Platinum‐based chemotherapy for early triple‐negative breast cancer

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the effects of platinum‐based chemotherapy as adjuvant and neoadjuvant treatment for patients with early triple negative breast cancer

Background

Description of the condition

Breast cancer is the most common type of cancer in women and the most common cause of cancer death (Ferlay 2018). Triple‐negative breast cancer (TNBC) is an aggressive subtype of breast cancer, which lacks hormone receptor and human epidermal growth factor receptor 2 (HER2) expression. It is associated with shorter survival and higher likelihood of recurrence, and comprises about 15% of breast cancer diagnoses (Foulkes 2010, Lin 2012). Early TNBC is defined as cancer that has not spread beyond the breast or axillary lymph nodes, and is potentially curable. Surgery, radiotherapy, and chemotherapy are used to minimise the chance of relapse.

TNBC is more likely to be associated with heritable causes than other breast cancer subtypes. Over 10% of women diagnosed under the age of 50 years, without known family history of breast or ovarian cancer and carrying a heritable mutation in either breast cancer gene 1 or gene 2 (BRCA1 or BRCA2), are found to have TNBC (Shimelis 2018). Whilst BRCA1 mutation is the most strongly associated, other heritable gene mutations, i.e. BRCA2; partner and localizer of BRCA2 (PALB2); RAD51 paralogue D (RAD51D); and BRCA1 associated RING domain 1 (BARD1) have also shown associations with TNBC and high lifetime risks of breast cancer. These mutations are implicated in DNA repair and genomic stability. A heritable mutation in either a high risk or moderate risk breast cancer gene was found in 12% of the study population with TNBC, highlighting the importance of referring women with triple negative breast cancer for genetic counselling, even when there is no known family history of cancer (Shimelis 2018). Guidelines recommend genetic testing for women who are diagnosed at young ages (< 50 years to 60 years), if there is a family history of breast, ovarian, prostate, or pancreatic cancer, or if they are of Ashkenazi Jewish ancestry.

Description of the intervention

Standard chemotherapy used in the adjuvant or neoadjuvant setting for TNBC involves anthracycline and taxane chemotherapy, combined with cyclophosphamide. The role of adjuvant chemotherapy is to treat micrometastatic systemic disease, which is not detectable by standard blood tests and imaging. Chemotherapy is indicated for most women with TNBC who are in good health. The National Comprehensive Cancer Network (NCCN) Guidelines recommend offering chemotherapy to women with TNBC whose cancer size is larger than 1 cm, or any size with involvement of their lymph nodes. Chemotherapy may also be considered for women with smaller tumours.

The intervention being studied is the addition of platinum‐based chemotherapy (cisplatin or carboplatin) to the standard adjuvant or neoadjuvant chemotherapy, to determine whether this improves survival from early TNBC. Our primary outcomes are overall survival and disease‐free survival. Achieving a pathological complete response (pCR) has strong prognostic value, particularly in the TNBC subtype (Cortazar 2014). As this association between survival and pCR has been reported, there are many trials assessing pCR whilst either waiting for data to mature, or as their primary endpoint, to decide whether larger trials are feasible. We will measure pCR, along with overall survival and disease‐free survival.

How the intervention might work

Platinum agents damage DNA by causing single‐strand DNA breaks, resulting in apoptosis. DNA repair deficiencies are associated with germline or somatic mutations in BRCA1, BRCA2, and PALB2, which are frequently associated with TNBC. This is a proposed mechanism for the increased efficacy of the DNA‐damaging effects of platinum chemotherapy for TNBC. With genomic profiling, women identified as having basal‐type TNBC are also seen to have DNA‐repair deficiency (Guo 2017). Besides breast cancer, an enhanced response to platinum‐based chemotherapy is seen in women with BRCA mutations who have ovarian cancer (Pennington 2014), and BRCA‐associated pancreatic cancer (O'Reilly 2020). Poly (ADP‐ribose) polymerase‐ (PARP) inhibitors have shown efficacy for women with advanced BRCA breast cancer, although this treatment has not been compared to their response to platinum.

Potential side effects of platinum include an increase in myelosuppression, which can lead to dose omissions, interruptions, or dose reduction of platinum, other chemotherapy drugs, or both. There are risks of additional toxicity from myelosuppression, with febrile neutropenia, anaemia, or bleeding due to thrombocytopenia. Long‐term toxicities from platinum include peripheral neuropathy, ototoxicity, and renal impairment.

Why it is important to do this review

This review will clarify the role of platinum‐based chemotherapy in early TNBC, to determine if there is a significant improvement in overall survival or other disease outcomes with acceptable toxicity.  Previous reviews on this topic suggested that the addition of platinum chemotherapy increases rates of pCR at the cost of an increase in adverse events (Poggio 2018, Pandy 2019). However, new trials have been published since these reviews.

Maximising the efficacy of treatment of early breast cancer will reduce rates of metastatic, incurable disease and premature death from this condition. However, given this is a population where the intention is long‐term survival, the prevention of permanent toxicity is also a priority.

