Adjuvant Treatment of Her2+ Breast Cancer with two HER2-targeted Therapies Offers Modest Benefit

microscope lens with a beam of green light

A phase III randomized (1:1) clinical study funded by Hoffmann-La Roche including 4,805 women with with operable HER2-positive breast cancer seems to suggests adding a second HER2 targeted medicine, pertuzumab (Perjeta?), to standard of care trastuzumab (Herceptin ?) after surgery may offer a modest benefit.[1]

Results of the double-blind, placebo-controlled, study, known as APHINITY (Adjuvant Pertuzumab and Herceptin IN Initial TherapY in Breast Cancer, NCT01358877/ BO25126/ BIG 4-11), were presented at the 53rd American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago, Ill, June 2 – 6, 2017

At an early follow up of three years, 93.2% of women who received trastuzumab alone had not developed invasive disease compared with 94.1% of those who received pertuzumab and trastuzumab, a difference of 1%. While the prognosis for patients who receive standard of care trastuzumab is already favorable, patients in the study who received pertuzumab and trastuzumab had a 19% lower chance of developing invasive breast cancer than those who received trastuzumab alone (HR=0.81; 95% CI 0.66-1.00, p=0.045). [1]

The researchers reported that the safety profile of the pertuzumab-based regimen was consistent with that seen in previous studies, with a low incidence of cardiac events and no new safety signals.

Furthermore, based on data available at the time of the primary analysis confirmed that at four years 92.3% of women people treated with the pertuzumab-based regimen did not have their breast cancer return compared to 90.6% treated with trastuzumab and chemotherapy.

Invasive breast cancer
Breast cancer that starts in the milk ducts or glands (lobules) and has metastasized or spread into surrounding breast tissue, is generally known as invasive breast cancers. From there it can spread to nearby lymph nodes and beyond. Invasive breast cancer, which includes includes a number of different cancers, including, invasive, or infiltrating, ductal carcinoma, and invasive lobular carcinoma, is generally more difficult to treat than non-invasive cancer.

Invasive, or infiltrating, ductal carcinoma is the most common form of breast cancer, including between 65-85% of all cases. On a mammogram, it is generally visualized as a mass with fine spikes radiating from the edges known as spiculation. It can also appear as a smooth edged lump in the breast, which, on physical examination, feels much harder or firmer than benign causes of lumps in the breast. Microscopic examination generally shows cancerous cells invading and replacing normal breast tissue.

According to the American Cancer Society, more than 60,000 new cases breast carcinoma in situ were diagnosed in 2015, accounting for about 20% of all breast cancers. The vast majority (83%) of them were invasive, or infiltrating, ductal carcinoma, and 12% were lobular carcinoma in situ, also known as lobular neoplasia. [2]
Photo 1.0: High grade invasive ductal carcinoma, with minimal tubule formation, marked pleomorphism, and prominent mitoses.

Changed outlook
?Women with HER2-positive breast cancer used to have a worse prognosis than those with HER2-negative cancer, but the advent of HER2-targeted therapy changed the outlook for these women,? said lead study author Gunter von Minckwitz, MD, PhD, President of the German Breast Group (GBG) in Neu-Isenburg, Germany.

?Our early findings suggest that we may be able to further improve outcomes for some women by adding a second HER2-targeted treatment, without increasing risk for serious side effects,? he added.

While trastuzumab targets only HER2, pertuzumab blocks HER2 and HER3. Pertuzumab is designed specifically to prevent the HER2 receptor from dimerising (or ‘pairing’) with other HER receptors (EGFR/HER1, HER3 and HER4) on the surface of cells, a process that is believed to play a role in tumor growth and survival.

Using both antibodies establishes a more complete blockade of cancer cell growth signals and may lower the chance of treatment resistance. The authors estimate that about 8% of all patients diagnosed with breast cancer (about 20,000 women in the United States alone) have early, HER2-positive disease and may benefit from this adjuvant therapy.

Study design
Following mastectomy or lumpectomy, nearly 5,000 patients with HER2-positive, early breast cancer were randomly assigned to receive standard adjuvant chemotherapy for 18 weeks plus one year of either trastuzumab and placebo or trastuzumab and pertuzumab. The study did not include patients with very small tumors (less than 1 cm across), as those patients could be treated with only chemotherapy (without the need for a HER2 blocker).

