Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Carcinoma

Breast Neoplasms

Carcinoma in Situ

Breast Carcinoma In Situ

Breast Diseases

Skin Diseases

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Andreas U Karakatsanis, MD, PhD

Andreas Karakatsanis

Peter A Barry

Andreas Karakatsanis, MD, PhD

The study aspires to provide outcomes on surgery, quality of life and time-to-event outcomes following the development and validation of a standardised surgical assessment tool in a shared decision-making framework for patients with pre-invasive or invasive breast cancer with breast conservation.

Oncoplastic breast-conserving surgery (OPBCS) has gained increasing popularity over the last years and tends to be considered the standard of care in surgical practice. OPBCS allows for the resection of larger volumes and tumors with acceptable cosmesis, by incorporating different techniques that have evolved mainly from mastopexy, mammoplasty, and breast reduction or volume replacement techniques, such as perforator flap reconstruction.

However, no randomized controlled trial data on indications, methods, decision-making and outcomes are available, and present practice is largely based on evidence from cohort data derived from single- or multi-institutional series. Along with that, the fact that surgical decision-making in OPBCS is highly individualized renders any effort for standardization of these operations highly challenging and controversial. This is a multifactorial phenomenon, owing to anatomic differences such as breast volume, breast shape, lesion volume, localization, ptosis, body mass index (BMI) but also patient preference and availability of surgical techniques. Efforts for standardization of techniques based on tumor location, breast size, and ptosis have been made, but they do not address the principle of tailored treatment and do not cover all clinical scenarios.

On the other hand, breast-conserving surgery (BCS) followed by whole breast irradiation (WBI) yields comparable to better outcomes compared with mastectomy without WBI in terms of survival, but much better in terms of quality of life (QoL) and patient-reported outcomes and measures (PROMS), even when compared to the reconstructed breast. At the same time, OPBCS seems to yield superior cosmesis and patient satisfaction compared to traditional wide local excisions (WLE), but it is unclear whether this comes at the cost of increased morbidity or unnecessary revisionary procedures, with an impact on the delivery of systemic treatment, QoL and health economy. In addition, patient preference is a factor that precludes randomization to the method of operation in the traditional meaning, as it would not be ethical to randomize surgery that may be unnecessarily extensive or oncologically dubious. Moreover, surgeon and patient preferences and expectations may involve bias which is hard to define and a non-randomized study on the subject of WLE vs OPBCS could inevitably be unclear in how to address this inherent flaw.

PROMS such as QoL and cosmesis are even more important in the case of benign lesions that need to be operated on. This has to do with the fact that no compromises need to be made for the sake of a radical breast cancer operation as well as that benign breast surgery is more common in women of younger age. There, despite the instinctive assessment that a well-placed incision should have better outcomes, there is a complete lack of high-quality data on the matter.

At the same time, the decision-making process of the choice of surgical technique is a phenomenon poorly investigated; surgeons tend to offer the techniques they are most comfortable with and offer therapy per patient preference largely dependent on the health setting. This may account for the lack of consistency in identifying factors related to re-excision, postoperative complications, and PROMS. In this procedure, patient preference has shown to vary depending on surgical consultation, not only on the choice not to undergo mastectomy but also on the extent of BCS. Another fact that needs to be taken into account is that, despite that several classification systems and algorithms have been proposed, everyday clinical practice represents more of a continuum. On the other hand, "standard surgical assessment" performed by breast surgeons is likely to reflect personal preferences, techniques one may be most comfortable with as well as variances in healthcare provision.

This may account for the lack of consistency in practice, resulting either in involved margins and requiring re-excision, with consequences on cosmesis and patient satisfaction (undertreatment), or the unnecessary utilization of OPBCS in cases where "simpler" could produce equivalent results with less operative time, complications or need for contralateral symmetrization (overtreatment). Therefore, any objective associations between the method of BCS and outcomes remain to be elucidated.

The rationale is to investigate whether the development of a tool for surgical decision-making may facilitate the identification of appropriate surgical techniques for each patient.