Objectives

To assess the effects of platinum‐based chemotherapy as adjuvant and neoadjuvant treatment for patients with early triple negative breast cancer

Methods

Criteria for considering studies for this review

Types of studies

We will include all randomised controlled trials (RCTs) examining platinum‐based chemotherapy for neoadjuvant or adjuvant treatment for women with triple negative breast cancer (TNBC). This may be delivered by adding platinum to another standard chemotherapy regimen, or by comparing a platinum regimen to a non‐platinum regimen. To be included, studies must report their findings for women with TNBC separately from other women, or only include a minority (< 20%) of included women with non‐TNBC.

Types of participants

Women, 18 years or older, with early TNBC, defined as breast cancers that lack expression of the oestrogen receptor and progesterone receptor (as defined by the trial), and are negative for human epidermal receptor 2 (HER2; negative with in situ hybridisation (ISH) testing; 0 to 1+ with immunohistochemistry (IHC); or 2+ with IHC and negative with fluorescence in situ hybridisation (FISH)). We will include trials with all study locations, and women of all ethnicities. We will exclude trials that did not assess women for HER2 status.

Types of interventions

The intervention of interest is any chemotherapy regimen that contains platinum chemotherapy, compared to regimens without platinum chemotherapy. Included studies will address either adjuvant (post‐surgery) or neoadjuvant (pre‐surgery) delivery of chemotherapy for early breast cancer. We will record and compare the dose and duration of chemotherapy used.

Types of outcome measures

Primary outcomes

• Disease‐free survival, defined as time from surgery (in neoadjuvant setting) or randomisation (in adjuvant setting) to first date of a local, regional, or distant relapse, diagnosis of a second primary cancer, or death from any cause. We will include similar outcomes, such as progression‐free survival and time to progression in this section

• Overall survival, defined as the time from randomisation or study entry until death from any cause

Secondary outcomes

• Rate of pathological complete response, defined as no invasive carcinoma in the breast or axillary lymph nodes (ypT0/isypN0 (TNM staging; AJCC 2010)) after neoadjuvant therapy

• Completion of regimens, assessed by absence of delay in treatment or dose reductions, or both, or early cessation of treatment

• Any grade III/IV toxicity related to chemotherapy (stratified by type haematological OR non‐haematological toxicity)

• Quality of life ‐ While quality of life information is typically not collected in these types of trials, we will aim to report any quality of life data as measured by the many validated tools available to trialists, and at all reported time points

Search methods for identification of studies

Electronic searches

We will search the following databases:

• The Cochrane Breast Cancer Group's (CBCG's) Specialised Register. Details of the search strategies used by the Group for the identification of studies and the procedure used to code references are outlined in the Group's module (https://breastcancer.cochrane.org/sites/breastcancer.cochrane.org/files/public/uploads/specialised_register_details.pdf). We will identify and consider for inclusion any trial with the key words: 'Cisplatin', 'cisplatinum', 'carboplatin', 'carboplatinum', 'platin', 'platinum', 'platinum diamminodichloride', 'cis‐diamminedichloroplatinum', 'cis‐dichlorodiammineplatinum', 'biocisplatinum', 'dichlorodiammineplatinum', 'nsc‐119875', 'platidiam', 'platino', 'Platinol', 'cis‐diamminedichloroplatinum', 'cis‐platinum', 'cis‐diammine (cyclobutanedicarboxylato) platinum', 'cbdca', 'jm‐8', 'nsc‐241240', 'paraplatin';

• CENTRAL (the Cochrane Library, latest issue); see Appendix 1

• MEDLINE OvidSP (top up search to complement CBCG's Specialised Register); see Appendix 2

• Embase OvidSP (1947 to present); see Appendix 3;

• The WHO International Clinical Trials Registry Platform (ICTRP) search portal for all prospectively registered and ongoing trials (apps.who.int/trialsearch/Default.aspx); see Appendix 4

• Clinicaltrials.gov (http://clinicaltrials.gov/); see Appendix 5

Searching other resources

We will screen the reference lists of identified relevant trials or reviews to help identify additional studies. We will obtain a copy of the full article for each reference reporting a potentially eligible trial. Where this is not possible, we will attempt to contact authors to request additional information. We will search the abstracts of recent conference proceedings not yet included in the CBCG's Specialised register or medical databases. This will include conference abstracts from the American Society of Clinical Oncology annual meeting, European Society of Medical Oncology Congress, and San Antonio Breast Cancer Symposium. We will search systematic reviews on the topic using PubMed Clinical Queries.

Data collection and analysis

Selection of studies

Two review authors (SM and AG) will independently apply the selection criteria to each reference identified by the search strategy, and resolve any disagreements by review by one review author (JB or RD). We will include English‐language and translated studies. We will record the selection process in the PRISMA flow diagram. We will record excluded studies in the 'Characteristics of excluded studies' table.

Data extraction and management

We will extract data using standard extraction forms. Information collected will include: study design; randomisation methods; baseline characteristics of participants; setting; chemotherapy regimens (chemotherapy agent, dose, number of cycles); deliverability of treatment, assessed by dose intensity, dose delays, or interruptions. We will also collect details regarding type of toxicity for grade III or IV events (according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, 2017)), length of follow‐up, sources of funding, and any relevant conflicts of interest of trial authors.