Overall, 63% of patients had cancer that had spread to the lymph nodes (node-positive disease), and 36% had hormone receptor-negative disease. There were similar proportions of patients with either disease characteristic in the two treatment groups.

Photo 2.0: Gunter Von Minckwitz, MD, PhD, German Breast Group (GBG), presenting Abstract LBA500, APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab, during the American Society of Clinical Oncology (ASCO) Annual Meeting.

Key Findings
The addition of pertuzumab to trastuzumab lowered the chance of developing invasive breast cancer by 19% compared to trastuzumab alone. At a median follow up of almost 4 years, 171 (7.1%) patients in the pertuzumab group had developed invasive breast cancer, compared to 210 (8.7%) patients in the placebo group.

At 3 years, an estimated 94.1% of patients in the pertuzumab group were free of invasive breast cancer, compared to 93.2% of patients in the placebo group. The benefit from pertuzumab appeared slightly greater among patients with node-positive disease ? the three-year invasive disease-free survival rate was 92% with pertuzumab vs. 90.2% with placebo. In contrast, in the patients with node-negative cancer, invasive disease-free survival rate was not influenced by pertuzumab at this early point of analysis.

Early results
?These are very early results, but given that the absolute benefit from adding pertuzumab was modest, we should consider using it primarily in women with the highest risk ? those with node-positive and hormone receptor-negative breast cancer,? Von Minckwitz, observed.

The rates of serious side effects were low and similar in both groups ? heart failure or heart-related death occurred in 0.7% of patients in the pertuzumab group and in 0.3% of patients in the placebo group. Severe diarrhea was more common with pertuzumab, occurring in 9.8% of patients, compared to 3.7% of those who received placebo.

Benefit
?The introduction and success of HER2 targeted treatment was a turning point in breast cancer care. It?s promising that some women in this study benefited more from treatment with two HER2-targeted therapies rather than one, but it?s clear this approach may not be advantageous for women with a lower risk for recurrence,? noted Harold J. Burstein, MD, PhD, FASCO, an Associate Professor of Medicine, Harvard Medical School and ASCO Expert not involved in the study.

High bar
?The goal of adjuvant treatment is to help each person with cancer have the best chance of a cure, and we come closer to this goal with each advance,? noted Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development at Roche. ?In the APHINITY study, the pertuzumab-based regimen improved upon the high bar set by trastuzumab in people with HER2-positive early breast cancer.?

Follow-up
The researchers will continue following patients to explore potential long-term benefits of pertuzumab. Meanwhile, they are exploring tumor samples collected in this study for biomarkers that may help predict which patients benefit from the addition of pertuzumab.

[Overall, the…] APHINITY study [offers] another example of the importance of industry-academic collaborations and their value in advancing cancer care for people affected by this challenging disease. The? early data are very encouraging. As we continue to follow patients up to 10 years, we hope that future analyses will provide additional insights on the role of a pertuzumab-based regimen in HER2-positive early breast cancer,? von Minckwitz said.

?We … need more research to determine the optimal duration of adjuvant therapy. It is possible that patients may not need a full year of treatment after surgery; six months may be enough,? he added.

The study was conducted in collaboration with the Breast International Group (BIG),?a not-for-profit organisation for academic breast cancer research groups from around the world, based in Brussels, Belgium, the Breast European Adjuvant Study Team (BrEAST), a specialised clinical trials unit located at the Institut Jules Bordet, Brussels, Belgium, and the Frontier Science Foundation (FS), a not-for-profit corporation that has gained an international reputation as a highly capable data management and statistical organisation, collaborating with research networks, pharmaceutical companies and others in the design, conduct and execution of clinical trials and long-term observation studies.


Last editorial review: June 8, 2017

Featured Image: Artwork Appendix Pain Illustration Courtesy: ? 2017 Fotolia. Used with permission. Photo 1.0:High grade invasive ductal carcinoma. Courtesy: ? 2017 Difi Wu.? This file is licensed under the Creative Commons Attribution-Share Alike 4.0 International, 3.0 Unported, 2.5 Generic, 2.0 Generic and 1.0 Generic license. Photo 2.0: Gunter Von Minckwitz, MD, PhD. Courtesy: ? 2017 ASCO/Scott Morgan.

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