BACKGROUND AND RATIONALE:

Triple negative and HER2 positive are high-risk as well as chemo-sensitive subtypes of breast cancer. We are comparing two strategies of treatment for high-risk breast cancer (Her2 positive and TNBC), the first, response adapted systemic therapy for Her2 positive and primary chemotherapy for TNBC with the second, peri-operative interventions. The first option in a randomized setting has shown significant difference in DFS and second option also in a randomized trial has shown significant difference in DFS as well as OS.

Role of neoadjuvant chemotherapy-

With Fisher’s hypothesis of early control of systemic micrometastases in breast cancer, there was a thrust on neoadjuvant chemotherapy followed by surgery. Hence, in early 1990s, a number of randomized trials were initiated worldwide to assess the difference in survival outcomes between chemotherapy given before and after surgery. However, despite showing an improvement in response rates, pathological complete response rates, there was no difference in survival outcomes(NSABP
27) Neoadjuvant chemotherapy thus largely failed to meet its promise of extending survival in breast cancer when compared to adjuvant chemotherapy. (NSABP 18) It is beneficial in downsizing for operability/resectability and achieving a higher conservation rate, along with the opportunity for in-vivo assessment of tumour response. However, only 25% patients additionally were downsized enough to achieve BCS. (Ref) In a recent EBCTCG meta-analysis of 18 studies, there was a higher rate of in-breast tumour recurrence in patients who had breast conservation surgery after pre-operative chemotherapy. (Ref) This meta-analysis of course included older studies wherein tumour margins assessment were not uniformly reported, nor was a tumour bed boost used routinely in planning of breast radiotherapy post breast conservation surgery. Also, the higher rate of IBTR could have been attributed by the inclusion of studies wherein surgery was not offered post pre-operative chemotherapy in complete responders. This proves a definitive role of surgery in patients’ post-chemotherapy, even in those who have excellent response to chemotherapy.

Triple negative and HER2 enriched breast cancers respond particularly well to chemotherapy as compared to luminal types. (REf-MARKER PG 264 LEFT LOWER 9) With modern chemotherapy comprising of anthracyclines, taxols, platinum agents and HER2 directed targeted therapy, whenever appropriately indicated, the pCR rates are as high as 50% in the TNBC and HER2 enriched patients. (Ref-MARKER PG 264, RIGHT UPPER9,11,12) However, pCR has been erroneously used a surrogate of efficacy of a new chemotherapeutic drug or regimen.A pathological complete response (pCR) defined as “absence of invasive disease in breast and axilla” is often considered as a surrogate of survival in triple negative and HER2 positive tumours. This is not true for hormone receptor positive tumours, in whom the pCR rate to chemotherapy alone is dismal (<10%) and does not correlate with survival.

Although patient level association of pCR and better outcome is proven in several neoadjuvant trials and meta-analysis (Cortazar et al, Lancet, 2014), it did not translate to improved outcomes in the trial. E.g., In her 2 positive patients, use of lapatinib along with trastuzumab in the NeoALTTO study led to a near significant 20% improvement in pCR (Baselga et al, Lancet, 2012) with no difference in EFS or OS at an updated 6-year analysis (Huober et al, JCO, 2017). It’s adjuvant counterpart ALTTO study further confirmed lack of survival benefit of lapatinib and trastuzumab combination. (Moreno-Aspitia et al, Eur J Cancer, 2021). Phase 2 NEOSPHERE trial reported results of 417 patients with tumor size >2cm, HER-2 positive patients who were randomized to 4 arms: docetaxel + trastuzumab, docetaxel + trastuzumab + pertuzumab, trastuzumab + pertuzumab, docetaxel + pertuzumab with primary end point being pathological complete response and secondary end point being progression free survival and disease-free survival. This study showed doubling of pCR using trastuzumab + pertuzumab combination along with docetaxel. The 5-year progression free survival was 81% in the docetaxel + trastuzumab arm versus 86% in the docetaxel + trastuzumab + pertuzumab arm (95% CI 0.34-1.40) (Gianni et al, Lancet, 2012, 2016). US-FDA fast-track approved the use of pertuzumab in the adjuvant setting based on pCR improvement and phase 2 study. The APHINITY trial randomized 4805 node positive and high risk node negative (1cm or 0.5-1cm with grade III disease, hormone receptor negative disease or age<35yrs) HER2 positive patients to receive pertuzumab in addition to standard trastuzumab based chemotherapy regimen in the adjuvant setting post after surgery. At 6 years from randomization, 91% patients in the pertuzumab group and 88% patients in the placebo group remained event-free, corresponding to an absolute benefit of 2.8% (95% CI 1.0-4.6). In the node positive subgroup, the HR was 0.72 (95% CI 0-59-0-87) and the 6-year IDFS was 88% in the pertuzumab group as compared to 83% in the placebo group, corresponding to an absolute benefit of 4.5%. There was, however, no additional benefit from addition of pertuzumab in the nodenegative cohort, even after 6 years after randomization (94.9% versus 95%, HR 1.02, 95%CI 0.69-1.53). This updated analysis of the APHINITY trial with median follow up of 8.4 years did not meet statistical significance for OS benefit (93.9% versus 94.8%, HR 0.85, 95% CI 0.67-1.07) of adding pertuzumab in the adjuvant setting for the overall trial population. (M Piccart, JCO, 2021 or screenshot 12.2.23).