Two review authors (SM and MW) will independently extract the data, and resolve disagreements with the support of one review author (AG). For studies with more than one publication, we will extract data from all publications, but we will consider the most recent version of the study to be the primary reference. We will combine records relating to the same study under the overall trial ID. We will enter data into RevMan Web (RevMan Web 2020).

Assessment of risk of bias in included studies

We will assess bias with Cochrane's risk of bias version 2 (RoB 2) tool (Higgins 2020). The effect of interest will be the effect of assignment to the intervention at baseline, regardless of whether the interventions are received as intended (the intention‐to‐treat (ITT) effect). The intention‐to‐treat analysis is used to better reflect 'real‐world' clinical practice, to include noncompliance and protocol deviations.

We will make overall judgements of risk of bias for the main outcomes listed in the summary of findings table (listed in the summary of findings section). We will categorise our judgements as low risk of bias, some concerns, or high risk of bias, as per the RoB 2 tool. We will assess these five domains: bias arising from the randomisation process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome, and bias in selection of the reported result. For each domain, we will answer a series of 'signalling questions' to arrive at a risk of bias judgement, by using the RoB 2 Excel tool.

Two review authors (SM and MW) will independently assess the risk of bias, with guidance provided by two other review authors (AG and SE). We will seek clarification from trial authors if the published data provide inadequate information for the review. We will incorporate the results of this risk of bias assessment into the interpretation of results.

We will make our consensus decisions for signalling questions available to readers in the supplemental data, available in the open access institutional (University of Sydney) repository, to ensure transparency of decision‐making.

In this review, bias due to deviations from intended interventions may be present. In oncology, an open‐label approach is often used as it is difficult to obscure differing treatment schedules and potential toxicities from patients and care providers. However, lack of blinding is unlikely to affect our primary outcomes including overall survival (OS) and disease‐free survival (DFS).

Measures of treatment effect

We will use the following measures of the effect of treatment:

• time‐to‐event data (overall survival, disease‐free survival), we will express as a hazard ratio (HR). If HRs and variances are not reported in the trial publications, we will calculate summary statistics indirectly, using the methods outlined in Tierney 2007. In the 'Notes' section of the 'Characteristics of included studies' tables, we will record the use of indirect methods, and whether the trial publications reported an assessment of the proportional hazards assumption;

• dichotomous outcomes (pCR, toxicity), we will express as a risk ratio (RR) with 95% confidence interval (CI). We will report the ratios of treatment effects for response so that RRs less than 1.0 favour regimens with platinum chemotherapy, and RRs greater than 1.0 favour regimens without platinum chemotherapy.

• continuous data (quality of life), we will express as a mean difference (MD) if the same scales has been used, with 95% confidence interval. If studies use different scales to measure quality of life, we will report the treatment effect as a standardised mean difference (SMD) with 95% confidence intervals. In writing the final report, we will interpret and report standardised mean difference in a more easily interpreted scale for readers, considering the minimal important clinical difference (MICD) to put results into context (McGlothlin 2014). Each quality of life measurement scale  may have a different MICD and we will review these estimates for each instrument.  We will use an MID of 0.2 to 0.5 as a guide for patient‐reported outcomes.

Unit of analysis issues

The women are the unit of analysis in this review. We expect that some trials be three‐ or four‐arm studies, but most will be two‐arm studies. We anticipate there may be multiple intervention groups, multiple comparator groups, or both, in some studies. We will review studies comparing more than one platinum‐based regimen, or more than one non‐platinum regimen, as separate treatment comparisons. We will calculate treatment effect summary statistics by dividing the number of women in the intervention group if there are multiple comparator groups, or in the control group if there are multiple intervention groups. The Cochrane Handbook for Systematic Reviews of Interventions suggest these methods to correct for multiple intervention or control groups (Higgins 2020a). We do not expect to identify other non‐standard designs, such as cross‐over trials or cluster‐randomised trials.

Dealing with missing data

We will contact authors of included studies in writing, to obtain missing data (e.g. dosing or toxicity), which we will include where possible. We do not anticipate using imputed values.

If there are completed studies recorded in the WHO ICTRP that have not yet published their results, we will attempt to obtain data by contacting trial authors. We will discuss the impact of any missing data.

Assessment of heterogeneity

Recommendations in the Cochrane Handbook for Systematic Reviews of Interventions will guide the assessment of heterogeneity (Deeks 2020). We will examine diversity by visually inspecting the forest plots, Chi² test, and I² statistic. We will use a cutoff point of P = 0.10 for the Chi² test. The I² statistic indicates the percentage of variability due to between‐study (or inter‐study) variability, as opposed to within‐study (or intra‐study) variability. We will use It as a rough guide for interpretation, using these thresholds for I²:

• 0% to 40%: might not be important;

• 30% to 60%: may represent moderate heterogeneity;

• 50% to 90%: may represent substantial heterogeneity;

• 75% to 100%: considerable heterogeneity.

The importance of the observed value of I² depends on (1) magnitude and direction of effects, and (2) strength of evidence for heterogeneity (e.g. P value from the Chi² test, or a confidence interval for I²: uncertainty in the value of I² is substantial when the number of studies is small; Deeks 2020).

