA-mutated, HER2-negative BC. Olaparib is approved in the USA for metastatic BC and in Europe for locally advanced/metastatic BC. Talazoparib is approved for locally advanced/metastatic BC in the USA and Europe. In phase 3 trials, olaparib and talazoparib monotherapies demonstrated significant progression-free survival benefits compared with chemotherapy. Common toxicities were effectively managed by supportive treatment and dose interruptions/reductions. Veliparib combined with platinum-based chemotherapy has also shown promise for locally advanced/metastatic BC in a phase 3 trial. Differences in efficacy and safety across PARP inhibitors (olaparib, talazoparib, veliparib, niraparib, rucaparib) may relate to differences in potency of PARP trapping on DNA and cytotoxic specificity. PARP inhibitors are being investigated in early BC, in novel combinations, and in patients without germline BRCA mutations, including those with somatic BRCA mutations and other HRR gene mutations. Ongoing phase 2/3 studies include PARP inhibitors combined with immune checkpoint inhibitors for the treatment of triple-negative BC. Wider access to testing for BRCA and other mutations, and to genetic counseling, are required to identify patients who could benefit from PARP inhibitor therapy. The advent of PARP inhibitors has potential benefits for BC treatment beyond the locally advanced/metastatic setting.

The human epidermal growth factor receptor 2 (HER2) is overexpressed in 13–22% of breast cancers (BC). Approximately 60–70% of HER2+ BC co-express hormone receptors (HRs). HR/HER2 co-expression modulates response to both anti-HER2–directed and endocrine therapy due to “crosstalk” between the estrogen receptor (ER) and HER2 pathways. Combined HER2/ER blockade may be an effective treatment strategy for patients with HR+/HER2+ BC in the appropriate clinical setting(s). In this review, we provide an overview of crosstalk between the ER and HER2 pathways, summarize data from recently published and ongoing clinical trials, and discuss clinical implications for targeted treatment of HR+/HER2+ BC.

PURPOSE: The achievement of pathologic complete response (pCR) is strongly prognostic for event-free survival (EFS) and overall survival (OS) in patients with early breast cancer (EBC), and adapting postneoadjuvant therapy improves long-term outcomes for patients with HER2-positive disease not achieving pCR. We sought to investigate prognostic factors for EFS and OS among patients with and without pCR after neoadjuvant systemic treatment consisting of chemotherapy plus anti-HER2 therapy. MATERIALS AND METHODS: We used individual data from 3,710 patients randomly assigned in 11 neoadjuvant trials for HER2-positive EBC with ≥100 patients enrolled, available data for pCR, EFS, and OS, and follow-up ≥3 years. We assessed baseline clinical tumor size (cT) and clinical nodal status (cN) as prognostic factors using stratified (by trial and treatment) Cox models separately for hormone receptor–positive versus hormone receptor–negative disease, and for patients who had pCR (pCR+; ypT0/is, ypN0) versus patients who did not achieve a pCR (pCR−). RESULTS: The median follow-up overall was 61.2 months. In pCR+ patients, cT and cN were significant independent prognostic factors for EFS, whereas only cT was a significant predictor for OS. In pCR− patients, cT, cN, and hormone receptor status were significant independent predictors for both EFS and OS. Regardless of hormone receptor status, cT, and cN, the 5-year EFS/OS rates were higher in pCR+ patients than in pCR− patients. In most subsets with regards to hormone receptor and pCR status, cT and cN were independent prognostic factors for both EFS and OS, including pCR+ patients. CONCLUSION: These results confirm that patients achieving pCR have far better survival outcomes than patients who do not. The traditional poor prognostic features, namely tumor size and nodal status, remain important even after a pCR.