The trial aims to investigate whether the application of a structured approach to select an appropriate surgical technique may have an impact on PROMS, complications, QoL, and health-economy. In that way, the effect of rationalized versus empiric employment of operative techniques (OPBCS vs WLE) may be elucidated. Additionally, it will allow for the accumulation of evidence regarding OPBCS in a way that does not come in conflict with ethics, patient preference, and real-world clinical practice. Moreover, the study will aspire to investigate whether there may be a more objective manner to define the minimum required type of surgery to obtain clear margins whilst maintaining breast function and form in a manner compatible with patient preference and optimal quality of life. As this is a multifaceted question, it is appropriate to examine it separately for different subgroups (volume replacement or displacement). Last but not least, the study may help elucidate the impact of locoregional and systemic oncologic treatment (radiotherapy, local and/or locoregional, and chemotherapy, immunotherapy, and endocrine therapy) in PROMS on the type of surgical treatment the patient has received. The design is intended to be highly pragmatic. Therefore, the systematic restructuring and the capitalization of the routinely available preoperative patient data will be used towards the effort of developing a clinical decision-making tool.

The study will look into surgical outcomes (complications, re-excision rates, conversion to mastectomy), patient-reported outcomes and experience, time-to-event outcomes (local recurrence-free survival, locoregional recurrence-free survival, disease-free survival, and overall survival) as well as health economy factors. These will be examined on an individual participant level, and a subgroup level, such as per oncoplastic reconstructive principle (volume displacement vs volume replacement), different oncoplastic techniques (eg. mastopexies vs reduction vs perforator flaps), onco-cosmetic surgery or not, concomitant contralateral symmetrization or not.

Oncoplastic breast-conserving surgery (OPBCS) has gained increasing popularity over the last years and tends to be considered the standard of care in surgical practice. OPBCS allows for the resection of larger volumes and tumors with acceptable cosmesis, by incorporating different techniques that have evolved mainly from mastopexy, mammoplasty, and breast reduction.

Variables that need to be prospectively registered and available:

1. Lesion biology data\* - Invasive cancer (Y/N)

   - Pure DCIS (Y/N)

   - Tumour type (1: Invasive Ductal Carcinoma, Non-specific type (IDC-NST) , 2: Invasive Lobular Carcinoma (ILC), 3: Mixed ductolobular carcinoma, 4: Other invasive subtypes, 5: Ductal Carcinoma In Situ (DCIS)

   - Nuclear Grade

   - Estrogen Receptor (ER)
   * Progesterone Receptor (PR)
   * Human Epidermal growth factor Receptor type 2 (HER2 status or erbb-2 status)
   * Ki67% (optional)
   * Any gene signature test (optional)
   * Tumour Infiltrating Lymphocytes (TIL) and Programmed Death Ligand-1 (PDL-1), provided that their report becomes standard of care. (optional)
   * For surgery following neoadjuvant, Residual Cancer Burden (optional) \*: Can be replicated from postoperative data in non-discordant cases.
2. Baseline Radiologic Assessment

   - Tumor size (d: maximum diameter in cm). If there is a discrepancy, then the size of the modality (Mammogram, US, MRI) on which the decision is made needs to be registered

   - Localization in the chest (Clock axis, cm from NAC); to be divided into the following categories during harmonization (Upper Outer Quadrant, Junction between Upper and Lower Outer Quadrant, Lower outer quadrant, Junction between Lower Outer and Lower Inner Quadrant, Lower Inner Quadrant, Junction between Lower and Upper Inner Quadrant, Upper Inner Quadrant, Junction between Inner and Outer Upper Quadrant, Retroareolar, Multiple site ipsilateral cancers (previously described as multifocal or multicentric)

   - Tumor size (max size) and Optimal Resection Volume (ORV = 4 / 3π (d / 2 + 1)3, d: maximum diameter in cm.

   - Calculated Resection Ratio: CRR = ORV / BrV, where BrV stands for Breast Volume (see below).
3. Baseline patient assessment:

   * Age at operation
   * Comorbidities (Charlson Comorbidity Index)
   * Smoking
   * Diabetes Mellitus with end-organ damage
   * Neoadjuvant therapy
   * Body mass index (BMI)
   * Ptosis (to be assessed according to the "Regnault" classification, as follows: 1) first degree: nipple at the level of the infra-mammary fold. 2) second degree: nipple below the level of the infra-mammary fold but above the level of the most dependent (inferior) part of the breast contour and 3) third degree: nipple below the level of the infra-mammary fold and sitting at the most dependent, inferior part of the breast contour
   * Breast volume estimate

Acceptable alternatives:

i) "Longo" Formula ii) Breast Cups iii) Bra cup size, if available literature on the conversion of cup size to volume is available) All measurements will be cross-validated by review of preoperative mammograms and calculation of the volume with either the "Kalbhen" or the "Katariya" formulae.