Assessment of reporting biases

If we include at least 10 studies in the meta‐analysis, we will investigate publication or other bias, using funnel plot asymmetry. Where possible. we will review the protocols of included studies to assess outcome reporting bias.

Data synthesis

We will use the following methods to synthesise the data:

• time‐to‐event data (overall survival, disease‐free survival) – we will use a fixed‐effect model with an inverse‐variance model; if there is evidence of substantial heterogeneity, we will use a random‐effects model (DerSimonian and Laird with inverse‐variance method)

• dichotomous outcomes (pCR, toxicity) – we will use a fixed‐effect model (Mantel‐Haenszel model; (Mantel 1959)); if there is evidence of substantial heterogeneity, we will use a random‐effects model (DerSimonian and Laird method; (DerSimonian 1986))

• continuous data (quality of life) – we will use a fixed‐effect model with an inverse variance method (Deeks 2011); if there is evidence of substantial heterogeneity, we will use a random‐effects model (DerSimonian and Laird with inverse‐variance method)

We will aim to include all trials, not only those with a low risk of bias. However, if sufficient studies are available, we will conduct a sensitivity analysis by restricting the analysis to RCTs with overall low risk of bias, or low or some concerns.

We will judge clinical homogeneity prior to synthesis by examining the characteristics of trial patients including age and prior treatments, and trial protocols including number of cycles of platinum chemotherapy delivered.

Subgroup analysis and investigation of heterogeneity

We will examine the following subgroups:

• Germline BRCA or other high risk gene mutations;

• Somatic mutation of DDR gene or HRD;

• Type of platinum agent used in the platinum arm: (a) cisplatin, (b) carboplatin;

• Types of chemotherapy

  1. trials that add platinum to another regimen, where the only difference in the treatment arm is the use of platinum: regimen A + platinum versus regimen A;

  2. Platinum‐containing regimen (non‐anthracycline) versus anthracycline‐containing regimen (may include taxane);

  3. Platinum and taxane‐containing regimen versus taxane‐containing regimen (which may include other types of chemotherapy)

• Timing of platinum agent, i.e. weekly versus every 3 weeks

We will conduct a subgroup analysis to assess the effects of the above factors on clinical outcomes and heterogeneity.

Sensitivity analysis

We will assess the effect of removing trials with a definition of triple negative that had a different hormone receptor (ER/PR) expression cutoff than < 1%.

Depending on overall risk of bias, we might assess the robustness of results of survival outcomes by excluding studies with a high risk of bias, and toxicity outcomes, by restricting the analysis to studies that adequately report toxicity outcomes (e.g. toxicities are reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, 2017)).

Summary of findings and assessment of the certainty of the evidence

We (SM, MW, AG and SE) will assess the certainty of the evidence for key outcomes with the GRADE approach. This approach uses five considerations: bias, inconsistency, indirectness, imprecision, and publication bias, to provide rationale for downgrading or upgrading the evidence (Schünemann 2013). We will assess each outcome, and present the information in a summary of findings table, using GRADEpro GDT software (GRADEpro GDT). The key outcomes being assessed are:

• disease‐free survival

• overall survival

• rate of pathological complete response after neoadjuvant therapy

• completion of regimens

  • dose intensity, number of cycles completed, treatment delays

• any grade III or IV toxicity related to chemotherapy (stratified by haematological, or non‐haematological toxicity)

  • non‐haematological toxicity, specifically peripheral neuropathy, renal impairment

  • haematological toxicity, specifically febrile neutropenia, anaemia

• quality of life

We will report summary of findings for time‐to‐event outcomes (overall survival, disease‐free survival) at 12 months and 5 years (with non‐platinum group risks estimated from the average of non‐platinum group Kaplan‐Meier probabilities at 12 months and 5 years). For all other outcomes, we will report when the outcome was measured (e.g. pathological complete response is measured shortly after the completion of treatment).

Summary of findings and assessment of the certainty of the evidence

We (SM, MW, AG and SE) will assess the certainty of the evidence for key outcomes with the GRADE approach. This approach uses five considerations: bias, inconsistency, indirectness, imprecision, and publication bias, to provide rationale for downgrading or upgrading the evidence (Schünemann 2013). We will assess each outcome, and present the information in a summary of findings table, using GRADEpro GDT software (GRADEpro GDT). The key outcomes being assessed are:

• disease‐free survival

• overall survival

• rate of pathological complete response after neoadjuvant therapy

• completion of regimens

  • dose intensity, number of cycles completed, treatment delays

• any grade III or IV toxicity related to chemotherapy (stratified by haematological, or non‐haematological toxicity)

  • non‐haematological toxicity, specifically peripheral neuropathy, renal impairment

  • haematological toxicity, specifically febrile neutropenia, anaemia

• quality of life

We will report summary of findings for time‐to‐event outcomes (overall survival, disease‐free survival) at 12 months and 5 years (with non‐platinum group risks estimated from the average of non‐platinum group Kaplan‐Meier probabilities at 12 months and 5 years). For all other outcomes, we will report when the outcome was measured (e.g. pathological complete response is measured shortly after the completion of treatment).

