AIMS:The pathological assessment of breast cancer resection specimens with neoadjuvant therapy (NAT) offers invaluable information for prognosis and further management. At times, these cases are difficult to pathologically evaluate, at least partly due to tumour bed obscuration after NAT. This study aimed to compare time and resource utilization by surgical pathology laboratories when handling breast specimens treated with NAT against those without NAT. We secondarily aimed to identify features associated with tumour bed identifiability at gross assessment. METHODS AND RESULTS:In this retrospective, single-institution study, we identified 241 breast resection specimens with systemic NAT between 2019 and 2025. A 1:1 non-NAT control group was randomly selected. The NAT cohort had a higher median number of tissue blocks (20.0 versus 13.0, P < 0.001), as well as larger proportions requiring gross resampling (23.7% versus 7.1%, P < 0.001) and pathologist review (16.2% versus 4.6%, P < 0.001) compared with the control. The NAT cohort had a longer median pathology report turnaround time (17.0 days versus 15.0 days, P < 0.001). In NAT cases, pretreatment clinical stage was associated with macroscopic identifiability of the tumour bed. CONCLUSIONS:Breast cancer resection specimens with NAT required significantly more time and laboratory resources than similar specimens without NAT. As NAT becomes more frequent across breast and other cancer types, pathological assessment of the excisional specimens from these patients is expected to become more challenging and time-consuming. By recognizing these trends early, healthcare systems can plan and allocate resources accordingly.

INTRODUCTION:Neuroendocrine tumors (NETs) are uncommon malignancies with increasing incidence in Canada. Long-acting somatostatin analogs (SSA) such as Lanreotide Autogel® (LAN-ATG) and Octreotide Long-Acting Release (OCT-LAR) are first-line treatments for well-differentiated gastroenteropancreatic neuroendocrine tumors either with or without carcinoid syndrome. Despite their efficacy, many patients require short-acting SSA for breakthrough symptoms. We investigated the impact of switching between long-acting SSAs on the usage of breakthrough medications and the incidence of above maximum recommended dose (AMRD) prescriptions. METHODS:This population-based study used claims data from the IQVIA Canadian Private Drug Plan (PDP) that includes data from all Canadian provinces and public drug programs from Ontario and Québec. We identified NET patients who switched SSAs between September 2015 and December 2021. We analyzed breakthrough medication usage and AMRD prescriptions before and after the switch. RESULTS:Among 170 patients who switched SSAs, there was a 59.1% overall reduction in breakthrough medication claims post-switch. Patients switching from OCT-LAR to LAN-ATG experienced a 66.5% reduction, while those switching from LAN-ATG to OCT-LAR saw a 21.9% decrease. Pre-switch, significantly more patients on OCT-LAR exceeded the AMRD threshold compared to those on LAN-ATG (43.8% vs. 18.2%, p value = 0.008). CONCLUSION:Switching between long-acting SSAs can reduce the need for breakthrough medications and lower the incidence of AMRD prescriptions, with a more pronounced effect observed when switching from OCT-LAR to LAN-ATG. These findings have potential implications for improving quality of life and reducing treatment costs for NET patients, which should be evaluated in a formal health economic analysis.

Canadian real-world data (RWD) regarding palbociclib as a first-line therapy for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) is limited. The PALbociclib CANadian (PALCAN) study examined palbociclib utilization patterns as first-line treatment for HR+/HER2- MBC using Alberta health administrative data. The final PALCAN cohort included 472 female patients with a median age of 64 years and a median follow-up time of 22.8 months (IQR: 0.7-88.2). The median (95% CI) duration of treatment was 13.8 (12.7-15.1) months in the overall cohort (IQR: 5.6, 24.8 months), and the probability of treatment discontinuation within the first year was 45%. Aromatase inhibitors (AIs) and fulvestrant were the accompanying endocrine therapies (ETs) in 83% (N = 393) and 14% (N = 64) (15 with unknown accompanying therapy) of patients, respectively. The median duration of treatment for patients receiving an AI as an accompanying therapy was 15.1 (13.6-17.4) months and 7.9 months (5.8-12.6) for patients receiving fulvestrant, which may suggest endocrine resistance in the latter group. The PALCAN data provides insights into practice patterns and the effectiveness of palbociclib as a first-line therapy in female patients with HR+/HER2- breast cancer in the Canadian real-world setting.