Another landmark phase III randomized open label KATHERINE trial was conducted among 1486 HER2 positive patients who had residual invasive disease after completion of neoadjuvant chemotherapy with adjuvant HER2 directed therapy and taxane with or without anthracycline. Those who did not achieve pCR were randomized to receive 14 cycles of adjuvant t-DM 1 versus trastuzumab in the maintenance phase. Invasive disease-free survival was significantly higher in the T-DM1 group (88.3%) as compared to trastuzumab group (77%) (HR 0.50, 95% CI 0.39-0.64). However, again, there was no overall survival benefit at 3 years.

Thus, the standard chemotherapy in the neoadjuvant or adjuvant setting for HER2 positive patients remains trastuzumab based chemotherapy with addition of pertuzumab in node positive patients with benefit in invasive disease-free survival. Switching to T-DM1 remains an option in those who continue to have residual disease at surgery after trastuzumab or trastuzumab + pertuzumab based neoadjuvant chemotherapy, again for an invasive disease-free survival benefit. Neither the addition of pertuzumab or switching to T-DM1 after response assessment seems to lead to an overall survival benefit in HER2 positive patients.

Triple negative breast cancer is a high-risk subgroup of breast cancer. These tumors are usually chemo-sensitive and achieve a high pCR rate. Earlier trials of carboplatin added to neoadjuvant/adjuvant chemotherapy showed a significant improvement in pCR. However, disease-free survival benefit was a secondary end point. In a recent individual participant data and trial level meta-analysis (Neha Pathak et al, The Breast, 2022), the authors systematically reviewed 8 trials with 2425 patients’ data. Carboplatin improved DFS (HR 0.60, 0.47-0.78) at both trial level and IPD level. It also improved overall survival (HR 0.69, 0.50-0.95). As expected, in the carboplatin arm, there was doubling of pCR. The TMH TNBC study similarly showed a benefit in OS as well as DFS with carboplatin when added in the neoadjuvant arm, especially in women < 50 years of age. Not achieving pCR confers a particularly poor prognosis in the TNBC patients. The landmark CREATE-X trial performed in Japan and Korea with 910 TNBC patients who had residual invasive disease after receiving neoadjuvant chemotherapy containing anthracycline, taxane or both. These patients were then randomised to receive 6 months of adjuvant capecitabine or placebo with primary end point being DFS and secondary end point OS. Disease free survival was 74.1% vs 67.6% in control group, p=0.01 and overall survival also being longer in the capecitabine group, 89.2% vs 83.6%, p=0.01. (ref) However, only 30% of patients in this study were triple negative and the at the dose of capecitabine that was used, 65% patients had significant toxicity to treatment. Further studies to assess the role of maintenance chemotherapy in TNBC patients who do not achieve a pCR are ongoing.