Summary of findings and assessment of the certainty of the evidence

We (SM, MW, AG and SE) will assess the certainty of the evidence for key outcomes with the GRADE approach. This approach uses five considerations: bias, inconsistency, indirectness, imprecision, and publication bias, to provide rationale for downgrading or upgrading the evidence (Schünemann 2013). We will assess each outcome, and present the information in a summary of findings table, using GRADEpro GDT software (GRADEpro GDT). The key outcomes being assessed are:

• disease‐free survival

• overall survival

• rate of pathological complete response after neoadjuvant therapy

• completion of regimens

  • dose intensity, number of cycles completed, treatment delays

• any grade III or IV toxicity related to chemotherapy (stratified by haematological, or non‐haematological toxicity)

  • non‐haematological toxicity, specifically peripheral neuropathy, renal impairment

  • haematological toxicity, specifically febrile neutropenia, anaemia

• quality of life

We will report summary of findings for time‐to‐event outcomes (overall survival, disease‐free survival) at 12 months and 5 years (with non‐platinum group risks estimated from the average of non‐platinum group Kaplan‐Meier probabilities at 12 months and 5 years). For all other outcomes, we will report when the outcome was measured (e.g. pathological complete response is measured shortly after the completion of treatment).

Summary of findings and assessment of the certainty of the evidence

We (SM, MW, AG and SE) will assess the certainty of the evidence for key outcomes with the GRADE approach. This approach uses five considerations: bias, inconsistency, indirectness, imprecision, and publication bias, to provide rationale for downgrading or upgrading the evidence (Schünemann 2013). We will assess each outcome, and present the information in a summary of findings table, using GRADEpro GDT software (GRADEpro GDT). The key outcomes being assessed are:

• disease‐free survival

• overall survival

• rate of pathological complete response after neoadjuvant therapy

• completion of regimens

  • dose intensity, number of cycles completed, treatment delays

• any grade III or IV toxicity related to chemotherapy (stratified by haematological, or non‐haematological toxicity)

  • non‐haematological toxicity, specifically peripheral neuropathy, renal impairment

  • haematological toxicity, specifically febrile neutropenia, anaemia

• quality of life

We will report summary of findings for time‐to‐event outcomes (overall survival, disease‐free survival) at 12 months and 5 years (with non‐platinum group risks estimated from the average of non‐platinum group Kaplan‐Meier probabilities at 12 months and 5 years). For all other outcomes, we will report when the outcome was measured (e.g. pathological complete response is measured shortly after the completion of treatment).

Summary of findings and assessment of the certainty of the evidence

We (SM, MW, AG and SE) will assess the certainty of the evidence for key outcomes with the GRADE approach. This approach uses five considerations: bias, inconsistency, indirectness, imprecision, and publication bias, to provide rationale for downgrading or upgrading the evidence (Schünemann 2013). We will assess each outcome, and present the information in a summary of findings table, using GRADEpro GDT software (GRADEpro GDT). The key outcomes being assessed are:

• disease‐free survival

• overall survival

• rate of pathological complete response after neoadjuvant therapy

• completion of regimens

  • dose intensity, number of cycles completed, treatment delays

• any grade III or IV toxicity related to chemotherapy (stratified by haematological, or non‐haematological toxicity)

  • non‐haematological toxicity, specifically peripheral neuropathy, renal impairment

  • haematological toxicity, specifically febrile neutropenia, anaemia

• quality of life

We will report summary of findings for time‐to‐event outcomes (overall survival, disease‐free survival) at 12 months and 5 years (with non‐platinum group risks estimated from the average of non‐platinum group Kaplan‐Meier probabilities at 12 months and 5 years). For all other outcomes, we will report when the outcome was measured (e.g. pathological complete response is measured shortly after the completion of treatment).

Summary of findings and assessment of the certainty of the evidence

We (SM, MW, AG and SE) will assess the certainty of the evidence for key outcomes with the GRADE approach. This approach uses five considerations: bias, inconsistency, indirectness, imprecision, and publication bias, to provide rationale for downgrading or upgrading the evidence (Schünemann 2013). We will assess each outcome, and present the information in a summary of findings table, using GRADEpro GDT software (GRADEpro GDT). The key outcomes being assessed are:

• disease‐free survival

• overall survival

• rate of pathological complete response after neoadjuvant therapy

• completion of regimens

  • dose intensity, number of cycles completed, treatment delays

• any grade III or IV toxicity related to chemotherapy (stratified by haematological, or non‐haematological toxicity)

  • non‐haematological toxicity, specifically peripheral neuropathy, renal impairment

  • haematological toxicity, specifically febrile neutropenia, anaemia

• quality of life

We will report summary of findings for time‐to‐event outcomes (overall survival, disease‐free survival) at 12 months and 5 years (with non‐platinum group risks estimated from the average of non‐platinum group Kaplan‐Meier probabilities at 12 months and 5 years). For all other outcomes, we will report when the outcome was measured (e.g. pathological complete response is measured shortly after the completion of treatment).

What's new

Date	Event	Description
2 September 2021	Amended	A technical error in the previous version of this protocol has now been corrected.