A 51-year-old female presented to the emergency department with vertigo, visual disturbances, involuntary rapid repetitive eye movements, incoordination, and imbalance. Physical examination revealed opsoclonus, myoclonus, and bilateral limb and gait ataxia. Initial workup was negative for intracranial abnormalities, and no abnormalities were noted on blood work or cerebrospinal fluid analysis. Tumor markers were within normal limits. As part of her diagnostic workup, a positron emission tomography (PET) scan was performed, which showed a highly FDG-avid solitary 7 mm left axillary lymph node. Ultrasound-guided percutaneous biopsy revealed metastatic poorly differentiated carcinoma. Histopathological examination could not conclusively distinguish between adenocarcinoma and squamous cell carcinoma. She was diagnosed with seronegative opsoclonus-myoclonus ataxia syndrome of paraneoplastic origin from an occult primary malignancy and started on pulsatile corticosteroids and intravenous immunoglobulin (IVIG), with only moderate symptomatic improvement. Given the anatomic location and immunohistochemical staining pattern of the lymph node, the malignancy was considered as being of primary breast origin. A left axillary lymph node dissection was performed, with 1/12 nodes testing positive for poorly differentiated carcinoma. The patient experienced significant improvement in her neurological symptoms 2–3 days following resection of the solitary malignant lymph node, largely regaining her functional independence. She went on to receive adjuvant radiotherapy to the breast and axilla, as well as adjuvant hormonal therapy.

The combination of CDK4/6 inhibitor+endocrine therapy (CDK4/6i+ET) is standard 1st-line (1L) systemic treatment for patients with ER+/HER2-negative metastatic breast cancer (MBC). Numerous agents are available / in development for subsequent lines of treatment. Circulating tumor DNA (ctDNA) via liquid biopsy presents a promising, non-invasive approach for blood-based tumor genotyping, patient stratification and response assessment with the potential to enhance biomarker-driven strategies and aid in development of new therapeutics. IND.241 is a master protocol platform design consisting of independent substudies monitoring patients with ER+/HER2- MBC prior to progression (PD) on CDK4/6i+ET and investigating novel agents or drug combinations in 2nd/3rd lines (2L, 3L) after progression on CDK4/6i+ET. The primary objective of the novel drug/combination substudies is to centrally interrogate ctDNA (Tempus xF+, a 523-gene liquid biopsy panel) and evaluate whether biomarker selection improves ORR or CBR (RECIST 1.1). Secondary objectives include safety and toxicity profile, PFS, and OS. The monitoring substudy (Substudy A) enrolls patients currently on CDK4/6i+ET treatment and aims to characterize molecular profile, clinical features, and ctDNA dynamics of acquired resistance. This platform trial enables creation and maintenance of a tissue and data bank including clinical data, genomics, and radiomics to evaluate surrogates of treatment outcomes and potential biomarkers of response, resistance, and disease progression. Patients with specific biomarkers detected in ctDNA will be enrolled to corresponding biomarker positive cohorts of substudies. Patients with no substudy-specific biomarkers are randomized to biomarker negative cohorts of available substudies. Treatment substudies follow a 2-stage design. Currently, the monitoring substudy A is actively accruing. Substudy B is evaluating lunresertib (PKMYT1 inhibitor) + gemcitabine in patients +/-CCNE1 overexpression / amplification. Substudy C is evaluating niraparib (PARP inhibitor) + fulvestrant (ET) in patients +/- alterations in BRCA1/2 (germline/somatic) or PALB2 (germline). These latter two substudies have now closed to accrual, with efficacy and safety evaluation ongoing. Substudy D, recently added, is evaluating lunresertib + camonsertib (ATR inhibitor) in patients +/- CCNE1 overexpression/amplification, FBXW7 or PPP2R1A alterations. Additional substudies are in development for this platform trial. IND.241 employs a biomarker-driven platform trial designed to evaluate CDK4/6i resistant ER+/HER2- MBC, using non-invasive ctDNA tumor genotyping to select patients for biomarker-driven substudies with the goal of defining the ctDNA landscape across 1L to 3L treatments. Moira Rushton, Dave W. Cescon, Nathalie Levasseur, Michelle B. Nadler, Daniel Rayson, Brooke E. Wilson, Sara K. Taylor, Rossanna Pezo, Arif Awan, Zahi Mitri, Vikaash Kumar, Jennifer Melvin, John Hilton, Stephen Chia, Philippe L. Bedard, Spencer Finn, Wei Tu, Courtney Coschi, Philippe Jamme, Elia Aguado-Fraile, Lesley Katie Seymour, Laura Pearce. IND.241: A Canadian cancer trials group liquid-biopsy informed platform trial to evaluate treatment in CDK4/6-inhibitor resistant ER+/HER2- metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT239.

