Subcutaneous injection of trastuzumab into the thigh versus abdominal wall in patients with HER2-positive early breast cancer: Pharmacokinetic, safety and patients' preference - Substudy of the randomised phase III GAIN-2 study

by Mattea Reinisch, Michael Untch, Rolf Mahlberg, Toralf Reimer, Thomas Hitschold, Frederik Marmé, Mustafa Aydogdu, Sabine Schmatloch, Hans-Joachim Lück, Marcus Schmidt, Ekkehart Ladda, Bruno Valentin Sinn, Peter Klare, Wolfgang Janni, Christian Jackisch, Carsten Denkert, Sabine Seiler, Thomas Göhler, Laura Michel, Nicole Burchardi, Elmar Stickeler, Julia Rey, Nicole Klutinus, Volker Möbus, Sibylle Loibl 

The Breast: Published: October 05, 2022

Background

Trastuzumab given intravenously in combination with chemotherapy is standard of care for patients with early HER2-positive breast cancer (BC). Different randomised studies have shown equivalent efficacy of a subcutaneous injection into the thigh compared to the intravenous formulation. Other body regions for injection have not been investigated but might be more convenient for patients.

Methods

After surgery, patients were randomised to receive either subcutaneous trastuzumab into the thigh or into the abdominal wall (AW). Patient preferences were evaluated using validated questionnaires (PINT). Primary objectives of this multicentre, non-blinded, randomised substudy of the GAIN-2 study were to investigate pharmacokinetics of the injection into the thigh versus AW and to determine patients' preferences of either administration site versus the previously received intravenous application.

Results

226 patients were randomised and 219 patients (thigh: N = 110; AW: N = 109) formed the modified intent-to-treat (mITT). Overall, 83.5% (out of N = 182 with information about patients’ preference) preferred subcutaneous over previous intravenous application or had no preference. Preference was similar between both administration sites (thigh: 80.6%; AW: 86.5; p = 0.322). Pharmacokinetic analysis included 30 patients. Geometric means of Cmax and AUC0-21d were higher in thigh than in AW group (geometric mean ratio with body weight adjustment: Cmax: 1.291, 90%-CI 1.052–1.584; AUC0-21d: 1.291, 90%-CI 1.026–1.626). Safety profile was in line with previous reports of subcutaneous trastuzumab.

Conclusion

Subcutaneous trastuzumab into the thigh showed an approximately 30% higher bioavailability. Injections were well tolerated and preferred over intravenous administration. The subcutaneous injection into the thigh should remain the standard of care.

 

Correlation Between Week 24 Trastuzumab-dkst Response and Week 48 Progression-Free Survival: The HERITAGE Trial

 

Correlation Between Week 24 Trastuzumab-dkst Response and Week 48 Progression-Free Survival: The HERITAGE Trial

by Hope S. Rugo, Eduardo J. Pennella, Unmesh Gopalakrishnan, Miguel Hernandez-Bronchud, Jay Herson, Hans Friedrich Koch, Subramanian Loganathan, Sarika Deodhar, Ashwani Marwah, Alexey Manikhas, Igor Bondarenko, Joseph D. Parra, Maria Luisa T. Abesamis-Tiambeng, Charuwan Akewanlop, Ihor Vynnychenko, Virote Sriuranpong, Sirshendu Roy, Eduardo Patricio Yanez Ruiz, Abhijit Barve, Cornelius F. Waller 

The Breast: Published: March 31, 2021

Background

Trastuzumab-dkst is a biosimilar of trastuzumab. The phase 3 HERITAGE trial demonstrated equivalent overall response rate (ORR) with trastuzumab-dkst or originator trastuzumab at 24 weeks in patients with HER2-positive metastatic breast cancer receiving chemotherapy. We now present the correlation of ORR with progression-free survival (PFS) for maintenance monotherapy with trastuzumab-dkst vs trastuzumab at 48 weeks of treatment, and the safety, tolerability, and immunogenicity.

Methods

HERITAGE is a multicenter, double-blind, randomized, parallel-group, phase 3 study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab in combination with taxane followed by continued monotherapy until disease progression. The analysis included PFS at 48 weeks to support the primary efficacy endpoint of ORR and safety, tolerability, and immunogenicity of trastuzumab-dkst vs trastuzumab as maintenance monotherapy.

Results

Of 500 randomized patients, 342 entered the monotherapy phase; 214 patients received ≥48 weeks of treatment. There were no statistically significant differences between PFS, ORR, or interim overall survival at week 48 between trastuzumab-dkst and trastuzumab. Week 24 ORR was highly correlated with week 48 PFS (rb = 0.75). Cumulative treatment-emergent adverse events (TEAEs) and serious AEs were similar in both groups, with few grade ≥3 TEAEs. Immunogenicity was low and similar in both groups at 48 weeks.

Conclusion

The correlation between ORR and PFS supports the design of first-line metastatic trials assessing biosimilar trastuzumab. Overall, trastuzumab-dkst and trastuzumab were well tolerated with similar efficacy, including ORR and PFS, in combination with a taxane followed by monotherapy.