History

Protocol first published: Issue 5, 2021

Appendices

Appendix 1. CENTRAL

#1    MeSH descriptor: [Breast Neoplasms] explode all trees
#2    triple negative breast near neoplasm*
#3    triple negative breast near carcinoma*
#4    triple negative breast near cancer*
#5    triple negative breast near tumour*
#6    triple negative breast near tumor*
#7    #1 or #2 or #3 or #4 or #5 or #6
#8    (locally advanced near breast neoplasm*):ti 
#9    (locally advanced near breast carcinoma*):ti
#10    (locally advanced near breast cancer*):ti
#11    (locally advanced near breast tumour*):ti
#12    (locally advanced near breast tumor*):ti
#13    (metasta* near breast neoplasm*):ti
#14    (metasta* near breast carcinoma*):ti
#15    (metasta* near breast cancer*):ti
#16    (metasta* near breast tumour*):ti
#17    (metasta* near breast tumor*):ti
#18    #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17
#19    #7 not #18
#20    platinum or cisplatin or cisplatinum or Oxaliplatin or Carboplatin or lobaplatin or nedaplatin or eptaplatin or miboplatin or sebriplatin
#21    MeSH descriptor: [Platinum] explode all trees
#22    MeSH descriptor: [Cisplatin] explode all trees
#23    MeSH descriptor: [Platinum Compounds] explode all trees
#24    MeSH descriptor: [Carboplatin] explode all trees
#25    MeSH descriptor: [Oxaliplatin] explode all trees
#26    #20 or #21 or #22 or #23 or #24 or #25
#27    #19 and #26 in Trials

Appendix 2. MEDLINE

#	Searches
1	exp Breast Neoplasms/
2	exp Triple Negative Breast Neoplasms/
3	Triple Negative Breast cancer$.tw.
4	Triple Negative Breast neoplasm$.tw.
5	Triple Negative Breast carcinoma$.tw.
6	Triple Negative Breast tumo?r$.tw.
7	or/1‐6
8	(local$ adj6 advance$ adj6 (breast adj6 (neoplasm$ or cancer$ or carcinoma$ or tumo?r$))).ti.
9	(metasta$ adj6 (breast adj6 (neoplasm$ or cancer$ or carcinoma$ or tumo?r$))).ti.
10	or/8‐9
11	7 not 10
12	exp Cisplatin/
13	exp Carboplatin/
14	exp Organoplatinum Compounds/
15	exp Platinum/
16	exp Platinum Compounds/
17	(cisplatinum or cisplat* or cisplatin).tw.
18	(carboplatinum or carboplat* or carboplatin).tw.
19	(platinum or platin*).tw.
20	platinum compound*.tw.
21	(platinum‐containing regime* or platinum containing regime*).tw.
22	(platinum‐based agent* or platinum based agent*).tw.
23	(Platinol or Platinol‐ AQ or CDDP or CACP or platidiam or platinum diamminodichloride or cis‐diamminedichloroplatinum or cis‐dichlorodiammineplatinum or biocisplatinum or dichlorodiammineplatinum or nsc‐119875 or nsc 119875 or cis‐platinum or Abiplatin or AI3‐62048 or AI3 62048 or Briplatin or CCRIS 221 or Cismaplat or Cisplatine or Cisplatyl or Neoplatin).tw.
24	(carboplatine or CCRIS 3404 or EINECS 255‐446‐0 or "EINECS 255 446 0" or HSDB 6957 or cbdca or jm‐8 or jm8 or nsc‐241240 or nsc 241240 or paraplatin or Paraplatin‐ AQ or NSC 201345 or NSC‐201345 or cis‐diammine cyclobutanedicarboxylato platinum).tw.
25	(lobaplatin or lobaplatinum or lobaplat* or D‐19466 or D 19466).tw.
26	(Nedaplatin or Aqupla or CCRIS 4088 or NSC 375101D or NSC‐375101D or cis‐Diammine glycolato platinum).tw.
27	(Heptaplatin or Eptaplatin or NSC D644591 or NSC‐D644591).tw.
28	(Oxaliplatin or oxalapatin or 1‐OHP or CCRIS 9143 or Dacplat or Eloxatin or Elplat or JM‐83 or JM83 or l‐OHP or Lipoxal or NSC 266046 or NSC‐266046 or Oxalatoplatin or Oxalatoplatinum or Oxaliplatin or Oxaliplatino or Oxaliplatinum or Oxalitin or Oxaloplatine or Oxaloplatino or RP‐54780 or RP54780 or SR‐96669 or SR 96669).tw.
29	(miboplatin or CCRIS 5235 or DWA 2114R).tw.
30	(sebriplatin or NK 121).tw.
31	or/12‐30
32	11 and 31
33	animals/ not humans/
34	32 not 33
35	randomized controlled trial.pt.
36	controlled clinical trial.pt.
37	randomized.ab.
38	placebo.ab.
39	Clinical Trials as Topic/
40	randomly.ab.
41	trial.ti.
42	(crossover or cross‐over).tw.
43	Pragmatic Clinical Trials as Topic/
44	pragmatic clinical trial.pt.
45	or/35‐44
46	34 and 45
47	remove duplicates from 46