LBA1005 Background: Standard first line therapy in ER+/ HER2 negative endocrine sensitive metastatic breast cancer (MBC) is a CDK4/6 inhibitor plus AI. Upon progression the majority of patients will receive further endocrine based therapy. Alterations in PI3K/AKT pathway genes are a known mechanism of endocrine resistance – either de novo or acquired. The MA.40 trial evaluated the efficacy and safety of the AKT inhibitor ipatasertib versus placebo plus fulvestrant in the metastatic breast cancer (MBC) setting immediately post progression on 1 st line CDK4/6 inhibitor and AI. Methods: This phase III, randomized, double-blind trial enrolled pre/peri/postmenopausal women and men with ER+/HER-2 negative MBC. Patients were randomly assigned 1:1 to receive ipatasertib plus fulvestrant versus (vs) placebo plus fulvestrant. Stratification factors included: AKT pathway altered ( PIK3CA , AKT1 , and/or PTEN genomic alteration(s)) vs wild-type/unknown and endocrine resistance (primary vs secondary). Primary objective: To compare investigator assessed PFS (RECIST 1.1) between treatment arms in the ITT population. Pre-specified secondary analysis: PFS in the AKT pathway altered cohort using a hierarchical procedure. The FoundationOne Liquid cfDNA NGS assay was utilized to assess genomic alterations in the AKT pathway for stratification. Results: 250 participants (females 247/males 3) were enrolled from Canada, Australia and New Zealand between January 2021 and May 2024. Baseline characteristics between arms were balanced. 44.4% of the study population had AKT pathway alteration(s) per cfDNA assay. Median follow-up 15.2 months(mo); proportion remaining on protocol treatment at time of analysis 21.0% ipatasertib vs 11.3% placebo arm. Median PFS ITT ipatasertib vs placebo arms were: 5.32 mo (95% CI: 3.58 to 5.62 mo) vs 1.94 mo (95% CI: 1.84 to 3.22 ) [HR 0.61, 95% CI: 0.46 to 0.81; p= 0.0007] and in the AKT pathway altered cohort: 5.45 mo (95% CI: 3.55 to 11.01 ) vs 1.91 mo (95% CI: 1.77 to 3.48) [HR = 0.47, 95% CI: 0.31 to 0.72; p= 0.0005]. Grade 3 or higher adverse events (AE) ipatasertib vs placebo arms (%):37.1 vs 27.4. Grade 3 or higher non haematological treatment related AE > 1% ipatasertib vs placebo arms: diarrhea (16% vs 0%); fatigue (3% vs 0%); vomiting (2% vs 0), rash (2% vs 0%). Treatment discontinuation due to AEs ipatasertib vs placebo arms: 6.5% vs 0.8%. Conclusions: Ipatasertib plus fulvestrant significantly prolongs PFS compared to placebo/fulvestrant in patients with hormone receptor–positive MBC post progression on 1 st line CDK 4/6 inhibitor and AI. Follow-up and additional analyses continue. Supported by Hoffmann-La Roche Ltd, CCS grant #707213. Clinical trial information: NCT04650581 .