Are Breast Implants Safe?

Are Breast Implants Safe?

by Rohrich, Rod J.; Kaplan, Jordan 

Plastic and Reconstructive Surgery: February 2020 - Volume 145 - Issue 2 - p 587-589

Breast implants are among the most well-studied implantable medical devices placed in humans. They have been used in both reconstructive and aesthetic breast surgery for more than 60 years. The safety of the device has been affirmed repeatedly through extensive long-term studies and further research continues to take place in order to ensure patient safety.1 Recent scientific studies have shown an infrequent correlation between textured breast implants and anaplastic large cell lymphoma (ALCL), which has resulted in a specific subset of textured breast implants to be removed from market secondary to a higher incidence of this disease.2 Such action reaffirms the importance of ongoing research in all aspects of plastic surgery as we always place patient safety first and foremost.

As physicians who took a Hippocratic oath to do no harm, we must adhere to these same scientific standards if we are to meaningfully define the wide range of symptoms that have collectively become known on social media as “breast implant illness.” This condition has been attributed to any and all types of saline and silicone breast implants and their surrounding silicone shells. It has been postulated that the implant shell itself may have toxins or other yet-to-be-defined elements that cause a myriad of symptoms yet to be articulated in a scientific manner.3 A 2006 study published in the Annals of Chemistry evaluated the total platinum concentration in both patient tissue and breast implant samples. The authors concluded that women with silicone breast implants have platinum levels that exceed that of the general population.4 However, a critical analysis highlighted that platinum concentrations in blood and urine samples showed no statistically significant difference and that both the control and implanted groups were shown to have platinum levels comparable to those in platinum industry workers. Furthermore, the study design was deemed nonreproducible.5,6 Pinpointing a material explanation for breast implant illness symptoms has been impeded by poor data collection and lack of science and dissemination of misinformation on social media, which places patients with breast implants at risk of making improperly informed decisions.

This is not to say that breast implant illness does not exist—both patient advocacy groups and the U.S. Food and Drug Administration recognize various symptoms as being risks related to breast implants7—but rather that there is no current scientific evidence to support such claims. It is therefore the responsibility of plastic surgeons to advise patients who may present with symptoms associated with breast implant illness to seek full evaluation by our medical and rheumatology colleagues to ensure we are not missing any type of disease process; the American Society of Plastic Surgeons is taking the lead in working with patients and with the Food and Drug Administration to investigate these widely reported symptoms in an effort to supplant speculation with data and science.

Bilateral DIEP Flap Breast Reconstruction to a Single Set of Internal Mammary Vessels: Technique, Safety, and Outcomes after 250 Flaps

Bilateral DIEP Flap Breast Reconstruction to a Single Set of Internal Mammary Vessels: Technique, Safety, and Outcomes after 250 Flaps

by Opsomer, Dries; D’Arpa, Salvatore; Benmeridja, Lara; Stillaert, Filip; Noel, Warren; Van Landuyt, Koenraad 

Plastic and Reconstructive Surgery: October 2019 - Volume 144 - Issue 4 - p 554e-564e

Background: The deep inferior epigastric artery perforator (DIEP) flap is considered the gold standard in autologous breast reconstruction. In bilateral cases, both flaps are often anastomosed to the internal mammary vessels on either side of the sternum. The authors propose a method in which both flaps are anastomosed to only the right side internal mammary artery and vein.

Methods: Between November of 2009 and March of 2018, 125 patients underwent bilateral DIEP flap breast reconstruction with this technique. One flap is perfused by the anterograde proximal internal mammary artery and the second one by the retrograde distal internal mammary artery after presternal tunneling. Patient demographics and operative details were reviewed retrospectively. Results: Two hundred fifty flaps were performed. One hundred fifty-two flaps were prophylactic or primary reconstructions (60.8 percent), 70 were secondary reconstructions (28 percent), and 28 were tertiary reconstructions (11.2 percent). Mean patient age was 46 years, and the mean body mass index was 25 kg/m2. Sixty patients underwent radiation therapy or chemotherapy (48 percent). The authors encountered one significant partial failure (0.4 percent) and nine complete flap failures (3.6 percent). The authors did not see a statistically significant predisposition for failure comparing the retrograde with the anterograde flow flaps, nor when comparing the tunneled with the nontunneled flaps.

Conclusions: The authors’ results show that anastomosing both DIEP flaps to a single set of mammary vessels is safe and reliable. The authors conclude that the retrograde flow through the distal internal mammary artery is sufficient for free flap perfusion and that subcutaneous tunneling of a free flap pedicle does not predispose to flap failure. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Safety Profiles of Fat Processing Techniques in Autologous Fat Transfer for Breast Reconstruction

Safety Profiles of Fat Processing Techniques in Autologous Fat Transfer for Breast Reconstruction

by Ruan, Qing Zhao; Rinkinen, Jacob R.; Doval, Andres F.; Scott, Benjamin B.; Tobias, Adam M.; Lin, Samuel J.; Lee, Bernard T.