(Kalbhen formula: BrV = 0.784x H x W x C, where H: is anteroposterior distance, W: is mediolateral distance, C: mammographic compression, all in centimeters on the craniocaudal projection of the mammogram ("CC image"), Katariya formula: BrV=π/12\*W2\*H on the CC image).

* Tumor size (max size) and Optimal Resection Volume (ORV = 4 / 3π (d / 2 + 1) 3, d: maximum diameter in cm.
* Calculated Resection Ratio: CRR = ORV / BrV.
* The rationale behind the recommendation:

To avoid mastectomy; to avoid volume displacement with asymmetry or the need for contralateral symmetrization; to avoid wide local excision with poor cosmetic outcomes.

This assessment will be cross-validated by the team of local PIs

d. Intraoperative data

- Type of volume replacement. The following alternatives are available: Lateral Intercostal Artery Perforator (LICAP), Lateral Thoracic Artery Perforator (LTAP), Lateral Hybrid (combination of LTAP and LICAP), Lateral advancement flap (LAF), Mini Latissimus Dorsi (Muscle sparing), TDAP, Medial or Anterior Intercostal Artery Perforator (MICAP/AICAP), Abdominal Advancement Flap (AAF).

* Single perforator-based flap
* Technique of placement (trapdoor, pendulum, propeller) (optional)
* Tumour localization technique regardless of type (ink, coal, guidewire, seed). Type of localization to be reported
* Axillary procedure (None, SLND, Axillary biopsy, TAD, ALND)
* Specimen weight (in grams, gr)
* Specimen shape, dimensions, and volume (Actual Resection Volume, ARV). The proposed methods are weight/0.958 or volumetry by registration of shape and dimensions.

Specimens are either rectangular and the volume is provided by the formula "V= h x w x l" or elliptical and the volume is provided by the formula "V= 4/3 x (h/2) x (w/2) x (l/2)= 0.654 x h x w x l", where "h": height (cm), "w": width (cm), and "l": length (cm) of the specimen.

* Operative time (min)
* Perioperative antibiotics (Y/N)
* Extended antibiotic administration (Y/N).
* Use of drains
* Day surgery (Y/N)
* Length of stay (days)

  e. Postoperative data
* e.1 Pathology report
* Invasive cancer (Y/N)
* Pure DCIS (Y/N)
* Tumour type (1: IDC, 2: ILC, 3: Mixed, 4: Other invasive, 5: DCIS, 6: Unknown)
* Nuclear Grade (1,2,3)
* Estrogen Receptor (ER) (%)
* Progesterone Receptor (PR) (%)
* HER2 (positive, negative)
* Ki67% -- Tumour Infiltrating Lymphocytes (TIL) and Programmed Death Ligand-1 (PDL-1), provided that their report becomes standard of care.
* Radical excision (Y/N), internationally defined as no "tumour-on-ink" for IBC and 2mm for pure DCIS. National variations in practice will be accepted if they modify the decision-making
* Need for reoperation for complication or margin control (Y/N)
* Type of reoperation (Re-excision, Mastectomy).
* Actual Resection Ratio (ARR), defined as (Specimen volume/Breast volume)
* Number of lymph nodes retrieved (Sentinel and total) (optional)
* Number of lymph nodes with metastases. (to define pN status)
* Type of metastasis (optional)
* e2 Complications at 28 days. Report type.
* Fat necrosis: report Grade according to scale from Lovey et al as follows:

  0 No fat necrosis
  1. Asymptomatic fat necrosis (only radiologic and/ or cytologic ﬁndings)
  2. Symptomatic fat necrosis not requiring medication (palpable mass with or without mild pain)
  3. Symptomatic fat necrosis requiring medication (palpable mass with signiﬁcant pain)
  4. Symptomatic fat necrosis requiring surgical intervention
* Alleged infection (clinical diagnosis)
* Infection (Verified with culture)
* Bleeding
* Symptomatic seroma requiring intervention
* Reporting of complications per the "Clavien Dindo" (CD) classification and Comprehensive Complication Index 2.0 (CCI 2.0) score.
* e3 Type of (Neo)Adjuvant Systemic therapy (None, Chemotherapy, Endocrine Therapy, Monoclonal antibodies, CDK 4-6 inhibitors or other)
* e4 Type of Adjuvant Radiotherapy (None, whole breast irradiation, reduced dose whole breast irradiation, partial breast irradiation plus minus nodal/regional irradiation) f. Patient Reported Outcomes (Optional) Questionnaires accepted

EORTC QLQ-c-30 BreastQ preoperative and postoperative modules Diseases of the Arm, Shoulder and Hand (DASH) score

g. Health-economy outcomes

h. Long-term follow-up Ipsilateral Local recurrence Ipsilateral Locoregional recurrence Distant Recurrence Breast Cancer-Specific Survival Overall Survival (All in months).