The success of immunotherapy in extending survival in metastatic TNBC paved way to KEYNOTE-522, a phase III randomized clinical trial conducted for 784, stage II and III TNBC patients. In this study, 4 cycles of 3 weekly pembrolizumab versus placebo were added to paclitaxel and carboplatin in the neoadjuvant setting following which both the groups received additional 4 cycle of pembrolizumab or placebo along with doxorubicin/epirubicin and cyclophosphamide. After surgery, the respective groups received additional 9 cycles of 3 weekly pembrolizumab or placebo. Primary end point waspCR and event free survival. pCR improved from 51.2% in the placebo arm to 64.4% in the pembrolizumab arm. Hazard ratio for event-free survival was 0.63 (0.43-0.93). Both were significantly higher in the pembrolizumab group in the recent fourth interim analysis (screenshot 12.2.23 at 11.40- 3)

Although, at an individual patient level, understanding responders versus non-responders is a useful prognostic marker with the potential for improved survival by further risk adapted maintenance chemotherapy planning. However, “A good surrogate endpoint should fulfil the condition of a meaningful association with the true endpoint at both patient and trial level.” (Buyse et al, Biostatistics, 2000) A  study by Fabio Conforti et al, considered 54 neoadjuvant randomised clinical trials comprising a total of 32,611 patients. A weighted regression analysis was performed on log transformed treatment effect estimates (hazard ratio for disease-free survival and overall survival and relative risk for pathological complete response), and the coefficient of determination (R²) was used to quantify the association. A weak association was observed between the log(relative risk) for pathological complete response and log(hazard ratio) for both disease-free survival (R²=0.14, 95% confidence interval 0.00 to 0.29) and overall survival (R² =0.08, 0.00 to 0.22). This association continued to be weak across all the subtypes of breast cancer including the triple negative and HER2 positive tumours. The poor association remained even when trials with small sample size and short follow up were removed from analysis and when relative risk was replaced with absolute difference in pCR in the two trial arms. A lack of surrogacy was confirmed between pCR and DFS/OS recommending that presence of or lack of pCR should not be used as a primary end point in regulatory neoadjuvant trials in early breast cancer.

Currently, the rationale for using pre-operative chemotherapy in TNBC and HER2 enriched early breast cancer is to segregate the non-responders from the responders and offer further risk adapted strategies. However, the use of pCR as a surrogate itself is questionable.

Role of surgery first-

Surgery is the most definitive treatment for majority of solid cancers including triple negative and HER2 positive breast cancer. Peri-operative interventions to change the homeostatic milieu at the time of surgery is an area for intervention which has not been explored previously. We found a 10% improvement in disease free survival in high-risk patients when early breast cancer patients undergoing surgery first were administered Injection Progesterone 500 mg deep IM 4-14 days before surgery. (JCO, 2010) This study was initiated with the retrospective observation from many previous studies of better surgical outcomes in breast cancer patients when operated in the luteal phase (progesterone dependent) of the menstrual cycle as compared to when operated in the follicular phase (estrogen dependent). (ref) A recently published study using injection of a local anaesthetic Lignocaine peri-tumourally, in 1600 early breast cancer patients resulted in a 6% absolute improvement in disease free survival and 4% absolute improvement in overall survival. The benefit was seen across all subtypes and across all risk categories.

With the advent of these peri-operative interventions showing significant improvement in long-term survival outcome, we aim to compare the results of two strategies of treatment for high-risk early (T1-2, N0-1) breast cancer (Her2 positive and TNBC), the first, response adapted systemic therapy for HER2 positive and primary chemotherapy for TNBC with the second, peri-operative interventions. Patients will be randomized to undergo surgery first versus pre-operative chemotherapy followed by surgery with disease-free survival as the primary endpoint.

Hypothesis-

Surgery first with perioperative interventions will be more beneficial in TNBC and HER2 positive tumours as compared to chemotherapy first.

OBJECTIVES:

Primary-

1)      To demonstrate an improvement in disease free survival in the “Surgery first” arm when compared to “Preoperative chemotherapy arm” in triple negative and HER2 positive early breast cancer.

2)      To demonstrate an improvement in overall survival in the “Surgery first” arm when compared “Preoperative chemotherapy arm” in triple negative and HER2 positive early breast cancer.

Secondary-

1)      To demonstrate local recurrence, breast cancer specific survival, regional recurrence, in the “Surgery first” arm when compared “Preoperative chemotherapy arm” in triple negative and HER2 positive early breast cancer.

2)      To evaluate pCR rate in the pre-operative chemotherapy arm

3)      Evaluation of margin positivity rate in the two arms after BCS

4)      BREAST-Q Quality of Life assessment

Primary endpoints-

1)      Disease free survival

2)      Overall survival

Secondary endpoints-

1)      Breast cancer specific survival

2)      Local recurrence (IBTR)

3)      Regional recurrence

4)      Evaluation of pathological complete response in the pre-operative chemotherapy arm

5)      Cosmetic assessment after breast conservation surgery (BCCT-Core software)

6)      Evaluation of margin positive rate in the 2 arms

7)     QOL assessment (BREAST-Q)

Definition of study endpoints:

Disease free survival (DFS): is defined as the time interval between randomization and occurrence of any recurrence (local, regional, or distant) of invasive breast cancer. Patients developing contralateral breast cancers or non-invasive recurrence will be excluded from this.