Appendix 3. Embase

#	Searches
1	exp breast cancer/
2	exp triple negative breast cancer/
3	Triple Negative Breast cancer$.tw.
4	Triple Negative Breast neoplasm$.tw.
5	Triple Negative Breast carcinoma$.tw.
6	Triple Negative Breast tumo?r$.tw.
7	or/1‐6
8	(local$ adj6 advance$ adj6 (breast adj6 (neoplasm$ or cancer$ or carcinoma$ or tumo?r$))).ti.
9	(metasta$ adj6 (breast adj6 (neoplasm$ or cancer$ or carcinoma$ or tumo?r$))).ti.
10	or/8‐9
11	7 not 10
12	exp cisplatin/
13	exp cisplatin derivative/
14	exp carboplatin/
15	exp platinum complex/
16	exp platinum/
17	exp platinum derivative/
18	exp platinum 1,2 diaminocyclohexane bisneodecanoate/
19	exp lobaplatin/
20	exp nedaplatin/
21	exp eptaplatin/
22	exp oxaliplatin/
23	exp miboplatin/
24	exp sebriplatin/
25	(cisplatinum or cisplat* or cisplatin).tw.
26	(carboplatinum or carboplat* or carboplatin).tw.
27	(platinum or platin*).tw.
28	platinum compound*.tw.
29	(platinum‐containing regime* or platinum containing regime*).tw.
30	(platinum‐based agent* or platinum based agent*).tw.
31	(Platinol or Platinol‐ AQ or CDDP or CACP or platidiam or platinum diamminodichloride or cis‐diamminedichloroplatinum or cis‐dichlorodiammineplatinum or biocisplatinum or dichlorodiammineplatinum or nsc‐119875 or nsc 119875 or cis‐platinum or Abiplatin or AI3‐62048 or AI3 62048 or Briplatin or CCRIS 221 or Cismaplat or Cisplatine or Cisplatyl or Neoplatin).tw.
32	(carboplatine or CCRIS 3404 or EINECS 255‐446‐0 or "EINECS 255 446 0" or HSDB 6957 or cbdca or jm‐8 or jm8 or nsc‐241240 or nsc 241240 or paraplatin or Paraplatin‐ AQ or NSC 201345 or NSC‐201345 or cis‐diammine cyclobutanedicarboxylato platinum).tw.
33	(lobaplatin or lobaplatinum or lobaplat* or D‐19466 or D 19466).tw.
34	(Nedaplatin or Aqupla or CCRIS 4088 or NSC 375101D or NSC‐375101D or cis‐Diammine glycolato platinum).tw.
35	(Heptaplatin or Eptaplatin or NSC D644591 or NSC‐D644591).tw.
36	(Oxaliplatin or oxalapatin or 1‐OHP pr CCRIS 9143 or Dacplat or Eloxatin or Elplat or JM‐83 or JM83 or l‐OHP or Lipoxal or NSC 266046 or NSC‐266046 or Oxalatoplatin or Oxalatoplatinum or Oxaliplatin or Oxaliplatino or Oxaliplatinum or Oxalitin or Oxaloplatine or Oxaloplatino or RP‐54780 or RP54780 or SR‐96669 or SR 96669).tw.
37	(miboplatin or CCRIS 5235 or DWA 2114R).tw.
38	(sebriplatin or NK 121).tw.
39	or/12‐38
40	Randomized controlled trial/
41	Controlled clinical study/
42	Random$.ti,ab.
43	randomization/
44	intermethod comparison/
45	placebo.ti,ab.
46	(compare or compared or comparison).ti.
47	(open adj label).ti,ab.
48	((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab.
49	double blind procedure/
50	parallel group$1.ti,ab.
51	(crossover or cross over).ti,ab.
52	((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or patient$1 or subject$1 or participant$1)).ti,ab.
53	(assigned or allocated).ti,ab.
54	(controlled adj7 (study or design or trial)).ti,ab.
55	(volunteer or volunteers).ti,ab.
56	trial.ti.
57	or/40‐56
58	11 and 39 and 57
59	remove duplicates from 58
60	limit 59 to (human and (conference abstracts or embase))

Appendix 4. WHO ICTRP

Basic Search:

Triple negative breast cancer AND platinum

Advanced Searches:

1. Condition: triple negative breast cancer OR triple negative breast neoplasm

Intervention: platinum

Recruitment status: All

2. Condition: triple negative breast cancer OR triple negative breast neoplasm

Intervention: platinum‐containing regime OR platinum compound OR platinum OR cisplatin OR carboplatin OR platin OR cisplatinum OR carboplatinum OR carboplatine OR cisplatine OR lobaplatin OR nedaplatin OR heptaplatin OR oxaliplatin OR oxalapatin OR miboplatin

Recruitment status: All

3. Condition: triple negative breast cancer OR triple negative breast neoplasm

Intervention: sebriplatin OR platinol OR platinol‐ AQ OR CDDP OR CACP OR platidiam OR platinum diamminodichloride OR cis‐diamminedichloroplatinum OR cis‐dichlorodiammineplatinum OR biocisplatinum OR dichlorodiammineplatinum OR nsc‐119875