Oncologic, Cosmetic and Patient Reported Outcomes in Value-Based Breast Surgery (OnCoPRO Value)

Oncologic, Cosmetic and Patient Reported Outcomes in Value-Based Breast Surgery. A Multicentre, Cohort Study

Type of axillary procedure performed at the time of breast surgery

Percenteage of patients not amenable to standard wide local excision following a standardized assessment, that are operated with oncoplastic breast conservation resulting in negative margins and avoid mastectomy.

Percenteage of patients not amenable to standard wide local excision following a standardized assessment, that undergo breast conservation, but require re-excision of margins without conversion to mastectomy as a final result.

The European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) is a validated 30 item instrument meant to assess some of the different aspects that define the quality of life of cancer patients. It assesses both quality of life domains and symptom domains in a scale score ranging from 0 to 100. For the quality of life domains, higher scores denote higher satisfaction or higher quality of life. For symptom scales, higher score denotes more severe symptoms. In the Summary Score of the Questionnaire, higher values denote higher quality of life

The BREAST-Q questionnaire is developed especially for breast cancer patients undergoing breast surgery. Independent modules are available for the different surgical interventions (e.g., mastectomy, reconstruction, augmentation). The BREAST-Q questionnaire has been validated and serves as of a standardized measurement instrument. The Satisfaction with Breasts module is summarized in a score ranging from 0 to 100, with higher scores denoting higher satisfaction

The BREAST-Q questionnaire is developed especially for breast cancer patients undergoing breast surgery. Independent modules are available for the different surgical interventions (e.g., mastectomy, reconstruction, augmentation). The BREAST-Q questionnaire has been validated and serves as of a standardized measurement instrument. The Physical Wellbeing: Chest module is summarized in a score ranging from 0 to 100, with higher scores denoting higher wellbeing

Postoperative complications, reported descriptively, per the modified Clavien Dindo classification and the Comprehensive Complication Index 2.0 (CCI 2.0)

Characteristics of patients that require mastectomy per surgeon assessment

Costs related with each surgical procedure

Time from Surgery to ipsilateral local recurrence (in situ or invasive)

Time from Surgery to ipsilateral locoregional recurrence (in situ or invasive)

Time from surgery to breast cancer related death

Time from surgery to death from any cause

Uppsala University Hospital

Royal Marsden NHS Foundation Trust

Westmead Breast Cancer Institute, Sydney University, Sydney, Australia

Breast Unit, University Campus Biomedico, Rome, Italy

Uppsala University

Associate Professor, MD, PhD

Gynecomastia

Central Nervous System Depressants

All Drugs and Chemicals

Other Dietary Supplements

Benzocaine

Tannic Acid

This group of patients will have their periareolar incisions closed with 4-0 Prolene sutures which are non-absorbable (require removal) and require knot-tying.

This group of patients will have their periareolar incisions closed with 4-0 Monocryl sutures which are absorbable (do not require removal) and require knot-tying.

This group of patients will have their periareolar incisions closed with 4-0 Stratafix sutures which are absorbable (do not require removal) and do not require knot-tying.

Any surgery involving incisions made along the nipple areolar complex. These would include transgender mastectomy, cisgender female breast reduction/augmentation/reconstruction, and cisgender male gynecomastia correction.

Breast surgery

The closing of a surgical incision by using sutures so appose and maintain apposition of two skin edges. Suturing may or may not require knot-tying depending on the material of suture used.

Suturing of surgical incision

Tanya Delyzer, MD

Aaron Grant, MD

This will be a single-blinded study where participants are blinded to the suture type but the surgeon will draw a random, unmarked envelope containing the designated suture type at the start of the surgery. The patient population will be all patients undergoing breast surgery at the London Health Sciences Center (LHSC) - ie. University Hospital, Victoria Hospital and the Nazem Kadri Surgical Center, and St. Joseph's Hospital. Three (3) main procedure groups will be transgender gender-affirming top surgery, cisgender female breast reduction or augmentation (including healthy and cancer patients; subgroup analysis will be performed), and cisgender male gynecomastia surgery. The goal is n=180 patients, n=60 per type of suture with n=20 per type of procedure (totaling n=60 per type of procedure).