Overall survival (OS): defined as the time interval between randomization and death due to any cause.

Breast cancer specific survival (BCSS): is defined as the time interval between randomization and death due to breast cancer with/without recurrence. 

Evaluation of pCR: defined as complete disappearance of all invasive disease from the primary and axilla both post pre-operative chemotherapy.  (Will be evaluated at baseline, 1^st follow up after completion of adjuvant treatment (+/- 3 months), at 2 years follow up visit).

Cosemesis: Cosmesis will be assessed in all breast conservation surgery patients with BCCT Core software at Baseline, 1^st follow Up after completion of adjuvant treatment (+/- 3 months), 2 year follow up visit)

Margins positivity: is defined as any tumour on inked surface (on final HPR)- in both arms of the study.

QOL: will be measured by BREAST-Q tool at Baseline, 1^st follow Up after completion of adjuvant treatment (+/- 3 months), 2 year follow up visit)

Inclusion Criteria:

1)      Histologically proved breast carcinoma

2)      Triple negative(ER, PgR, HER2-neu) and HER2-neu positive (ER/PgR +/-)

3)      T1-2 (excluding T1a), N0-1 (non-metastatic)

4)      > 18 years < 65 years

5)      ECOG 0-1

6)      Written informed consent

7)      Fit for surgery or chemotherapy

Exclusion Criteria :

1)      Pregnant, lactating women

2)      Previous h/o breast or any other non-skin malignancy

3)      Previous treatment for excision biopsy/other cancer.

4)      History of allergy to Inj. Lignocaine

TRIAL INTERVENTIONS

All eligible patients will be randomized into two arms.

Arm A – Surgery first

Arm B - Pre-operative chemotherapy followed by surgery.

The chemotherapy in both arms will be as per standard of care as per MDT decision of breast cancer-disease management group.

1)      4# Adriamycin, Cyclophosphamide 2 or 3 weekly

2)      4# Paclitaxel 2 or 3 weekly

3)      12# weekly Paclitaxel

4)      12# weekly Paclitaxel + Trastuzumab

5)      6# Docetaxel, Carboplatin, Trastuzumab

6)      6# Docetaxel, Carboplatin, Trastuzumab, Pertuzumab

STUDY DESIGN

Open label, Phase III, randomized controlled trial, 1:1.

Stratification Criteria :

1)     Premenopausal /peri-menopausal versus postmenopausal

2)     Clinically node positive versus node negative

3)     TNBC versus HER2 positive

Trial procedures-

All patients of early breast cancer will be screened from the OPD. Histological proof will be obtained with a trucut biopsy and immunohistochemical assessment with routine methods. FISH test will be done in all cases with HER2 result equivocal on IHC. All triple negative and HER 2 positive, T1-2, N0-1 patients will be explained the consent and those consenting will be randomized. The surgical plan will be as per clinico-radiological assessment and patient choice – i.e., either a BCS or mastectomy. Upfront surgery for axilla will include either low axillary sampling or sentinel node biopsy, or axillary dissection if positive node is found in the axilla. All patients in the surgery first arm will receive Inj. Proluton 4-14 days prior to surgery and Inj. Lignocaine as peritumoral infiltration 5-10 minutes before surgical resection. In the pre-operative chemotherapy group, patients will receive appropriate chemotherapy regimen as per conventional standard. Response assessment will be as per usual care, i.e., clinical assessment at each cycle and radiological assessment at the end line of chemotherapy. Patients with good response to chemotherapy will go on to complete all chemotherapy first while those with stable or progressive disease will be considered for surgery after the first line chemotherapy. Hematological and cardiac assessment will be as per usual care. Prior to surgery, clinico-radiological assessment and patient choice will determine the type of surgery, i.e., BCS vs mastectomy. Patients undergoing surgery after pre-operative chemotherapy will undergo complete axillary dissection or equivalent procedure. Appropriate oncoplastic procedure after BCS and post mastectomy whole breast reconstruction will be offered to all the patients as per patient choice and surgeon assessment. Those patients not having pCR in the pre-operative chemotherapy group will be offered maintenance capecitabine (if TNBC) or InjT-DM1 (if HER2 positive) as per standard of care, patient tolerance and affordability. All patients will receive at least 6 months or up to 1 year of adjuvant Trastuzumab as per cardiac fitness and risk stratification.