TPS1121 Background: The combination of a CDK4/6 inhibitor + endocrine therapy (CDK4/6i+ET) is standard first-line systemic treatment for patients with ER+/HER2-negative metastatic breast cancer (MBC). Beyond this initial therapy, there are numerous therapeutic agents available/ in development for subsequent lines of treatment. Circulating tumor DNA (ctDNA) via liquid biopsy is a promising, non-invasive approach for blood-based tumor genotyping, patient stratification and response assessment with the potential to enhance biomarker-driven strategies and aid in development of new therapeutics. Methods: IND.241 is a master protocol platform design consisting of independent substudies monitoring patients with ER+/HER2- MBC prior to progression (PD) on CDK4/6i+ET and investigating novel agents or drug combinations in 2 nd /3 rd lines after progression on CDK4/6i+ET. The primary objective of the novel drug/combination substudies is to centrally interrogate ctDNA (Tempus xF+, a 523-gene liquid biopsy panel) and evaluate whether biomarker selection improves ORR or CBR as assessed by RECIST 1.1. Secondary objectives include safety and toxicity profile for each drug/combination, PFS, and OS. The monitoring substudy (Substudy A) enrolls patients currently on CDK4/6i+ET treatment and aims to characterize the molecular profile, clinical features, and ctDNA dynamics of acquired resistance. This platform trial enables creation and maintenance of a tissue and data bank including clinical data, genomics, and radiomics from all substudies to evaluate surrogates of treatment outcomes and potential biomarkers of response, resistance, and disease progression. Patients with specific biomarkers detected in ctDNA will be enrolled into corresponding biomarker positive cohorts of substudies. Patients with no substudy-specific biomarkers are randomized to biomarker negative cohorts of available substudies. Treatment substudies follow a 2-stage design. Currently, the monitoring substudy A is actively accruing. Substudy B is evaluating lunresertib (PKMYT1 inhibitor) + gemcitabine in patients +/-CCNE1 overexpression / amplification. Substudy C is evaluating niraparib (PARP inhibitor) + fulvestrant (ET) in patients +/- alterations in BRCA1/2 (germline/somatic) or PALB2 (germline). These latter two substudies have now closed to accrual, with efficacy and safety evaluation ongoing. Substudy D, which has recently been added, is evaluating lunresertib + camonsertib (ATR inhibitor) in patients +/- CCNE1 overexpression/amplification, FBXW7 or PPP2R1A alterations. Additional substudies are in development for inclusion in this platform trial. Clinical trial information: NCT05601440 .

Purpose: It remains unclear whether patients with HER2-negative, low-estrogen receptor (ER-low)-positive early breast cancer (BC) benefit from Oncotype DX® (ODX) testing. Methods: We conducted a retrospective review of cases referred for ODX testing over a seven-year period from a breast biomarker testing referral center (n = 854). For each case, we recorded the ODX Recurrence Score (RS) along with percentage of ER nuclear positivity and staining intensity on immunohistochemistry. Our criteria for ER-low was defined as ≤10% cells with nuclear positivity and/or weak intensity of staining. Slides from all ER-low cases were reviewed and the reported ODX ER gene scores were recorded. We randomly selected a comparator group of 56 patients with ER > 10% positivity and non-weak staining intensity (ER-high). Results: We identified 27 cases (3.2%) that met our criteria for ER-low. Of these, 92.6% had a high RS (>25), and 7.4% had a RS of 25. All cases with ≤10% ER nuclear positivity had a high RS. Most ER-low cases (85.2%) had ODX quantitative ER gene scores in the negative range, whereas all (100%) ER-high cases had positive ER gene scores. Conclusion: ODX does not appear to add significant additional information to inform treatment decisions for most patients with ER-low BC. Incorporating weak ER staining intensity in addition to low percentage of nuclear positivity identifies about twice as many ER-low patients, although with reduced specificity for high RS. Our study supports the contention that most ER-low early BC should be regarded similarly to ER-negative BC.