HannaH (NCT00950300) was a phase III, randomized, international, open-label study that compared pharmacokinetics (PK), efficacy, and safety of two different trastuzumab formulations [subcutaneous (s.c.) and intravenous (i.v.)] in HER2-positive, operable, locally advanced, or inflammatory breast cancer in the neoadjuvant/adjuvant setting. The co-primary end points, to show noninferiority of s.c. versus i.v. trastuzumab in terms of serum concentration (C_trough) and pathologic complete response (pCR) were met; safety profiles were comparable at 12 months' median follow-up. Secondary end points included safety and tolerability, PK profile, immunogenicity, and event-free survival (EFS). We now report updated safety and efficacy data after a median follow-up of 20 months. Patients (N = 596) were treated with eight cycles of neoadjuvant chemotherapy, administered concurrently with 3-weekly s.c. trastuzumab (fixed dose of 600 mg) or the standard weight-based i.v. method. Following surgery, patients continued trastuzumab treatment to complete 1 year of therapy. Updated analyses of PK, efficacy, safety, and immunogenicity data were carried out. s.c. trastuzumab was generally well tolerated and the incidence of adverse events (AEs), including grade 3 or 4 AEs, between treatment groups was comparable. A slightly higher incidence of serious AEs (SAEs), mainly due to infections, was reported with s.c. treatment {64 [21.5%; 95% confidence interval (CI) 17.0%–26.7%] versus 42 (14.1%; 95% CI 10.4%–18.6%) in the i.v. group}; however, the differences were small and often based on rare events, with no observable pattern across reported events. An early analysis of EFS showed rates of 95% in both groups 1 year postrandomization. Exploratory analyses did not reveal an association between toxicity and body weight or exposure. Overall, the safety profile of s.c. trastuzumab was consistent with the previously published data from HannaH and the known safety profile of i.v. trastuzumab. EFS rates were comparable between the i.v. and s.c. groups. NCT00950300.

Treatment with monoclonal antibodies (mabs) has become an established component of oncological therapy. The monoclonal antibodies available for this purpose are mainly administered intravenously in individually adapted doses according to body weight over longer treatment times. For other chronic diseases such as, for example, diabetes mellitus, the subcutaneous administration of drugs is an established therapy option. For the subcutaneous administration of larger volumes as needed for mab solutions the extracellular matrix of the subcutaneous tissue represents a problem. The co-formulation with recombinant human hyaluronidase makes the relatively pain-free administration of larger fluid volumes and thus the subcutaneous administration of monoclonal antibodies possible, as illustrated by the development of a subcutaneous formulation of trastuzumab. This constitutes a less invasive, time-optimised and flexible form of administration for patients with HER2-positive breast cancer that, with its fixed dosing possibilities, contributes to therapeutic safety. The example of trastuzumab shows that the subcutaneous administration of monoclonal antibodies can simplify oncological long-term therapy not only for the patients but also for the medical personnel. Die Behandlung mit monoklonalen Antikörpern (mAK) ist ein fester Bestandteil der onkologischen Therapie geworden. Die dafür zur Verfügung stehenden monoklonalen Antikörper werden überwiegend intravenös, individualisiert gewichtsadaptiert und über längere Behandlungszeiträume verabreicht. Bei anderen chronischen Erkrankungen wie beispielsweise Diabetes mellitus stellt die subkutane Applikation von Medikamenten, eine etablierte Therapieform dar. Für die subkutane Applikation größerer Volumina stellt die Physiologie der extrazellulären Matrix des subkutanen Gewebes ein Hindernis dar, wie sie für die Lösung mAK erforderlich ist. Die Koformulierung mit rekombinanter humaner Hyaluronidase ermöglicht die schmerzarme Gabe größerer Volumina und damit die subkutane Applikation von monoklonalen Antikörpern, wie die Entwicklung einer subkutanen Formulierung für Trastuzumab zeigt. Mit dieser steht Patientinnen mit HER2-positivem Mammakarzinom eine weniger invasive, zeitoptimierte und flexiblere Applikationsform zur Verfügung, die mit einer fixen Dosierungsmöglichkeit zur Therapiesicherheit beiträgt. Das Beispiel Trastuzumab zeigt, dass die subkutane Verabreichung monoklonaler Antikörper die onkologische Langzeittherapie sowohl für Patienten als auch für medizinisches Fachpersonal vereinfachen könnte.

Subcutaneous trastuzumab may offer several advantages compared with intravenous trastuzumab, including shorter treatment times, a reduction in the use of health care resources, increased convenience for patients, and greater patient preference.^1-4 In the primary analysis of the HannaH (Enhanced Treatment With Neoadjuvant Herceptin) trial,⁵ subcutaneous trastuzumab was shown to be noninferior to intravenous trastuzumab for patients with ERBB2 (HER2)–positive early breast cancer (EBC), based on the coprimary end points of pathologic complete response (absence of invasive neoplastic cells in the breast; remaining ductal carcinoma in situ was accepted) and serum trough concentration predose dose cycle 8. The 2-year follow-up analyses demonstrated similar 3-year event-free survival (EFS) rates⁶ and confirmed the comparability of the safety profiles for subcutaneous trastuzumab and intravenous trastuzumab observed in the primary analysis.^5-7 The overall safety profile for subcutaneous trastuzumab in the HannaH trial was also shown to be consistent with the known safety profile for subcutaneous trastuzumab for patients with ERBB2-positive EBC in both SafeHer, which had a study population of more than 2500 patients,⁸ and PrefHer.^1,4,9