NAC width for each breast will be measured intraoperatively, at 2 weeks postop, 6 weeks postop, 3 months postop, and 6 months postop. These measurements will be deidentified and logged into a secure data entry form. Information on whether a secondary outcome occurred (ie. infection, dehiscence, revision and nipple necrosis) will be logged in this form as well.

Because the sutures will be kept non-visible under dressings until the clinical followup appointment 2 weeks postop, the patient will remain blinded as to the type of suture used on their NAC(s). At this point, absorbable sutures will have been largely dissolved and non-absorbable sutures will be removed.

This will be a single-blinded study where the participants will be blinded to the type of suture. The patient population will be all patients undergoing breast surgery at the London Health Sciences Center (LHSC) - ie. University Hospital, Victoria Hospital and the Nazem Kadri Surgical Center - and St. Joseph's Hospital falling into one of 3 categories: transmasculine gender affirming top surgery, cisgender female elective or oncologic breast surgery (mastopexy, breast reduction, breast augmentation, or nipple-sparing mastectomy), and cisgender male gynecomastia correction.

Three sutures will be used: 4-0 Prolene, 4-0 Monocryl and 4-0 Stratafix. We will aim for n=180 participants, n=60 per type of suture, and n=60 per surgical category. This way, each suture type can be equally distributed among each surgical category. This means n=20 of each suture type will be used in n=20 of each surgery type. For example, n=20 top surgery patients will receive Prolene sutures, n=20 receive Monocryl, and n=20 receive Stratafix. All patients will be consented in the preop area on the day of their surgery by a member of the research team.

The primary outcomes will be NAC diameter or "width" intraoperatively immediately after closing compared to NAC width 2 weeks, 6 weeks, 3 months, and 6 months postoperatively. The horizontal and vertical widths will be measured at each time. Measurements are done with a ruler and recorded in centimeters. Prolene sutures will be removed at the 6-week postop visit as per current clinical practice. Absorbable will not be removed because they are absorbable.

Statistical regression will be used to determine whether a certain type(s) of suture is optimal for minimizing NAC widening after surgery. Subgroup analyses will also be conducted to determine any confounding factors from heterogeneity in patient factors within each group. Secondary outcomes will be rates of infection, tip loss, nipple necrosis and dehiscence, and whether certain types of sutures increase these adverse outcomes.

All patients will receive the surgical treatment they consented for, the only difference among them being the type of suture material used to close their perioareolar incisions (3 different types are investigated in this study).

The type of suture used to close the periareolar incision will be determined by drawing the name of the suture from a random, sealed envelope at the start of the procedure in the operating room. The patient will not be informed of the suture type and they are unable to see the suture type due to postoperative dressings being placed overtop, until they see the surgeon at their 2-week followup appointment.

Effect of Suture Material on Postoperative Nipple Areolar Complex Widening

Effect of Suture Material on Postoperative Nipple Areolar Complex Widening: A Randomized Controlled Trial

Postoperative change in diameter of the nipple areolar complex as an adverse outcome

Death of nipple tissue as an adverse outcome following surgery

Loss of projection of the nipple tip due to effacement as an adverse outcome following surgery

Colonization of the surgical area by bacteria leading to immune response

Separation of the apposed skin edges along the surgical incision

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Oncologic, Cosmetic and Patient Reported Outcomes in Value-Based Breast Surgery (OnCoPRO Value)	NCT06401304	Breast Cancer Breast Carcinom... Breast Cancer I... Breast Asymmetr...		18 Years -	Uppsala University
Oncologic, Cosmetic and Patient Reported Outcomes in Value-Based Breast Surgery (OnCoPRO Value)	NCT06401304	Breast Cancer Breast Carcinom... Breast Cancer I... Breast Asymmetr...		18 Years -	Uppsala University
Effect of Suture Material on Postoperative Nipple Areolar Complex Widening	NCT06070324	Breast Cancer Gynecomastia Transgenderism Breast Asymmetr...	Breast surgery Suturing of sur...	18 Years -	Lawson Health Research Institute
Oncologic, Cosmetic and Patient Reported Outcomes in Value-Based Breast Surgery (OnCoPRO Value)	NCT06401304	Breast Cancer Breast Carcinom... Breast Cancer I... Breast Asymmetr...		18 Years -	Uppsala University

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