Background: The PI3K/AKT/mTOR pathway is a rational target in the metastatic disease setting for hormone receptor positive breast cancer based on preclinical and clinical data demonstrating that pathway inhibition improves outcome (Baselga 2012, Andre 2019, Jones 2019). Combining fulvestrant and AKT inhibition demonstrated efficacy in pts with HR+aBC (Howell 2022). Ipatasertib is a potent, highly selective, small-molecule inhibitor of three isoforms of serine/threonine kinase AKT. We hypothesize that Ipatasertib plus fulvestrant will improve PFS compared to fulvestrant in the second line setting post disease progression on aromatase inhibitor (AI) + CDK 4/6 inhibitor therapy. Methods: MA40 is a double blind, placebo-controlled trial in patients with hormone receptor positive, HER2-negative breast cancer with prior progression on AI plus CDK4/6 inhibitor therapy. Patients are randomized to fulvestrant/ipatasertib 400 mg po days 1-21 every 28 day or fulvestrant/placebo. The primary objective is to compare Progression Free Survival (PFS) between arms (RECIST 1.1, investigator assessed). Secondary objectives include comparisons between arms: PIK3CA/AKT1/PTEN altered cohort and non-altered cohorts; PFS by Blinded Central Radiology Review (all enrolled patients, PIK3CA/AKT1/PTEN altered and non-altered cohorts), Response rate; Duration of Response; Clinical Benefit Rate; Overall Survival; Time to Commencement of Subsequent Line of Systemic Therapy or Death; Safety and Tolerability (CTCAE version 5.0); QOL (EORTC QLQ-C30, NCI PRO-CTCAE); Economic Evaluation, (healthcare utilization and health utilities(EQ-5D-5L)). Statistical Design: Allocation 1:1 balanced for: PIK3CA/PTEN/AKT1 mutation status (ctDNA analysis using FoundationOne®Liquid Platform) (altered vs wildtype/unknown); prior treatment duration with CDK4/6 inhibitor (< 6 months vs > 6 months) and centre. Sample size is 250 to detect a benefit in PFS with the addition of ipatasertib. Eligibility Criteria: Histologically and/or cytologically confirmed ER positive and HER-2 negative breast cancer by local assessment that is advanced; postmenopausal status; clinical and/or radiographic progression during treatment with or within 28 days after discontinuation of first line of treatment with a CDK 4/6 inhibitor and an AI; only one prior line of chemotherapy in the advanced setting. Conduct to Date: Enrollment is ongoing. Supported by Hoffmann-La Roche Limited, CCS Citation Format: Stephen K. Chia, David W. Cescon, Andrew D. Redfern, Danielle Rodin, Christine Simmons, Jean-Pierre Ayoub, Haji Ibrahim Chalchal, Daniel Rayson, Moira Rushton-Marovac, Tracey Hay, Lisa Gallinaro, Bingshu Chen, Wendy Parulekar. CCTG MA40: DOUBLE-BLIND PLACEBO CONTROLLED PHASE III TRIAL OF FULVESTRANT AND IPATASERTIB FOR ADVANCED HER-2 NEGATIVE AND ESTROGEN RECEPTOR POSITIVE (ER+) BREAST CANCER POST FIRST LINE CDK 4/6 AND AROMATASE INHIBITOR THERAPY (FINER) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-26-01.

(1) Background: Cancer is the leading cause of death in Canada, with significant resource limitation impacting the delivery of cancer care nationwide. The onset of the COVID-19 pandemic forced additional resource restriction and diversion, further impacting care delivery. Our intention is to analyze the impact COVID-19 on a provincial medical oncology workload and bring attention to the limitations of the current workload metric for oncologists. (2) Methods: All medical oncology patient encounters were extracted and compared, collected by year and encounter type, from April 2014 through March 2022. (3) Results: There was an increase in all patient encounters by an average of 9.5% per year, including during the strictest COVID-19 restrictions. There was an increase in virtual care encounters from 37.9% to 52.1%. (4) Conclusions: Medical Oncology workloads have increased over time and estimates suggest growing demand. Little data exist to inform workforce requirements and actual workload is not captured by the current metric. Though volume of new consults continues to increase, COVID-19 has highlighted additional changes in the delivery of care, likely with lasting impact, little of which are included in the current workload metric.

Ongoing advances in precision cancer therapy have increased the number of molecularly targeted and immuno-oncology agents for a variety of cancers, many of which have been associated with a risk of pulmonary complications, among the most concerning being drug-induced interstitial lung disease/pneumonitis (DI-ILD). As the number of patients undergoing treatment with novel anticancer agents continues to grow, DI-ILD is expected to become an increasingly significant clinical challenge. Trastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate targeting human epidermal growth factor receptor 2 that is gaining widespread use in the metastatic breast cancer setting and is undergoing exploration for other oncologic indications. ILD/pneumonitis is an adverse event of special interest associated with T-DXd, which has potentially fatal consequences if left untreated and allowed to progress. When identified in the asymptomatic stage (grade 1), T-DXd-related ILD can be monitored and treated effectively with the possibility of treatment continuation. Delayed diagnosis and/or treatment, however, results in progression to grade 2 or higher toxicity and necessitates immediate and permanent discontinuation of this active agent. Strategies are, therefore, needed to optimize careful monitoring during treatment to ensure patient safety and optimize outcomes. Several guidance documents have been developed regarding strategies for the early identification and management of T-DXd-related ILD, although none have been within the context of the Canadian health care environment. A Canadian multidisciplinary steering committee was, therefore, convened to evaluate existing recommendations and adapt them for application in Canada. A multidisciplinary approach involving collaboration among medical oncologists, radiologists, respirologists, and allied health care professionals is needed to ensure the proactive identification and management of T-DXd-related ILD and DI-ILD associated with other agents with a similar toxicity profile.