Plastic and Reconstructive Surgery: April 2019 - Volume 143 - Issue 4 - p 985-991

Background: Autologous fat transfer is common in breast reconstruction because of its versatility for use in contour deformities. The authors examined three different fat grafting processing techniques for complications and safety profile using their institutional database.

Methods: Retrospective review was performed of patients from a single institution who had undergone autologous fat transfer following breast reconstruction from 2012 to 2016. Individuals were separated into three cohorts according to fat harvest technique: (1) centrifugation, (2) Telfa gauze, or (3) Revolve. Complications between the groups were assessed. Results: A total of 267 cases of autologous fat transfer were identified (centrifugation, n = 168; Telfa, n = 44; and Revolve, n = 55). Grafting by means of centrifugation was associated with the greatest incidence of oil cysts (12.5 percent; p = 0.034), postoperative adverse events observed in the clinic (13.7 percent; p = 0.002), and total complications (25.6 percent; p = 0.001). The use of Telfa resulted in the lowest rates of oil cyst formation (0 percent; p = 0.002) and total complications (2.3 percent; p = 0.001). Grafting by means of centrifugation was also associated with the highest frequency of repeated injections among the three techniques after initial grafting (19.6 percent; p = 0.029). In contrast, Revolve demonstrated a repeated injection rate of just 5.45 percent, significantly lower when independently compared with centrifugation (p = 0.011). Multivariate analysis demonstrated that higher total graft volume (p = 0.002) and the use of centrifugation (p = 0.002) were significant risk factors for adverse events seen in the clinic postoperatively.

Conclusions: Significant differences in postoperative outcomes exist between varying fat transfer techniques. Autologous fat transfer by means of centrifugation harbored the highest rates of complication, whereas Telfa and Revolve exhibited similar safety profiles. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

[Articles] Short-term safety outcomes of mastectomy and immediate implant-based breast reconstruction with and without mesh (iBRA): a multicentre, prospective cohort study

[Articles] Short-term safety outcomes of mastectomy and immediate implant-based breast reconstruction with and without mesh (iBRA): a multicentre, prospective cohort study

 by Shelley Potter, Elizabeth J Conroy, Ramsey I Cutress, Paula R Williamson, Lisa Whisker, Steven Thrush, Joanna Skillman, Nicola L P Barnes, Senthurun Mylvaganam, Elisabeth Teasdale, Abhilash Jain, Matthew D Gardiner, Jane M Blazeby, Chris Holcombe, iBRA Steering Group, Breast Reconstruction Research Collaborative  

The Lancet Oncology: Volume 20, issue 2, P254-266, February 01, 2019

Complications after immediate implant-based breast reconstruction are higher than recommended by national standards. A randomised clinical trial is needed to establish the optimal approach to immediate implant-based breast reconstruction.

Five-Year Safety Data for More than 55,000 Subjects following Breast Implantation: Comparison of Rare Adverse Event Rates with Silicone Implants versus National Norms and Saline Implants

Five-Year Safety Data for More than 55,000 Subjects following Breast Implantation: Comparison of Rare Adverse Event Rates with Silicone Implants versus National Norms and Saline Implants
Singh, N et al
Plastic and  Reconstructive Surgery: October 2017 - Volume 140 - Issue 4 - p 666–679

Background: The U.S. Food and Drug Administration has required postapproval studies of silicone breast implants to evaluate the incidence of rare adverse events over 10 years after implantation. Methods: The Breast Implant Follow-Up Study is a large 10-year study (>1000 U.S. sites) evaluating long-term safety following primary augmentation, revision-augmentation, primary reconstruction, or revision-reconstruction with Natrelle round silicone breast implants compared with national norms and outcomes with saline implants. Targeted adverse events in subjects followed for 5 to 8 years included connective tissue diseases, neurologic diseases, cancer, and suicide. 
Results: The safety population comprised 55,279 women (primary augmentation, n = 42,873; revision-augmentation, n = 6837; primary reconstruction, n = 4828; and revision-reconstruction, n = 741). No targeted adverse events occurred at significantly greater rates in silicone implant groups versus national norms across all indications. The standardized incidence rate (observed/national norm) for all indications combined was 1.4 for cervical/vulvar cancer, 0.8 for brain cancer, 0.3 for multiple sclerosis, and 0.1 for lupus/lupus-like syndrome. Silicone implants did not significantly increase the risk for any targeted adverse events compared with saline implants. The risk of death was similar with silicone versus saline implants across all indications. The suicide rate (10.6 events per 100,000 person-years) was not significantly higher than the national norm. No implant-related deaths occurred. 
Conclusions: Results from 5 to 8 years of follow-up for a large number of subjects confirmed the safety of Natrelle round silicone implants, with no increased risk of systemic disease or suicide versus national norms or saline implants.