All patients will receive radiation therapy as per standard institutional protocol (All BCS, All mastectomy > 5 cm and node positive). Adjuvant endocrine treatment will be offered to patients if ER+/-PR positive along with HER2 + as per standard institutional guidelines.

Follow-up

All patients will be followed up every 6 monthly for the first 5 years and yearly after that until progression and death. In case of progression, further management will be as per the standard Institutional policies/ BC-DMG decision.

SERIOUS ADVERSE EVENT RECORDING AND REPORTING

A serious adverse event (SAE) is defined as any untoward medical occurrence (due to the participation in the concerned trial) that at any dose:

·         -Results in death.

·         -Is life-threatening.

·         Requires inpatient hospitalization or prolongation of an existing hospitalization.

·         Results in a persistent or significant disability or incapacity.

·         Results in a congenital anomaly or birth defect.

If patient’s disease progresses during course of active treatment, endpoint for the same patient will be achieved, thus event after the disease progression of patient will not be notified.

Patients on the study will be receiving standard treatment as both the arm of the study is standard of care. Hence toxicities related to chemotherapy such as febrile neutropenia, neuropathy and cardiac toxicities will not be considered as SAE. Also hospitalization related to any adjuvant treatment toxicities will not be reported as serious adverse event. However, any toxicity more than grade 3, death will be reported as SAE All other SAEs, including other information reportable as SAE information will be get reported to DSMU /IEC as per institutional and regulatory guidelines.

STATISTICAL CONSIDERATION

A total sample size of 1513 (1600 with accounting for lost-to-follow-up) split equally between the two groups, or 288 events, achieves 80% power to detect a hazard rate of 0.70173 when the proportions surviving in each group are 0.78 and 0.84 at a significance level (alpha) of 0.05 using a two-sided log rank test. These results assume that 2 sequential tests are made using the Pocock spending function (as detailed below) to determine the test boundaries and that the hazards are proportional.

Details when Spending = Pocock, N = 1513, d = 287, S1 = 0.78, S2 = 0.84

Drift  2.97174

The total study duration is 9 years with accrual period of 4 years and follow-up for 5 years.

Analysis of the variables-

Data will be recorded in CRFs and SPSS/Redcap. Kaplan Meir curves will be plotted for disease free and overall survival and other survival outcomes such as locoregional recurrence free survival etc. All other clinic-pathological characteristics will be captured and compared with spss/SAS using standard tests such as chi-square, Mann Whitney, Logistic regression. Multivariate analyses for survival will be done using Cox regression method. Significance will be considered for 2-sided p value of 0.05.

Feasibility-

At the Tata Memorial Centre (TMH and ACTREC), we treat a minimum of 2000 patients annually with curative intent and surgery. At least 1000 of these are early breast cancer. They will be eligible for the study. We hope to have at least a 40% accrual rate, hence, the study should be completed within 4 years.

References-

1.         Bear HD, Anderson S, Smith RE, Geyer CE, Mamounas EP, Fisher B, et al. Sequential Preoperative or Postoperative Docetaxel Added to Preoperative Doxorubicin Plus Cyclophosphamide for Operable Breast Cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol [Internet]. 2006 May 1 [cited 2023 Apr 16];24(13):2019–27. Available from: https://ascopubs.org/doi/10.1200/JCO.2005.04.1665

2.         Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr. 2001;(30):96–102.

3.         Buchholz TA, Mittendorf EA, Hunt KK. Surgical Considerations After Neoadjuvant Chemotherapy: Breast Conservation Therapy. JNCI Monogr [Internet]. 2015 May 1 [cited 2023 Apr 16];2015(51):11–4. Available from: https://doi.org/10.1093/jncimonographs/lgv020

4.         Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. The Lancet [Internet]. 2014 Jul 12 [cited 2023 Apr 17];384(9938):164–72. Available from: https://www.sciencedirect.com/science/article/pii/S0140673613624228

5.         Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. The Lancet [Internet]. 2012 Feb 18 [cited 2023 Apr 17];379(9816):633–40. Available from: https://www.sciencedirect.com/science/article/pii/S0140673611618473