Recruitment status: All

4. Condition: triple negative breast cancer OR triple negative breast neoplasm

Intervention:abiplatin OR AI3‐62048 OR AI3 62048 OR briplatin OR CCRIS 221 OR cismaplat OR cisplatyl OR neoplatin OR CCRIS 3404 OR EINECS 255‐446‐0 OR HSDB 6957 OR cbdca OR jm‐8 OR nsc‐241240 OR paraplatin OR paraplatin‐ AQ OR NSC 201345

Recruitment status: All

5. Condition: triple negative breast cancer OR triple negative breast neoplasm

Intervention: cis‐diammine cyclobutanedicarboxylato platinum OR lobaplatinum OR D‐19466 OR Aqupla OR CCRIS 4088 OR NSC 375101D OR cis‐Diammine glycolato platinum OR Eptaplatin OR NSC D644591 OR  CCRIS 9143 OR Dacplat OR Eloxatin OR Elplat OR JM‐83 OR JM83 OR l‐OHP

Recruitment status:All

6. Condition: triple negative breast cancer OR triple negative breast neoplasm

Intervention: Lipoxal OR NSC 266046 OR Oxalatoplatin OR Oxalatoplatinum OR Oxaliplatino OR Oxaliplatinum OR Oxalitin OR Oxaloplatine OR Oxaloplatino OR RP‐54780 OR SR‐96669 OR CCRIS 5235 OR DWA 2114R OR NK 121

Recruitment status: All

Appendix 5. ClinicalTrials.gov

Basic search:

Condition or disease: Triple negative breast cancer

Other terms: platinum

Advanced searches:

1. Condition or disease: Triple negative breast cancer OR triple negative breast neoplasm

Intervention/treatment: platinum‐containing regime OR platinum compound OR platinum OR cisplatin OR carboplatin OR platin OR cisplatinum OR carboplatinum OR carboplatine OR cisplatine OR lobaplatin OR nedaplatin OR heptaplatin OR oxaliplatin OR oxalapatin OR miboplatin

Study type: All studies

2. Condition or disease: Triple negative breast cancer OR triple negative breast neoplasm

Intervention/treatment: sebriplatin OR platinol OR platinol‐ AQ OR CDDP OR CACP OR platidiam OR platinum diamminodichloride OR cis‐diamminedichloroplatinum OR cis‐dichlorodiammineplatinum OR biocisplatinum OR dichlorodiammineplatinum OR nsc‐119875

Study type: All studies

3. Condition or disease: Triple negative breast cancer OR triple negative breast neoplasm

Intervention/treatment: abiplatin OR AI3‐62048 OR AI3 62048 OR briplatin OR CCRIS 221 OR cismaplat OR cisplatyl OR neoplatin OR CCRIS 3404 OR EINECS 255‐446‐0 OR HSDB 6957 OR cbdca OR jm‐8 OR nsc‐241240 OR paraplatin OR paraplatin‐ AQ OR NSC 201345

Study type: All studies

4. Condition or disease: Triple negative breast cancer OR triple negative breast neoplasm

Intervention/treatment: cis‐diammine cyclobutanedicarboxylato platinum OR lobaplatinum OR D‐19466 OR Aqupla OR CCRIS 4088 OR NSC 375101D OR cis‐Diammine glycolato platinum OR Eptaplatin OR NSC D644591 OR CCRIS 9143 OR Dacplat OR Eloxatin OR Elplat OR JM‐83 OR JM83 OR l‐OHP

Study type: All studies

5. Condition or disease: Triple negative breast cancer OR triple negative breast neoplasm

Intervention/treatment: Lipoxal OR NSC 266046 OR Oxalatoplatin OR Oxalatoplatinum OR Oxaliplatino OR Oxaliplatinum OR Oxalitin OR Oxaloplatine OR Oxaloplatino OR RP‐54780 OR SR‐96669 OR CCRIS 5235 OR DWA 2114R OR NK 121

Study type: All studies

Contributions of authors

• Draft the protocol: All authors

• Study selection: MW, AG, SM, The Cochrane Breast Cancer Group’s Information Specialist will help perform these tasks

• Extract data from studies: SM, MW with support of AG

• Enter data into RevMan: MW, SM

• Carry out the analysis:  SM, MW, AG, SE with support of all authors

• Interpret the analysis: SM, AG, JB, RD with support of all authors

• Draft the final review: SM, AG, RD, JB with support of all authors

• Disagreement resolution: JB and RD

• Update the review: SM, AG

Sources of support

Internal sources

• NHMRC Clinical Trials Centre, University of Sydney, Australia

External sources

• No sources of support provided

Declarations of interest

Sofia Mason: none known. 
Jane Beith: none related to this review. Jane has received funding to travel to conferences from Roche and Novartis. Jane has served on advisory boards for Roche, Pfizer, Novartis, Lilly and Specialised Therapeutics for unrelated matters and payment has been made to her institution.
Melina L Willson: none known.
Sam J Egger: none known.
Rachel F Dear: none known.
Annabel Goodwin: none related to this review. There is no competing interest associated with funding of travel to attend a national and international educational meeting, or to provide expertise regarding Cancer Genetic counselling in Australia. Annabel has served on advisory boards for Pfizer in August 2019 and for AstraZeneca in 2018 for unrelated matters. Pfizer has no interest in the outcome of this review.

Edited (no change to conclusions)