The addition of pertuzumab to neoadjuvant trastuzumab and chemotherapy for women with early-stage, high-risk, HER2+ breast cancer has been observed to lead to higher pathologic complete response rates (pCR), and improved event-free survival compared to trastuzumab and chemotherapy alone. Based on available data, neoadjuvant pertuzumab is recommended by ESMO, ASCO, and NICE as well as by a Canadian Consensus Guideline Group. We discuss the implications for Canadian patients with HER2+ early breast cancer due to a second and final negative funding decision by the Canadian Agency for Drugs and Technologies in Health (CADTH) related to neoadjuvant pertuzumab. This decision will have adverse impacts for up to 1 in 6 women receiving neoadjuvant therapy for high-risk HER2+ breast cancer, due to suboptimal pCR rates and higher risks of invasive breast cancer recurrent events, resulting in the need for more toxic adjuvant therapy.

Current guidelines recommend HER2 testing on all primary invasive breast cancers and re-biopsy at disease relapse. The discordance rate between HER2-negative primaries and HER2 IHC2+ metastases that are ISH-amplified is unknown. We hypothesize that the majority of such cases are non-amplified. ISH testing is time-consuming and resource-intensive, and there may be situations where it is unnecessary. A retrospective review of IHC2+ metastatic lesions assessed with ISH at our center from 2013 to 2021 was undertaken. 105 cases were identified after exclusion of cases missing HER2 results, with primaries of unconfirmed origin, and cases of synchronous primary and metastatic disease. IHC and ISH results were recorded with detailed slide review of discordant cases. 91/105 metastases had HER2-negative primaries (87%). A metastasis was significantly more likely to be HER2-negative when the primary was HER2-negative (93%) versus positive (43%) (p < 0.0001). 54/91 primaries were IHC2+/ISH-non-amplified, and 50/54 (93%) corresponding metastases had identical results. Of the 37 HER2-negative primaries that were IHC0/1+, 35 (95%) corresponding metastases were ISH-non-amplified. Six metastases in cases with HER2-negative primaries were discordant. Characteristics of metastases suggesting ISH testing was warranted to assess for discordance included IHC heterogeneity, morphological discordance, increased staining of moderate intensity, and ER/PR discordance. One or more of these factors were present in all discordant metastases. Our results suggest selective ISH testing on HER2 IHC2+ breast cancer metastases in the context of HER2-negative primary disease may be appropriate when there is careful review of the IHC. Validation of our findings awaits further studies with larger sample sizes.