6.         Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D, et al. Survival outcomes of the NeoALTTO study (BIG 1–06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer [Internet]. 2019 Sep 1 [cited 2023 Apr 17];118:169–77. Available from: https://www.sciencedirect.com/science/article/pii/S0959804919302989

7.         Moreno-Aspitia A, Holmes EM, Jackisch C, de Azambuja E, Boyle F, Hillman DW, et al. Updated results from the international phase III ALTTO trial (BIG 2–06/Alliance N063D). Eur J Cancer OxfEngl 1990 [Internet]. 2021 May [cited 2023 Apr 17];148:287–96. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103014/

8.         Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomisedmulticentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25–32.

9.         Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016 Jun;17(6):791–800.

10.       Piccart M, Procter M, Fumagalli D, de Azambuja E, Clark E, Ewer MS, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years’ Follow-Up. J Clin Oncol Off J Am Soc Clin Oncol. 2021 May 1;39(13):1448–57.

11.       von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med [Internet]. 2019 Feb 14 [cited 2023 Apr 17];380(7):617–28. Available from: https://doi.org/10.1056/NEJMoa1814017

12.       Pathak N, Sharma A, Elavarasi A, Sankar J, Deo SVS, Sharma DN, et al. Moment of truth-adding carboplatin to neoadjuvant/adjuvant chemotherapy in triple negative breast cancer improves overall survival: An individual participant data and trial-level Meta-analysis. Breast EdinbScotl. 2022 Aug;64:7–18.

13.       Helwick C. Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer Carboplatin Adds Benefit New Study Shows - The ASCO Post [Internet]. [cited 2023 Apr 17]. Available from: https://ascopost.com/issues/february-25-2023/neoadjuvant-chemotherapy-in-triple-negative-breast-cancer-carboplatin-adds-benefit-new-study-shows/

14.       Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med [Internet]. 2017 Jun 1 [cited 2023 Apr 17];376(22):2147–59. Available from: https://doi.org/10.1056/NEJMoa1612645

15.       Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med [Internet]. 2020 Feb 27 [cited 2023 Apr 17];382(9):810–21. Available from: https://doi.org/10.1056/NEJMoa1910549

16.       Helwick C. Neoadjuvant Pembrolizumab Improves Event-Free Survival in Triple-Negative Breast Cancer - The ASCO Post [Internet]. [cited 2023 Apr 17]. Available from: https://ascopost.com/issues/august-10-2021/neoadjuvant-pembrolizumab-improves-event-free-survival-in-triple-negative-breast-cancer/

17.       Buyse M, Molenberghs G, Burzykowski T, Renard D, Geys H. The validation of surrogate endpoints in meta-analyses of randomized experiments. BiostatOxf Engl. 2000 Mar;1(1):49–67.

18.       Conforti F, Pala L, Sala I, Oriecuia C, Pas TD, Specchia C, et al. Evaluation of pathological complete response as surrogate endpoint in neoadjuvant randomised clinical trials of early stage breast cancer: systematic review and meta-analysis. BMJ [Internet]. 2021 Dec 21 [cited 2023 Apr 17];375:e066381. Available from: https://www.bmj.com/content/375/bmj-2021-066381

19.       Badwe R, Hawaldar R, Parmar V, Nadkarni M, Shet T, Desai S, et al. Single-Injection Depot Progesterone Before Surgery and Survival in Women With Operable Breast Cancer: A Randomized Controlled Trial. J Clin Oncol [Internet]. 2011 Jul 20 [cited 2023 Apr 17];29(21):2845–51. Available from: https://ascopubs.org/doi/10.1200/JCO.2010.33.0738

20.       Badwe RA, Gregory WM, Chaudary MA, Richards MA, Bentley AE, Rubens RD, et al. Timing of surgery during menstrual cycle and survival of premenopausal women with operable breast cancer. The Lancet [Internet]. 1991 May 25 [cited 2023 Apr 17];337(8752):1261–4.Available from:https://www.sciencedirect.com/science/article/pii/014067369192927T

21.       Badwe RA, Parmar V, Nair N, Joshi S, Hawaldar R, Pawar S, et al. Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer. J Clin Oncol [Internet]. 2023 Apr 6 [cited 2023 Apr 17];JCO.22.01966. Available from: https://ascopubs.org/doi/10.1200/JCO.22.01966