CMAJ | February 22, 2022 | Volume 194 | Issue 7 © 2022 CMA Impact Inc. or its licensors O ne October clinic afternoon, I met M me D, an impeccably dressed woman in her seventies with a heavy French accent. I learned that roughly nine months earlier, she had noticed a new dimpling within a longstanding area of thickening in her right breast. She told me that years ago, a seat belt had saved her life but damaged her breast tissue, and a number of physicians and mammograms over the years had never raised any concerns. With the new dimpling, she had felt her breast becomi n g f i r m e r a n d i n e x o r a b l y m o r e deformed. Then a thin red line in the skin had become thickened and started oozing malodourously, triggering low-grade nausea that she couldn’t shake. She finally went to the doctor who quickly surmised the problem and ordered a confirmatory mammogram and biopsy. A bone scan found the metastases that accounted for the discomfort in her upper back and left hip, which had led her to use a cane. When I walked into the clinic room that afternoon, I had not been expecting to find such an elegantly dressed, superbly coiffed and glamorously smiling woman. Mme D was radiant in her purples, blacks and golds, shimmering against the dreary backdrop of the hospital-beige examination room. Her jewellery came as close to sparkling as possible under the dismal fluorescent lighting. Throughout our conversation she dropped hints of an interesting life spent travelling the world, perhaps sharing more with me than she might have with others because we were able to converse in her native language. I wondered how she had ended up in a remote, half-abandoned fishing village in rural Nova Scotia, a town I had driven through many times to admire the handsome yet increasingly dilapidated grand homes facing the water. As far as I could glean, she lived there alone, without a partner or close friends. I could easily imagine sea captains once casting covetous eyes on her as she strolled through the single main street on her way to the general store for supplies. There was no doubt that in her day, she would have stirred interest wherever she went. Her breast was stretched tight by disease, with a gaping wound oozing the creamy yellow-green slime of a cancerous infection. A mixed dressing of toilet paper, gauze squares and imperfectly applied scotch tape was barely hanging on, threatening to unleash the toxic sludge through to her high-end clothing. It was clear to me that her nausea was likely caused by the eye-watering odour I was now experiencing. Focusing on the feasible, I discussed the nature of her condition and the palliative intent of all treatment options. With endocrine therapy, her cancer likely could be meaningfully controlled without exposing her to the many adverse effects of chemotherapy, an option she dismissed as soon as I mentioned it. Mme D left that day with a prescription for antibiotics and an aromatase inhibitor as well as a low-dose narcotic to help with her back pain. I said that I would call her in three weeks and faxed a palliative care consultation request to one of my colleagues for wound and further supportive care needs. My hope was that she would respond quickly to the medication, her symptoms would improve and care intensity could de-escalate. Two weeks after seeing her, I received a call from my colleague. Mme D was doing well. Supplied with appropriate dressings and instruction, she was taking much better care of the wound and had noticed that the oozing discharge had begun to lessen. She still used a cane but reported less pain. This exceeded even my optimistic expectations and further supported my hope that she had a chance of longterm disease control. One week later, I was checking voicemail messages in the office: “Cher docteur, it is Mme D. Thank you for the medicine — it has helped. I will stay on it until the end, which will be on November twentieth. Merci infiniment. Bonjour.” I was stunned. Before the era of modern cancer medicine, the lines between “active treatment” and “symptomatic and supportive care” were sharp and often unequivocal. To paraphrase Thomas Hobbes, for many with metastatic disease, life was nasty, brutish and short, with the concept of “palliative chemotherapy” oxymoronic at best. Coincident with treatment developments has been the addition of palliative care alongside active cancer treatment. This has been shown to improve quality of life as well as survival outcomes.1,2 Thus, as time under treatment has lengthened, care under treatment has expanded. The “us” and “them” that historically served as the basis for professional relationships between medical oncology and palliative care has been largely replaced by “we,” although this is sometimes more aspirational than factual. Despite this, we still have patients who suffer greatly from the combination of disease and treatment, and there are situations where there are simply not enough milligrams of narcotic, steroids or psychotropes to dull the pain, stimulate Humanities | Encounters

[Voir la version anglaise de l’article ici: www.cmaj.ca/lookup/doi/10.1503/cmaj.211748][1] C’est un après-midi d’octobre que j’ai rencontré à la clinique Mme D., une septuagénaire impeccablement vêtue, qui parlait avec un fort accent français. Elle m’a dit qu’environ neuf mois

Background: Evidence to date supports continued human epidermal growth factor receptor 2 (HER2) suppression beyond progression on HER2-directed therapy for advanced HER2-positive breast cancer. Data from several phase II and III trials evaluating HER2-directed therapy following second-line T-DM1 have recently become available. Methods: We performed a systematic search of the published and presented literature to identify phase II and phase III trials assessing novel HER2-targeted agents as third-line therapy or beyond for HER2-positive advanced breast cancer using search terms ‘breast cancer’ AND ‘HER2’ AND ‘advanced’ AND (‘phase II’ OR ‘phase III’). Results: Eight clinical trials reporting efficacy outcomes on third-line or greater HER2-directed therapy for HER2-positive advanced breast cancer were identified. In phase III trials, margetuximab and neratinib combinations demonstrated significant 1.3-month (hazard ratio, HR = 0.71, p < 0.001) and 0.1-month (HR = 0.76, p = 0.006) net improvements in median progression-free survival (PFS), respectively, with no significant improvements in overall survival (OS). Tucatinib added to trastuzumab and capecitabine demonstrated a significant 2.7-month improvement in median PFS (HR = 0.57, p < 0.00001) and a 5.5-month improvement in median OS (HR = 0.73, p = 0.004) in a randomized phase II trial, including significant clinical benefit for patients with brain metastases. Finally, trastuzumab-deruxtecan, zenocutuzumab, and poziotinib demonstrated benefit in phase II trials with the most robust overall response rate (62.0%) and median duration of response (18.2 months) observed for trastuzumab-deruxtecan among heavily pretreated patients. Conclusion: Tucatinib plus trastuzumab and capecitabine significantly prolongs OS, and promising preliminary response outcomes for trastuzumab-deruxtecan suggest that sequencing of these regimens following second-line therapy is reasonable.